The signal distinguishing between targeting of outer membrane β-barrel protein to plastids and mitochondria in plants.

Abstract: The proteome of the outer membrane of mitochondria and chloroplasts consists of membrane proteins anchored by α-helical or β-sheet elements. While proteins with α-helical transmembrane domains are present in all cellular membranes, proteins with β-barrel structure are specific for these two membranes. The organellar β-barrel proteins are encoded in the nuclear genome and thus, have to be targeted to the outer organellar membrane where they are recognized by surface exposed translocation complexes. In the last years, the signals that ensure proper targeting of these proteins have been investigated as essential base for an understanding of the regulation of cellular protein distribution. However, the organellar β-barrel proteins are unique as most of them do not contain a typical targeting information in form of an N-terminal cleavable targeting signal. Recently, it was discovered that targeting and surface recognition of mitochondrial β-barrel proteins in yeast, humans and plants depends on the hydrophobicity of the last β-hairpin of the β-barrel. However, we demonstrate that the hydrophobicity is not sufficient for the discrimination of targeting to chloroplasts or mitochondria. By domain swapping between mitochondrial and chloroplast targeted β-barrel proteins atVDAC1 and psOEP24 we demonstrate that the presence of a hydrophilic amino acid at the C-terminus of the penultimate β-strand is required for mitochondrial targeting. A mutation of the chloroplast β-barrel protein psOEP24 which mimics such profile is efficiently targeted to mitochondria. Thus, we present the properties of the signal for mitochondrial targeting of β-barrel proteins in plants.

Klinger|Anna|A| Gosch|Victoria|V| Bodensohn|Uwe|U| Ladig|Roman|R| Schleiff|Enrico|E|

D057927:Hydrophobic and Hydrophilic Interactions

β-Barrel proteins
Membrane proteins
targeting signal
Intracellular protein sorting
Protein targeting


Prevalence of Body Dysmorphic Disorder Among Patients Seeking Breast Reconstruction.

Abstract:
BACKGROUND
Body dysmorphic disorder (BDD) is characterized by a preoccupation with a slight or imagined defect in physical appearance. It has significant implications for patients who desire breast reconstruction, because patient satisfaction with the aesthetic outcome is a substantial contributor to the success of the procedure.

OBJECTIVES
The authors estimated the prevalence of BDD among women seeking breast reconstruction by surveying patients with the previously validated Dysmorphic Concerns Questionnaire (DCQ).

METHODS
One hundred eighty-eight women who presented for immediate or delayed breast reconstruction completed the DCQ anonymously, during initial consultation with a plastic surgeon. Two groups of respondents were identified: those who desired immediate reconstruction and those who planned to undergo delayed reconstruction. The prevalence of BDD among breast reconstruction patients was compared between the 2 groups, and the overall prevalence was compared with published rates for the general public.

RESULTS
Body dysmorphic disorder was significantly more prevalent in breast reconstruction patients than in the general population (17% vs 2%; P < .001). It also was much more common among patients who planned to undergo delayed (vs immediate) reconstruction (34% vs 13%; P = .004).

CONCLUSIONS
Relative to the general public, significantly more women who sought breast reconstruction were diagnosed as having BDD. Awareness of the potential for BDD will enable clinicians to better understand their patients' perspectives and discuss realistic expectations at the initial consultation. Future studies are warranted to examine the implications of BDD on patient satisfaction with reconstructive surgery.

LEVEL OF EVIDENCE
3.

Metcalfe|Drew B|DB|
Duggal|Claire S|CS|
Gabriel|Allen|A|
Nahabedian|Maurice Y|MY|
Carlson|Grant W|GW|
Losken|Albert|A|

D010342:Patient Acceptance of Health Care

transverse rectus abdominis myocutaneous (TRAM) flap


Time perspective, sports club membership, and physical self-concept among adolescents: A person-centered approach.

Abstract:
INTRODUCTION
Time perspective is defined as thoughts and feelings about the past, present, and future and is theorized to underlie human behavior. Prior research has shown relationships among time perspective and academic achievement, substance use, and risky-driving. In this study, time perspective was extended to sports club membership and physical self-concept among adolescents.

METHODS
Time perspective was assessed with a scale that measures positive and negative feelings about the past, present, and future. Latent time attitude profiles were generated with data that included sports club membership and physical self-concept. Participants were German (N = 901; 46.2% female), Luxembourgian (N = 661; 46.7% female), and Spanish (N = 789; 49.0% female) adolescents (12-18 years-old).

RESULTS
Latent profile analyses indicated that across the three samples the same number and type of profiles were observed: Ambivalent, Balanced, Optimistic, Past Negative, and Positive. Time attitude profiles were related to sports club membership and physical self-concept. Adolescents with positive attitudinal profiles were more engaged in sports clubs and reported a higher physical self-concept than adolescents in negative attitudinal profiles.

CONCLUSIONS
Time perspective was conceptualized as time attitudes and operationalized as positive and negative feelings about the past, present, and future. Results showed that five latent time attitudes profiles were observed and that profile membership was associated with sports club membership and physical self-concept. These associations were demonstrated with three independent samples. Findings were discussed in light of implications for intervention programs that use time perspective to promote physical health among adolescents.

Konowalczyk|Svenja|S|
Rade|F Clemens A|FCA|
Mello|Zena R|ZR|

Time perspective
Sports club membership
Physical self-concept
Adolescents
Adolescent time attitude scale


Tardibacter chloracetimidivorans gen. nov., sp. nov., a novel member of the family Sphingomonadaceae isolated from an agricultural soil from Jeju Island in Republic of Korea.

Abstract: A pale yellow bacterial strain, designated JJ-A5T, was isolated form an agricultural soil from Jeju Island in Republic of Korea. Cells of the strain were Gram-stain-negative, motile, flagellated and rod-shaped. The strain grew at 15-30°C, pH 6.0-9.0, and in the presence of 0-1.5% (w/v) NaCl. Growth occurred on R2A, but not on Luria-Bertani agar, nutrient agar, trypticase soy agar and MacConkey agar. The strain utilized alachlor as a sole carbon source for growth. The strain JJ-A5T showed 16S rRNA gene sequence similarities lower than 95.4% with members of the family Sphingomonadaceae. Phylogenetic analysis showed that the strain belongs to the family Sphingomonadaceae and strain JJ-A5T was distinctly separated from established genera of this family. The strain contained Q-10 as dominant ubiquinone and spermidine as major polyamine. The predominant cellular fatty acids were summed feature 8 (C18:1ω7c and/or C18:1ω6c), summed feature 3 (C16:1ω7c and/or C16:1ω6c), 11-methyl C18:1ω7c, C16:0 and C14:0 2-OH. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol, sphingoglycolipid, and phosphatidylcholine. The DNA G + C content of the strain was 62.7 mol%. On the basis of the phenotypic, genomic and chemotaxonomic characteristics, strain JJ-A5T is considered to represent a novel genus and species within the family Sphingomonadaceae, for which the name Tardibacter chloracetimidivorans gen. nov., sp. nov. is proposed. The type strain of Tardibacter chloracetimidivorans is JJ-A5T (= KACC 19450T = NBRC 113160T).

Lee|Hyosun|H| Kim|Dong-Uk|DU| Park|Sooyeon|S| Yoon|Jung-Hoon|JH| Ahn|Jae-Hyung|JH| Ka|Jong-Ok|JO|

Tardibacter
Tardibacter chloracetimidivorans
novel genus
novel species
polyphasic taxonomy


Competitive sgRNA Screen Identifies p38 MAPK as a Druggable Target to Improve HSPC Engraftment.

Abstract: Previous gene therapy trials for X-linked chronic granulomatous disease (X-CGD) lacked long-term engraftment of corrected hematopoietic stem and progenitor cells (HSPCs). Chronic inflammation and high levels of interleukin-1 beta (IL1B) might have caused aberrant cell cycling in X-CGD HSPCs with a concurrent loss of their long-term repopulating potential. Thus, we performed a targeted CRISPR-Cas9-based sgRNA screen to identify candidate genes that counteract the decreased repopulating capacity of HSPCs during gene therapy. The candidates were validated in a competitive transplantation assay and tested in a disease context using IL1B-challenged or X-CGD HSPCs. The sgRNA screen identified Mapk14 (p38) as a potential target to increase HSPC engraftment. Knockout of p38 prior to transplantation was sufficient to induce a selective advantage. Inhibition of p38 increased expression of the HSC homing factor CXCR4 and reduced apoptosis and proliferation in HSPCs. For potential clinical translation, treatment of IL1B-challenged or X-CGD HSPCs with a p38 inhibitor led to a 1.5-fold increase of donor cell engraftment. In summary, our findings demonstrate that p38 may serve as a potential druggable target to restore engraftment of HSPCs in the context of X-CGD gene therapy.

D018380:Hematopoietic Stem Cell Transplantation

D048051:p38 Mitogen-Activated Protein Kinases


Anxiety and substance use during adolescence.

Abstract:
BACKGROUND
The primary goal of this study was to examine the relationship between anxiety symptomatology and substance use (alcohol use and drug use) during adolescence, systematically by gender and race/ethnicity.

METHODS
Self-report surveys were administered to 905 15-17-year-old adolescents (54% girls) in the spring of 2007.

RESULTS
RESULTS from multiple group analyses indicated that the relationship between anxiety and substance use differs by gender and race/ethnicity. For Caucasian and African American boys, higher levels of social anxiety and separation anxiety were related to less substance use. In contrast, higher levels of generalized anxiety disorder and panic disorder were associated with more substance use for African American boys. The pattern was much less striking for girls. For Caucasian girls, higher levels of significant school avoidance were linked to more substance use, and consistent with the results for boys, higher levels of separation anxiety were associated with less substance use. None of the anxiety disorders were related to substance use for African American girls or Hispanic girls or boys.

CONCLUSIONS
Findings from this study highlight the need to distinguish between different anxiety disorders. In addition, they underscore the importance of considering both gender and race/ethnicity when examining the relationship between anxiety and substance use during adolescence.


Tracing overlapping biological signals in mid-infrared using colonic tissues as a model system.

Abstract:
AIM
To understand the interference of carbohydrates absorbance in nucleic acids signals during diagnosis of malignancy using Fourier transform infrared (FTIR) spectroscopy.

METHODS
We used formalin fixed paraffin embedded colonic tissues to obtain infrared (IR) spectra in the mid IR region using a bruker II IR microscope with a facility for varying the measurement area by varying the aperture available. Following this procedure we could measure different regions of the crypt circles containing different biochemicals. Crypts from 18 patients were measured. Circular crypts with a maximum diameter of 120 μm and a lumen of about 30 μm were selected for uniformity. The spectral data was analyzed using conventional and advanced computational methods.

RESULTS
Among the various components that are observed to contribute to the diagnostic capabilities of FTIR, the carbohydrates and nucleic acids are prominent. However there are intrinsic difficulties in the diagnostic capabilities due to the overlap of major absorbance bands of nucleic acids, carbohydrates and phospholipids in the mid-IR region. The result demonstrates colonic tissues as a biological system suitable for studying interference of carbohydrates and nucleic acids under ex vivo conditions. Among the diagnostic parameters that are affected by the absorbance from nucleic acids is the RNA/DNA ratio, dependent on absorbance at 1121 cm-1 and 1020 cm-1 that is used to classify the normal and cancerous tissues especially during FTIR based diagnosis of colonic malignancies. The signals of the nucleic acids and the ratio (RNA/DNA) are likely increased due to disappearance of interfering components like carbohydrates and phosphates along with an increase in amount of RNA.

CONCLUSION
The present work, proposes one mechanism for the observed changes in the nucleic acid absorbance in mid-IR during disease progression (carcinogenesis).

Sahu|Ranjit Kumar|RK|
Salman|Ahmad|A|
Mordechai|Shaul|S|

D017550:Spectroscopy, Fourier Transform Infrared

Colonic tissue
Nucleic acids
Malignancy
Fourier transform infrared diagnosis
Spectral interference


Chronic myeloid leukemia patients and treatment-free remission attitudes: a multicenter survey.

Abstract:
Background
Treatment-free remission (TFR) is becoming an essential goal for chronic myeloid leukemia (CML) patients in clinical practice. Few studies have emphasized patient attitudes or preferences about discontinuing tyrosine kinase inhibitors treatment. This study aimed to evaluate the characteristics of Chinese CML patients and their views and perspectives on TFR.

Methods
A total of 329 CML patients participated in this multicenter, questionnaire-based, standardized, semi-structured, interview-guided, open-ended, cross-sectional study. Information about demographics, diagnosis information, treatment history, quality of life (QoL), and TFR preference was collected.

Results
The adherence rate was 50% (N=163) and sex dependent (males, OR=2.24, 95% CI=1.40-3.58). Physical activity, symptom burden, mood impact, and daily impact were found to be better among adherent patients. Thirty-four percent of the patients were willing to attempt TFR positively. The reasons for preferring TFR were due to side effects (56%) followed by high cost (52%), inconvenience (42%), and pregnancy need (41%). Multivariate analysis indicated that patients who were younger (OR=0.96, 95% CI=0.94-0.99) with shorter disease duration (OR=0.90, 95% CI=0.82-0.98) and higher disease symptom burden (OR=1.08, 95% CI=0.98-1.21) were more likely positive about TFR.

Conclusion
Patients who were younger with shorter disease duration and higher disease symptom burden were more likely to try TFR. They expressed several perceived noncost factors of TFR. Our data may help promote the management of CML and designing of clinical trials for TFR in some developed regions of China.

Lou|Jin|J| Huang|Junjie|J| Wang|Zitong|Z| Wen|Bingbing|B| Tu|Chuanqing|C| Huang|Wangxiang|W| Zhai|Zhimin|Z| Du|Xin|X|


Biomarkers for predicting cognitive decline in those with normal cognition.

Abstract: Most studies evaluating Alzheimer's disease (AD) biomarkers longitudinally have studied patients with mild cognitive impairment (MCI) who progress to AD; data on normal subjects are scarce. We studied which biomarkers best predict cognitive decline on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) among those with normal cognition at baseline, and derived cut points to predict decline. We studied 191 subjects in the Alzheimer's Disease Neuroimaging Initiative (ADNI) who had normal cognition at baseline, 2 + visits (mean follow-up 3.1 years), and data on neuropsychological tests, cerebrospinal fluid (CSF) biomarkers, and structural MRI. We used repeated measures linear regression of log ADAS-Cog on age, race, gender, education, APOE4 status, baseline biomarker values, and follow-up time; an interaction between biomarker and time assessed predictive power. Neuropsychological tests did not significantly predict ADAS-Cog decline, while both MRI variables and CSF biomarkers did; CSF markers were the strongest predictors. Optimal cut points for baseline CSF markers to distinguish decliners were < 220 pg/ml (Aβ42), ≥61 pg/ml (t-tau), ≥21 pg/ml (p-tau), ≥0.31 (t-tau/Aβ42), and ≥0.10 (p-tau/Aβ42). For progression to MCI/AD (n = 28), the best markers were t-tau, t-tau/Aβ42, and p-tau/Aβ42, with optimal cut points of 58, 0.31, and 0.08, respectively. The optimal cut points across all markers and cut points predicted decline in ADAS-Cog, as well as transition to MCI, with a 65% accuracy. Our findings support current models of AD progression and suggest it is feasible to establish biomarker criteria to predict cognitive decline in individuals with normal cognition. Larger studies will be needed to more accurately characterize optimal cut points.

Steenland|Kyle|K| Zhao|Liping|L| Goldstein|Felicia|F| Cellar|Janet|J| Lah|James|J|

D011569:Psychiatric Status Rating Scales

biomarkers
cognition
mild cognitive impairment
cerebrospinal fluid


Combining PD-1 Inhibitor Nivolumab with Radiotherapy Successfully Treated a Patient with Refractory Primary Mediastinal Large B-Cell Lymphoma: A Case Report and Literature Review.

Abstract: Primary mediastinal large B-cell lymphoma (PMBCL) is relatively infrequent and generally has a good prognosis with standard immunochemotherapy. However, treatment options are limited for patients with relapsed/refractory PMBCL who are ineligible for stem cell transplantation. In this report, we treated a refractory PMBCL patient, who did not respond to salvage chemotherapy, with combined nivolumab and radiotherapy. The patient achieved a complete remission with mild adverse reactions and has survived without relapse 2 years after treatment.

Yan|Zheng|Z|0000-0001-9324-2161 Yao|Zhi-Hua|ZH| Yao|Shu-Na|SN| Xia|Qing-Xin|QX| Wang|Hai-Ying|HY| Chu|Jun-Feng|JF| Song|Ming|M| Zhao|Shuang|S| Liu|Yan-Yan|YY|0000-0002-3887-0840

primary mediastinal large B-cell lymphoma


Astrocytes Are Required for Oligodendrocyte Survival and Maintenance of Myelin Compaction and Integrity.

Abstract: Astrocytes have been implicated in regulating oligodendrocyte development and myelination in vitro, although their functions in vivo remain less well defined. Using a novel approach to locally ablate GFAP+ astrocytes, we demonstrate that astrocytes are required for normal CNS myelin compaction during development, and for maintaining myelin integrity in the adult. Transient ablation of GFAP+ astrocytes in the mouse spinal cord during the first postnatal week reduced the numbers of mature oligodendrocytes and inhibited myelin formation, while prolonged ablation resulted in myelin that lacked compaction and structural integrity. Ablation of GFAP+ astrocytes in the adult spinal cord resulted in the rapid, local loss of myelin integrity and regional demyelination. The loss of myelin integrity induced by astrocyte ablation was greatly reduced by NMDA receptor antagonists, both in vitro and in vivo, suggesting that myelin stability was affected by elevation of local glutamate levels following astrocyte ablation. Furthermore, targeted delivery of glutamate into adult spinal cord white matter resulted in reduction of myelin basic protein expression and localized disruption of myelin compaction which was also reduced by NMDA receptor blockade. The pathology induced by localized astrocyte loss and elevated exogenous glutamate, supports the concept that astrocytes are critical for maintenance of myelin integrity in the adult CNS and may be primary targets in the initiation of demyelinating diseases of the CNS, such as Neuromyelitis Optica (NMO).

Tognatta|Reshmi|R|
Karl|Molly T|MT|
Fyffe-Maricich|Sharyl L|SL|
Popratiloff|Anastas|A|
Garrison|Eric D|ED|
Schenck|Jessica K|JK|
Abu-Rub|Mohammad|M|
Miller|Robert H|RH|

astrocytes
NMDA receptors
glutamate
electron microscopy
myelin maintenance


Application of deep neural techniques in predictive modelling for the estimation of Escherichia coli growth rate.

Abstract:
AIMS
To develop a predictive model for Escherichia coli using deep neural networks.

METHODS AND RESULTS
Batch experiments are conducted at different temperatures closer to optimum value (36·5°C, 37°C, 37·5°C, 38°C and 38·5°C) to obtain the growth curves of E .coli K-12. Two primary models namely modified Gompertz and new logistic are chosen. Three secondary models namely Gaussian, nonlinear autoregressive eXogenous (NARX) model and long short-term memory (LSTM) are developed. The novelty in this paper is the development of secondary models using artificial neural network (ANN) and deep network. The performance measures chosen to compare the developed primary and secondary models are correlation coefficient (R2 ), root-mean-square error (RMSE) and accuracy factor (Af ). Results show that modified Gompertz model has better R2 (0·99) and RMSE (0·019) when compared to new logistic model. Also, the deep network model outperforms other secondary models. Based on the primary and novel secondary model, a predictive model (tertiary model) is developed with improved accuracy and is validated.

CONCLUSIONS
The proposed predictive model exhibit good validation results in terms of RMSE and R2 values and can be applied for determining the growth rate of E. coli at a particular temperature value.

SIGNIFICANCE AND IMPACT OF THE STUDY
The proposed model can be used in food processing industries during enzyme production such as Chymosin, to predict the growth rate of E. coli as a function of temperature. Also, the developed LSTM and NARX models can be used to predict maximum specific growth rate of other microbial strains with proper training.

D004926:Escherichia coli
D005525:Food-Processing Industry
D008954:Models, Biological
D016571:Neural Networks, Computer
D015203:Reproducibility of Results
D013696:Temperature

predictive model
temperature
Gaussian
NARX
deep networks
chymosin


A significant productive in vivo infection of resting cells with simian immunodeficiency virus in a macaque with AIDS.

Abstract: Identifying the cells that can be infected with HIV in vivo and thus potentially persist as latent reservoirs is of high priority. Here, we report the major infected cells in a chronically simian immunodeficiency virus (SIV)-infected macaque that developed AIDS and encephalitis. A majority of the infected cells were detected as non-proliferating resting cells. SIV-infected non-proliferating resting cells were found to be playing an important role in viral pathogenesis, persistence, or reservoir formation.

Pahar|Bapi|B| Lala|Wendy|W| Kuebler|Dot|D| Liu|David|D|

D016097:Simian Acquired Immunodeficiency Syndrome

infection
resting cells
simian immunodeficiency virus
reservoir
T cells
macrophage
simian immunodeficiency virus RNA


Raspberrylike SiO2@reduced graphene oxide@AgNP composite microspheres with high aqueous dispersity and excellent catalytic activity.

Abstract: The hybridizations of functional microspheres with graphene or graphene oxide (GO) sheets often suffer from severe agglomeration behaviors, leading to poor water dispersity of the resultant composite materials. Here, we first demonstrate that the sonication-assisted self-assembly of tiny GO sheets (whose lateral size less than 200 nm) on microspheric substrates like cationic polyelectrolyte-modified SiO2 microspheres could effectively overcome such a common drawback. On the basis of this facile strategy, we further developed reduced graphene oxide/silver nanoparticle composite film wrapped SiO2 microspheres, which not only possessed unique raspberrylike structure and high aqueous dispersity but also exhibited exceptional catalytic activity toward the reduction of 4-nitrophenol.

graphene
microspheres
sonication-assisted self-assembly
silver nanoparticles
catalytic reduction


Hb Phnom Penh Showing Falsely High or Reasonable HbA1c Values Depending on the Type of High-performance Liquid Chromatography System.

Abstract: We herein report a 50-year-old Chinese woman with Hb Phnom Penh (α117Phe-Ile-α118Thr) showing high or reasonable HbA1c values depending on the type of high-performance liquid chromatography (HPLC) system. A high HbA1c value of 7.5% (HPLC assay: G9) and a reasonable HbA1c value of 5.2% (assay unknown) were observed. Therefore, the patient was refereed to our hospital; the oral glucose tolerance test showed normal glucose tolerance. The HbA1c values measured by an enzymatic assay, immunoassay, and affinity assay, as well as most HPLC assays were within the reference range, whereas those measured by the Tosoh HPLC systems were high.

Hara|Kenji|K| Koga|Masafumi|M| Shinozaki|Hiroyuki|H| Yamauchi|Mototaka|M| Suzuki|Tatsuhiko|T| Naruse|Rika|R| Tsuchiya|Takafumi|T| Takebayashi|Kohzo|K| Inukai|Toshihiko|T| Hashimoto|Koshi|K|

D002851:Chromatography, High Pressure Liquid

Hb Phnom Penh
HbA1c
high performance liquid chromatography
variant hemoglobin


Scoliosis with peculiar radiological features in a patient with McCune-Albright syndrome.

Abstract: Patients with McCune-Albright Syndrome (MAS) should always attend regular follow-up. Beside the endocrinological aspects, the screening must take into account osteoarticular complications such as scoliosis, even in patients without fibrous dysplasia.

scoliosis
fibrous dysplasia
McCune‐Albright Syndrome
haller index


Co-evolution of activity and thermostability of an aldo-keto reductase KmAKR for asymmetric synthesis of statin precursor dichiral diols.

Abstract: Aldo-keto reductase KmAKR-catalyzed asymmetric reduction offers a green approach to produce dichiral diol tert-butyl 6-substituted-(3R,5R/S)-dihydroxyhexanoates, which are important building blocks of statins. In our previous work, we cloned a novel gene of NADPH-specific aldo-keto reductase KmAKR (WT) from a thermotolerant yeast Kluyveromyces marxianus ZJB14056 and a mutant KmAKR-W297H/Y296W/K29H (Variant III) has been constructed and displayed strict diastereoselectivity towards tert-butyl 6-cyano-(5R)-hydroxy-3-oxohexanoate ((5R)-1) but moderate activity and stability. Herein, to further co-evolve its activity and thermostability, we performed semi-rational engineering of Variant III by using a combinational screening strategy, consisting of tertiary structure analysis, loop engineering, and alanine scanning. As results, the "best" variant KmAKR-W297H/Y296W/K29H/Y28A/T63M (Variant VI) was acquired, whose Km, kcat/Km towards (5R)-1 was 0.66 mM and 210.77 s-1 mM-1, respectively, with improved thermostability (half-life of 14.13 h at 40 °C). Combined with 1.5 g dry cell weight (DCW) L-1Exiguobacterium sibiricum glucose dehydrogenase (EsGDH) for NADPH regeneration, 4.5 g DCW L-1Variant VI completely reduced (5R)-1 of up to 450 g L-1 within 7.0 h at 40 °C, yielding the corresponding optically pure tert-butyl 6-cyano-(3R,5R)-dihydroxyhexanoate ((3R,5R)-3, >99.5% d.e.p) with a space-time yield (STY) of 1.24 kg L-1 day-1, and this was the highest level documented in literatures so far on substrate loading and STY of producing (3R,5R)-3. Besides (5R)-1, Variant VI displayed strong activity on tert-butyl 6-chloro-(5S)-hydroxy-3-oxohexanoate ((5S)-2). 4.5 g DCW L-1Variant VI completely reduced 400 g L-1 (5S)-2, within 5.0 h at 40 °C, yielding optically pure tert-butyl 6-chloro-(3R,5S)-dihydroxyhexanoate ((3R,5S)-4, >99.5% d.e.p) with a STY of 1.34 kg L-1 day-1. In summary, Variant VI displayed industrial application potential in statins biomanufacturing.

Qiu|Shuai|S| Cheng|Feng|F| Jin|Ling-Jun|LJ| Chen|Yi|Y| Li|Shu-Fang|SF| Wang|Ya-Jun|YJ| Zheng|Yu-Guo|YG|

Co-evolution
Aldo-keto reductase
Dichiral diol
Asymmetric reduction
Biocatalysis


Outcomes Of Intensive Care Patients Having Septic Shock At A Tertiary Care Hospital Of Islamabad.

Abstract:
BACKGROUND
Septic shock is defined as sepsis with circulatory, cellular and metabolic abnormalities which are associated with greater mortality more than 40%. The objective of this study was to identify shortcomings and act promptly and adequately.

METHODS
This case series included 32 patients over a period of 03 months, September to November 2016 done at ICU of KRL Hospital Islamabad.

RESULTS
The study only enrolled patients who fulfilled the criteria of septic shock. Mortality was as high as 50%. (UTI) was the most common infection (43.75%). In patients who died Pneumonia was commonest infection (43.75%). Mean TLC, CRP and lactate was 17.48×109/l, 29.28 mg/L and 6.81mmom/L respectively. Escherichia Coli (E. coli) was the most common isolated pathogen (31.25%) followed by Staphylococcus Aureus (12.5%). Mean initial MAP was 49.7 mmHg and mean MAP at end of 3-day period was 71.4 mmHg. Mean norepinephrine dose given on day 1, 2 & 3 was 0.90 μg/kg/min, 1.01 μg/kg/min & 1.28 μg/kg/min respectively. Mean hospital stay was 7.1 days. Six out of 08 (75%) patients who needed ventilator support died while 02 out of 08 (25%) patients survived. Acute Kidney Injury (AKI) was the most common End Organ Damage (EOD).

CONCLUSIONS
Mortality remains high in septic shock despite maximum efforts. In current study MAP, serum lactate level, hospital stay, need for ventilator support, comorbidities, need for newer generation antimicrobials were the important cofounders in differentiating patients who died and those who survived with significant p-values in the 1st four conditions.

Ali|Azmat|A|
Abbasi|Awais Saeed|AS|
Sheikh|Maliha|M|


The Effects of Gene Duplication Modes on the Evolution of Regulatory Divergence in Wild and Cultivated Soybean.

Abstract: Regulatory changes include divergence in both cis-elements and trans-factors, which play roles in organismal evolution. Whole genome duplications (WGD) followed by diploidization are a recurrent feature in the evolutionary history of angiosperms. Prior studies have shown that duplicated genes have different evolutionary fates due to variable selection constraints and results in genomic compositions with hallmarks of paleopolyploidy. The recent sequential WGDs and post-WGD evolution in the common ancestor of cultivated soybean (Glycine max) and wild soybean (Glycine soja), together with other models of gene duplication, have resulted in a highly duplicated genome. In this study, we investigated the transcriptional changes in G. soja and G. max. We identified a sizable proportion of interspecific differentially expressed genes (DEGs) and found parental expression level dominance of G. max in their F1 hybrids. By classifying genes into different regulatory divergence types, we found the trans-regulatory changes played a predominant role in transcriptional divergence between wild and cultivated soybean. The same gene ontology (GO) and protein family (Pfam) terms were found to be over-represented in DEGs and genes of cis-only between JY47 and GS, suggesting the substantial contribution of cis-regulatory divergences to the evolution of wild and cultivated soybeans. By further dissecting genes into five different duplication modes, we found genes in different duplication modes tend to accumulate different types of regulatory differences. A relatively higher proportion of cis-only regulatory divergences was detected in singleton, dispersed, proximal, and tandem duplicates than WGD duplicates and genome-wide level, which is in line with the prediction of gene balance hypothesis for the differential fates of duplicated genes post-WGD. The numbers of cis-only and trans-only regulated genes were similar for singletons, whereas there were more genes of trans-only than cis-only in the rest duplication types, especially in WGD in which there were two times more trans-only genes than that in cis-only type. Tandem duplicates showed the highest proportion of trans-only genes probably due to some special features of this class. In summary, our results demonstrate that genes in different duplication modes have different fates in transcriptional evolution underpinned by cis- or trans-regulatory divergences in soybean and likely in other paleopolyploid higher organisms.

Zhao|Na|N|
Ding|Xiaoyang|X|
Lian|Taotao|T|
Wang|Meng|M|
Tong|Yan|Y|
Liang|Di|D|
An|Qi|Q|
Sun|Siwen|S|
Jackson|Scott A|SA|
Liu|Bao|B|
Xu|Chunming|C|

regulatory divergence
soybean
duplicate gene
Glycine max
Glycine soja
hybrid


Physiological effects of mercury-contaminated Oxisols on common bean and oat.

Abstract: The heavy metal mercury (Hg) is one of the most complex and toxic pollutants. When present in soils, it may impair plant growth, but the intensity of damage depends on the physical-chemical properties of the soil such as pH, clay, and organic matter content, which in turn affects Hg sorption and bioavailability. Understanding Hg potential damage to staple food crops is of paramount relevance. Here, we evaluated the physiological effects of Hg in Phaseolus vulgaris (common bean) and Avena sativa (oat) cultivated in two Oxisols with contrasting properties: Rhodic Acrudox (RA) and Typic Hapludox (TH). We performed four independent experiments (one per species/soil combination) that lasted 30 days each. Treatments were composed by HgCl2 concentrations in soils (0 to 80 mg kg-1 Hg). At the end of the experiment, we determined the impact of Hg on photosynthesis, nutritional status, and oxidative stress. Cultivation in TH contaminated with Hg resulted in oxidative stress in common bean and decreased photosynthesis/P accumulation in oat. No deleterious effects on physiological variables were detected in both species when cultivated in the RA soil. In general, we conclude that the lower Hg sorption in the TH soil resulted in toxicity-like responses, while acclimation-like responses were observed in plants cultivated in RA, reinforcing soil physical-chemical properties as key features driving Hg toxicity in Oxisols. Graphical abstract.

Dos Reis|Rayner Hugo Cassa Louzada|RHCL|

Catalase
Gas exchange
Malonaldehyde
Proline
Superoxide dismutase
Tropical soils


The decrease in silicon concentration of the connective tissues with age in rats is a marker of connective tissue turnover.

Abstract: Silicon may be important for bone and connective tissue health. Higher concentrations of silicon are suggested to be associated with bone and the connective tissues, compared with the non-connective soft tissues. Moreover, in connective tissues it has been suggested that silicon levels may decrease with age based upon analyses of human aorta. These claims, however, have not been tested under controlled conditions. Here connective and non-connective tissues were collected and analysed for silicon levels from female Sprague-Dawley rats of different ages (namely, 3, 5, 8, 12, 26 and 43 weeks; n=8-10 per age group), all maintained on the same feed source and drinking water, and kept in the same environment from weaning to adulthood. Tissues (696 samples) were digested in nitric acid and analysed by inductively coupled plasma optical emission spectrometry for total silicon content. Fasting serum samples were also collected, diluted and analysed for silicon. Higher concentrations of silicon (up to 50-fold) were found associated with bone and the connective tissues compared with the non-connective tissues. Although total silicon content increased with age in all tissues, the highest connective tissue silicon concentrations (up to 9.98 μg/g wet weight) were found in young weanling rats, decreasing thereafter with age (by 2-6 fold). Fasting serum silicon concentrations reflected the pattern of connective tissue silicon concentrations and, both measures, when compared to collagen data from a prior experiment in Sprague-Dawley rats, mirrored type I collagen turnover with age. Our findings confirm the link between silicon and connective tissues and would imply that young growing rats have proportionally higher requirements for dietary silicon than mature adults, for bone and connective tissue development, although this was not formally investigated here. However, estimation of total body silicon content suggested that actual Si requirements may be substantially lower than previously estimated which could explain why absolute silicon deficiency is difficult to achieve but, when it is achieved in young growing animals, it results in stunted growth and abnormal development of bone and other connective tissues.

Jugdaohsingh|Ravin|R|
Watson|Abigail I E|AI|
Pedro|Liliana D|LD|
Powell|Jonathan J|JJ|

Connective tissues
Collagen
Growth & development
Silicon requirement
Silicon status
Whole body Si content


Titanium Dioxide Nanoparticles Evoke Proinflammatory Response during Murine Norovirus Infection Despite Having Minimal Effects on Virus Replication.

Abstract: Noroviruses (NoV) have enhanced tropism for the gastrointestinal (GI) tract and are the major cause of nonbacterial gastroenteritis in humans. Titanium dioxide (TiO2) nanoparticles (NPs) used as food additives, dietary supplements, and cosmetics accumulate in the GI tract. We investigated the effect anatase TiO2 NPs on NoV replication and host response during virus infection, using murine norovirus (MNV-1) infection of RAW 264.7 macrophages. Pretreatment with 20 μg/ml anatase NPs significantly reduced the viability of macrophages alone or during virus infection, but did not alter virus replication. In contrast, pre-incubation with 2 μg/ml anatase NPs reduced virus replication fivefold at 48 h. The presence of anatase NPs during MNV-1 infection evoked a pro-inflammatory response, as measured by a significant increase in expression of cytokines, including IL-6, IFN-γ, TNFα and the TGFβ1. No genotoxic insults due to anatase TiO2 NPs alone or to their presence during MNV-1 infection were detected. This study highlights important safety considerations related to NP exposure of the GI tract in individuals infected with noroviruses or other foodborne viruses.

Agnihothram|Sudhakar|S|
Mullis|Lisa|L|
Townsend|Todd A|TA|
Watanabe|Fumiya|F|
Mustafa|Thikra|T|
Biris|Alexandru|A|
Manjanatha|Mugimane G|MG|
Azevedo|Marli P|MP|
|||

Titanium
Nanoparticles
Murine Norovirus
Pro-inflammatory response
Genotoxicity
Biomarkers


Fatal Penetrating Head Injuries Caused by Projectile Tear Gas Canisters.

Abstract:
BACKGROUND
Since their advent in the 1920s, tear gas canisters (TGCs) have been frequently used in crowd control. Few reports have documented nonpenetrating injuries attributed directly to TGCs. In this study, we report a case series of fatal penetrating head injuries caused by TGCs.

METHODS
We conducted a retrospective chart review of all the patients who were admitted to the Neurosurgery Teaching Hospital in Baghdad, Iraq, since the start of the antigovernment protests (October 2019). All patients who suffered penetrating head trauma caused by TGCs were included in our study. We collected patient demographics, wound location, neurologic examination, computed tomography (CT) scan findings, surgical management, and clinical outcomes.

RESULTS
We found 10 cases of penetrating head trauma caused by TGCs. All victims were men, with a mean age of 16 years (range, 14-19 years). The mean Glasgow Coma Scale score was 7 (range, 3-10). The neurologic examination revealed unilateral hemiplegia/hemiparesis and pupillary abnormality in 40% (n = 4) and 50% (n = 5) of the patients, respectively. CT scans revealed an extensive pattern of brain damage. Surgical intervention was done in 80% of cases (n = 8), which included removal of the TGC, wound debridement, and hemostasis. The in-hospital mortality rate was 100% (N = 10), with all fatalities occurring within 1-3 days of admission.

CONCLUSIONS
TGCs have the potential to cause lethal penetrating head injuries, calling for a reevaluation of their safety and methods of use in terms of human health.

Hoz|Samer S|SS|
Aljuboori|Zaid S|ZS|
Dolachee|Ali A|AA|
Al-Sharshahi|Zahraa F|ZF|
Alrawi|Mohammed A|MA|
Al-Smaysim|Ammar M|AM|

Penetrating
Head
Tear gas
Canister
Trauma
Brain


Muscle Cell Morphogenesis, Structure, Development and Differentiation Processes Are Significantly Regulated during Human Ovarian Granulosa Cells In Vitro Cultivation.

Abstract: Granulosa cells (GCs) have many functions and are fundamental for both folliculogenesis and oogenesis, releasing hormones and communicating directly with the oocyte. Long-term in vitro cultures of GCs show significant stem-like characteristics. In the current study, RNA of human ovarian granulosa cells was collected at 1, 7, 15 and 30 days of long-term in vitro culture. Understanding the process of differentiation of GCs towards different cell lineages, as well as the molecular pathways underlying these mechanisms, is fundamental to revealing other possible stemness markers of this type of cell. Identifying new markers of GC plasticity may help to understand the aetiology and recurrence of a wide variety of diseases and health conditions and reveal possible clinical applications of the ovarian tissue cells, affecting not only the reproductive ability but also sex hormone production. Granulosa cells were the subject of this study, as they are readily available as remnant material leftover after in vitro fertilisation procedures and exhibit significant stem-like characteristics in culture. The change in gene expression was investigated through a range of molecular and bioinformatic analyses. Expression microarrays were used, allowing the identification of groups of genes typical of specific cellular pathways. This candidate gene study focused on ontological groups associated with muscle cell morphogenesis, structure, development and differentiation, namely, "muscle cell development", "muscle cell differentiation", "muscle contraction", "muscle organ development", "muscle organ morphogenesis", "muscle structure development", "muscle system process" and "muscle tissue development". The results showed that the 10 most upregulated genes were keratin 19, oxytocin receptor, connective tissue growth factor, nexilin, myosin light chain kinase, cysteine and glycine-rich protein 3, caveolin 1, actin, activating transcription factor 3 and tropomyosin, while the 10 most downregulated consisted of epiregulin, prostaglandin-endoperoxide synthase 2, transforming growth factor, interleukin, collagen, 5-hydroxytryptmine, interleukin 4, phosphodiesterase, wingless-type MMTV integration site family and SRY-box 9. Moreover, ultrastructural observations showing heterogeneity of granulosa cell population are presented in the study. At least two morphologically different subpopulations were identified: large, light coloured and small, darker cells. The expression of genes belonging to the mentioned ontological groups suggest the potential ability of GCs to differentiate and proliferate toward muscle lineage, showing possible application in muscle regeneration and the treatment of different diseases.

Dompe|Claudia|C|
Kranc|Wiesława|W|0000-0001-7518-4834
Jopek|Karol|K|
Kowalska|Katarzyna|K|
Ciesiółka|Sylwia|S|
Chermuła|Błażej|B|
Bryja|Artur|A|0000-0002-4338-8119
Jankowski|Maurycy|M|0000-0001-9476-0235
Perek|Joanna|J|
Jozkowiak|Małgorzata|M|
Moncrieff|Lisa|L|
Hutchings|Greg|G|
Janowicz|Krzysztof|K|
Pawelczyk|Leszek|L|
Bruska|Małgorzata|M|
Petitte|James|J|0000-0003-2764-6007
Mozdziak|Paul|P|0000-0002-1575-3123
Kulus|Magdalena|M|
Piotrowska-Kempisty|Hanna|H|
Spaczyński|Robert Z|RZ|
Nowicki|Michał|M|0000-0002-7265-8181
Kempisty|Bartosz|B|

in vitro culture
proliferation
human GCs
muscle differentiation


Processes in cognitive behavior therapy for social anxiety disorder: Predicting subsequent symptom change.

Abstract: Although cognitive behavior therapy (CBT) is an effective treatment for social anxiety disorder, little is known about the processes during treatment that bring about change. The aim of this study was to investigate whether the proposed processes of change according to the cognitive model of social anxiety disorder predicted subsequent symptom reduction in CBT delivered as therapist-guided bibliotherapy. We analyzed data from patients with social anxiety disorder (N = 61) who participated in an effectiveness trial of CBT in primary care. Seven putative processes and outcome (i.e., social anxiety) were assessed on a weekly basis throughout treatment. We used linear mixed models to analyze within-person relations between processes and outcome. The results showed a unidirectional effect of reduced avoidance on subsequent decrease in social anxiety. Further, we found support for reciprocal influences between four of the proposed processes (i.e., estimated probability and cost of adverse outcome, self-focused attention, and safety behaviors) and social anxiety. The remaining two processes, (i.e., anticipatory and post-event processing) did not predict subsequent social anxiety, but were predicted by prior symptom reduction. The findings support that several of the change processes according to the cognitive model of social anxiety disorder are involved in symptom improvement.

Santoft|Fredrik|F| Salomonsson|Sigrid|S| Hesser|Hugo|H| Lindsäter|Elin|E| Ljótsson|Brjánn|B| Lekander|Mats|M| Kecklund|Göran|G| Öst|Lars-Göran|LG| Hedman-Lagerlöf|Erik|E|

Processes
Cognitive behavior therapy
Social anxiety disorder
Mechanisms


Circumscription and synopsis of Eugenia section Speciosae Bünger & Mazine (Myrtaceae).

Abstract: A new section of Eugenia (Myrtaceae) is described, segregate from Eugenia sect. Phyllocalyx. Phylogenetic studies suggest that Eugenia sect. Phyllocalyx as traditionally delimited is paraphyletic. To maintain the monophyly of each of the sections in Eugenia s.l., we herein opt to circumscribe a new section and recognize six taxa in sect. Speciosae, which has a distribution mostly in southeastern Brazil and northern South America. Nomenclatural notes are made and a taxonomic key is provided for the species of the section.

de Oliveira Bünger|Mariana|M|
Mazine|Fiorella Fernanda|FF|
Lucas|Eve J|EJ|
Stehmann|João Renato|JR|

Amazon Forest
Atlantic Forest
Myrteae
Neotropics


Aging and chromatoid body assembly: Are these two physiological events linked?

Abstract: The chromatoid body is a cytoplasmic male germ cell structure that plays a role in the regulation of mRNA transcription during spermatogenesis. A proteomic analysis of this structure has identified the presence of its classic molecular markers (MVH and MIWI), as well as a significant number of transient proteins. Circadian locomotor output cycles protein kaput (CLOCK) and brain and muscle ARNT-like 1 (BMAL1), which are molecular components of the circadian clock, are likely located in the chromatoid body in a transient fashion. This study sought to determine whether aging produces morphological changes in the chromatoid bodies of round spermatids similar to those previously observed in BMAL1 knockout mice. A sample of 30 male mice was divided into three groups: juvenile mice (45 days old), adult mice (120 days old), and old mice (+180 days old). Aging was confirmed by viability and sperm count analyses and testosterone dosage. Squash slides prepared with fragments of seminiferous tubules were immunostained for MVH, MIWI, BMAL1, and CLOCK detection. In juvenile and adult specimens, single round chromatoid bodies were observed using MVH/BMAL1 and MIWI/CLOCK immunostaining. In old specimens, many chromatoid bodies displayed changes in number and morphology, as well as an increase in the interactions between MVH and BMAL1; MIWI and CLOCK. Changes in chromatoid body morphology increased interactions between the proteins analyzed herein, and decreased amounts of these proteins in seminiferous tubules of older mice may indicate that aging influences the assembly and physiology of chromatoid bodies, which may, in turn, affect fertility. Impact statement The results discussed in this paper indicate that aging compromises the structure and physiology of chromatoid bodies (CBs) in post-meiotic male cells. Since CB is a fundamental structure for the differentiation of the mature male germ cell it is possible that this imbalance in CB physiology may play a role in the reduction of fertility in older men. It is important to note that not only the classic CB markers (such as the MIWI and MVH proteins) were used to showcase the structural changes in the CBs but also the main components of circadian cycle control (the CLOCK and BMAL1 proteins), indicating that the reduction of circadian control in aged males may contribute to these changes in CBs as well. Therefore, it is intriguing to evaluate the hypothesis that controlling these physiological/structural changes in CBs may be a way of delaying the effects of aging in males.

Santos|Elisa G|EG|
Silva|Maraisa A|MA|
Amorim|Renata P|RP|
Giordano|Leticia de Souza|LS|
Silva|Dayana de Sales|DS|
Rasmussen|Lucas T|LT|
Peruquetti|Rita L|RL|

Aging
chromatoid body
spermatogenesis
fertility


Definitive radiotherapy for Merkel cell carcinoma confers clinically meaningful in-field locoregional control: A review and analysis of the literature.

Abstract:
BACKGROUND
Merkel cell carcinoma (MCC) is an uncommon radiosensitive, neuroendocrine malignancy. Treatment often involves surgery; however, older, sicker patients may not be candidates for an operation. Institutions have published data favoring the role of definitive radiotherapy for macroscopic locoregional disease.

OBJECTIVE
Our objective was to report the outcome of patients treated with definitive radiotherapy.

METHODS
We performed a systematic review of Medline, PubMed, and Embase databases for reported cases or series of definitive radiotherapy for macroscopic locoregional MCC.

RESULTS
The mean radiation dose did not significantly differ between primary and regional sites (48.7 ± 13.2 vs 49.4 ± 10.1 Gy, P = .74). The rate of recurrence was calculated on the basis of the site of disease (11.7%) and per patient (14.3%). Recurrence was significantly more likely to occur at regional than at primary irradiated sites (16.3% vs 7.6%, P = .02). There was no association between radiotherapy dose and incidence of recurrence or nonrecurrence; primary (42.7 ± 23 vs 49.3 ± 11.8 Gy, P = .197) and regional (48.6 ± 10 vs 49.5 ± 10.3 Gy, P = .77).

LIMITATIONS
A limitation of this report is that most publications were retrospective; heterogeneity was present in the size of MCC and in radiotherapy details.

CONCLUSIONS
Definitive radiotherapy for locoregional macroscopic MCC was found to confer clinically meaningful local and regional in-field control.

Gunaratne|Dakshika A|DA|
Howle|Julie R|JR|
Veness|Michael J|MJ|

D015266:Carcinoma, Merkel Cell
D006801:Humans
D012878:Skin Neoplasms

radiotherapy
Merkel cell carcinoma
neuroendocrine
recurrence
definitive treatment


Uterine rupture without previous caesarean delivery: a population-based cohort study.

Abstract:
OBJECTIVE
To determine incidence and patient characteristics of women with uterine rupture during singleton births at term without a previous caesarean delivery.

STUDY DESIGN
Population based cohort study. Women with term singleton birth, no record of previous caesarean delivery and planned vaginal delivery (n=611,803) were identified in the Danish Medical Birth Registry (1997-2008). Medical records from women recorded with uterine rupture during labour were reviewed to ascertain events of complete uterine rupture. Relative Risk (RR) and adjusted Relative Risk Ratio (aRR) of complete uterine rupture with 95% confidence intervals (95% CI) were ascertained according to characteristics of the women and of the delivery.

RESULTS
We identified 20 cases with complete uterine rupture. The incidence of complete uterine rupture among women without previous caesarean delivery was about 3.3/100,000 deliveries. Multiparity (RR 8.99 (95% CI 1.86-43.29)), induction of labour (RR 3.26 (95% CI 1.24-8.57)), epidural analgesia (RR 10.78 (95% CI 4.25-27.39)), and augmentation by oxytocin (RR 9.50 (95% CI 3.15-28.63)) were associated with uterine rupture. Induction of labour was not significantly related to uterine rupture when adjusted for parity, epidural analgesia and augmentation by oxytocin.

CONCLUSION
Although uterine rupture is rare, its association with epidural analgesia and augmentation of labour with oxytocin in multipara should be considered. Thus, vigilance should be exercised when labour is obstructed and there is need for epidural analgesia and/or augmentation by oxytocin in multiparous women. Due to the rare occurrence of uterine rupture caution should be exerted when interpreting the findings of this study.

Thisted|Dorthe L A|DL|
Mortensen|Laust H|LH|
Krebs|Lone|L|

Uterine rupture
Multiparity
Epidural analgesia
Augmentation of labour
Induced labour
Spontaneous rupture


SPT5 stabilization of promoter-proximal RNA polymerase II.

Abstract: Based on in vitro studies, it has been demonstrated that the DSIF complex, composed of SPT4 and SPT5, regulates the elongation stage of transcription catalyzed by RNA polymerase II (RNA Pol II). The precise cellular function of SPT5 is not clear, because conventional gene depletion strategies for SPT5 result in loss of cellular viability. Using an acute inducible protein depletion strategy to circumvent this issue, we report that SPT5 loss triggers the ubiquitination and proteasomal degradation of the core RNA Pol II subunit RPB1, a process that we show to be evolutionarily conserved from yeast to human cells. RPB1 degradation requires the E3 ligase Cullin 3, the unfoldase VCP/p97, and a novel form of CDK9 kinase complex. Our study demonstrates that SPT5 stabilizes RNA Pol II specifically at promoter-proximal regions, permitting RNA Pol II release from promoters into gene bodies and providing mechanistic insight into the cellular function of SPT5 in safeguarding accurate gene expression.

Aoi|Yuki|Y|
Takahashi|Yoh-Hei|YH|
Shah|Avani P|AP|
Iwanaszko|Marta|M|
Rendleman|Emily J|EJ|
Khan|Nabiha H|NH|
Cho|Byoung-Kyu|BK|
Goo|Young Ah|YA|
Ganesan|Sheetal|S|
Kelleher|Neil L|NL|
Shilatifard|Ali|A|

SPT5
RNA polymerase II
elongation
transcription
degradation
Cullin 3
VCP
CDK9
NELF
auxin-inducible degron


Mechanism and preclinical prevention of increased breast cancer risk caused by pregnancy.

Abstract: While a first pregnancy before age 22 lowers breast cancer risk, a pregnancy after age 35 significantly increases life-long breast cancer risk. Pregnancy causes several changes to the normal breast that raise barriers to transformation, but how pregnancy can also increase cancer risk remains unclear. We show in mice that pregnancy has different effects on the few early lesions that have already developed in the otherwise normal breast-it causes apoptosis evasion and accelerated progression to cancer. The apoptosis evasion is due to the normally tightly controlled STAT5 signaling going astray-these precancerous cells activate STAT5 in response to pregnancy/lactation hormones and maintain STAT5 activation even during involution, thus preventing the apoptosis normally initiated by oncoprotein and involution. Short-term anti-STAT5 treatment of lactation-completed mice bearing early lesions eliminates the increased risk after a pregnancy. This chemoprevention strategy has important implications for preventing increased human breast cancer risk caused by pregnancy. DOI: http://dx.doi.org/10.7554/eLife.00996.001.

Haricharan|Svasti|S|
Dong|Jie|J|
Hein|Sarah|S|
Reddy|Jay P|JP|
Du|Zhijun|Z|
Toneff|Michael|M|
Holloway|Kimberly|K|
Hilsenbeck|Susan G|SG|
Huang|Shixia|S|
Atkinson|Rachel|R|
Woodward|Wendy|W|
Jindal|Sonali|S|
Borges|Virginia F|VF|
Gutierrez|Carolina|C|
Zhang|Hong|H|
Schedin|Pepper J|PJ|
Osborne|C Kent|CK|
Tweardy|David J|DJ|
Li|Yi|Y|

breast cancer
pregnancy
STAT5
chemoprevention


Surgical treatment for recurrent solitary fibrous tumor invading atlas.

Abstract:
BACKGROUND
Solitary fibrous tumor (SFT), a rare neoplasm, usually originates in the pleura. Extrapleural SFTs occasionally occur in the head and neck.

METHODS
In this study, the extirpation of a rare case of recurrent SFT invading the atlas is discussed.

RESULTS
Ten years after surgical resection of an SFT in the right parapharyngeal space, the patient returned with a complaint of swelling sensation in the right neck. MRI and CT showed an enhanced lobulated mass invading the right lateral C1 vertebral body and canal and encasing the right vertebral artery. Extirpation of the recurrent tumor with a combined transcervical and midline posterior approach was successful. The surgical margin was negative for cancer and the postoperative course was uneventful.

CONCLUSION
Although an SFT is generally benign, recurrence can occur even after several years, therefore, careful long-term follow-up is essential for early detection. A combined transcervical and midline posterior approach proved useful for resection of the atlas body.

Tsutsumi|Nao|N| Kojima|Yasutaka|Y| Nishida|Kotaro|K| Maeno|Koichiro|K| Kakutani|Kenichiro|K| Kawakami|Fumi|F| Kanzawa|Maki|M| Itoh|Tomoo|T| Otsuki|Naoki|N| Nibu|Ken-ichi|K|

D001270:Cervical Atlas
D005500:Follow-Up Studies
D006801:Humans
D008279:Magnetic Resonance Imaging
D008297:Male
D009361:Neoplasm Invasiveness
D009364:Neoplasm Recurrence, Local
D009367:Neoplasm Staging
D010610:Pharyngeal Neoplasms
D035583:Rare Diseases
D018570:Risk Assessment
D054364:Solitary Fibrous Tumors
D013125:Spinal Neoplasms
D014057:Tomography, X-Ray Computed
D016896:Treatment Outcome
D055815:Young Adult

surgical treatment
recurrent
solitary fibrous tumor
atlas
combined approach


Automatic Classification of Users' Health Information Need Context: Logistic Regression Analysis of Mouse-Click and Eye-Tracker Data.

Abstract:
BACKGROUND
Users searching for health information on the Internet may be searching for their own health issue, searching for someone else's health issue, or browsing with no particular health issue in mind. Previous research has found that these three categories of users focus on different types of health information. However, most health information websites provide static content for all users. If the three types of user health information need contexts can be identified by the Web application, the search results or information offered to the user can be customized to increase its relevance or usefulness to the user.

OBJECTIVE
The aim of this study was to investigate the possibility of identifying the three user health information contexts (searching for self, searching for others, or browsing with no particular health issue in mind) using just hyperlink clicking behavior; using eye-tracking information; and using a combination of eye-tracking, demographic, and urgency information. Predictive models are developed using multinomial logistic regression.

METHODS
A total of 74 participants (39 females and 35 males) who were mainly staff and students of a university were asked to browse a health discussion forum, Healthboards.com. An eye tracker recorded their examining (eye fixation) and skimming (quick eye movement) behaviors on 2 types of screens: summary result screen displaying a list of post headers, and detailed post screen. The following three types of predictive models were developed using logistic regression analysis: model 1 used only the time spent in scanning the summary result screen and reading the detailed post screen, which can be determined from the user's mouse clicks; model 2 used the examining and skimming durations on each screen, recorded by an eye tracker; and model 3 added user demographic and urgency information to model 2.

RESULTS
An analysis of variance (ANOVA) analysis found that users' browsing durations were significantly different for the three health information contexts (P<.001). The logistic regression model 3 was able to predict the user's type of health information context with a 10-fold cross validation mean accuracy of 84% (62/74), followed by model 2 at 73% (54/74) and model 1 at 71% (52/78). In addition, correlation analysis found that particular browsing durations were highly correlated with users' age, education level, and the urgency of their information need.

CONCLUSIONS
A user's type of health information need context (ie, searching for self, for others, or with no health issue in mind) can be identified with reasonable accuracy using just user mouse clicks that can easily be detected by Web applications. Higher accuracy can be obtained using Google glass or future computing devices with eye tracking function.

Internet
consumer health information
information-seeking behavior
medical informatics
social media


Efficacy of a Word- and Text-Based Intervention for Students With Significant Reading Difficulties.

Abstract: We examine the efficacy of an intervention to improve word reading and reading comprehension in fourth- and fifth-grade students with significant reading problems. Using a randomized control trial design, we compare the fourth- and fifth-grade reading outcomes of students with severe reading difficulties who were provided a researcher-developed treatment with reading outcomes of students in a business-as-usual (BAU) comparison condition. A total of 280 fourth- and fifth-grade students were randomly assigned within school in a 1:1 ratio to either the BAU comparison condition ( n = 139) or the treatment condition ( n = 141). Treatment students were provided small-group tutoring for 30 to 45 minutes for an average of 68 lessons (mean hours of instruction = 44.4, SD = 11.2). Treatment students performed statistically significantly higher than BAU students on a word reading measure (effect size [ES] = 0. 58) and a measure of reading fluency (ES = 0.46). Though not statistically significant, effect sizes for students in the treatment condition were consistently higher than BAU students for decoding measures (ES = 0.06, 0.08), and mixed for comprehension (ES = -0.02, 0.14).

Vaughn|Sharon|S|
Roberts|Garrett J|GJ|
Miciak|Jeremy|J|
Taylor|Pat|P|
Fletcher|Jack M|JM|

efficacy reading comprehension treatment age elementary


Elucidating the multi-drug resistance mechanism of Enterococcus faecalis V583: A gene interaction network analysis.

Abstract: Resistance to antibiotics have created havoc around the globe due to the emergence of multi-drug resistant (MDR) pathogenic bacterial strains. To decipher this problem, a detailed understanding of the antimicrobial resistance (AMR) genes and their resistant mechanisms are obligatory. The present study is mainly focused on an opportunistic, nosocomial bacterial strain Enterococcus faecalis V583, which possess acquired exogenous AMR genes portraying resistance against Chloramphenicol, Tetracycline, Vancomycin, Linezolid, Ampicillin and other antibiotics. An interaction network of eight AMR genes along with 40 functional partners have been constructed and analysed. Functional enrichment analysis highlighted 20, 21 and 22 genes having significant roles in Cellular Component (CC), Molecular Functions (MF) and Biological Process (BP) respectively. Clustering analysis resulted in four densely interconnected clusters (C1-C4) which were associated with three AMR mechanisms that include the alteration in drug target (pbps, mur and van genes), complete replacement/bypass of target sites (van genes) and ATP Binding Cassette (ABC) transporter efflux pump mechanisms (msrA, EF_1680, EF_1682 and pbps). Our results showed that the genes responsible for β-lactams resistance (pbp1A, 1C, 2A, 2B); glycopeptide resistance (ddl, vanBHBRBSBWXYB); Erythromycin, Macrolides, Lincosamide and Streptogramin-B (MLSB) resistance (msrA, EF_1680, EF_1682) along with mur genes (murABBCDEFG) played an important role in MDR mechanisms. Network analysis has shown the genes mraY, pbpC, murE, murG and murD possessed 26, 24, 23, 22 and 22 interactions respectively. With more number of direct interactions, these genes can be considered as hub genes that could be exploited as potential drug targets for new drug discovery.

Naha|Aniket|A|
Kumar Miryala|Sravan|S|
Debroy|Reetika|R|
Ramaiah|Sudha|S|
Anbarasu|Anand|A|

D024901:Drug Resistance, Multiple, Bacterial

Multi-drug resistance
Enterococcus faecalis
Antibiotic therapy
Gene ontology
Novel targets


Carbamylation of vimentin is inducible by smoking and represents an independent autoantigen in rheumatoid arthritis.

Abstract:
OBJECTIVES
Smoking has been connected to citrullination of antigens and formation of anti-citrullinated peptide antibodies (ACPAs) in rheumatoid arthritis (RA). Since smoking can modify proteins by carbamylation (formation of homocitrulline), this study was conducted to investigate these effects on vimentin in animal models and RA.

METHODS
The efficiency of enzymatic carbamylation of vimentin was characterised. B-cell response was investigated after immunisation of rabbits with different vimentin isoforms. Effects of tobacco smoke exposure on carbamylation of vimentin and formation of autoantibodies were analysed in mice. The antibody responses against isoforms of vimentin were characterised with respect to disease duration and smoking status of patients with RA.

RESULTS
Enzymatic carbamylation of vimentin was efficiently achieved. Subsequent citrullination of vimentin was not disturbed by homocitrullination. Sera from rabbits immunised with carbamylated vimentin (carbVim), in addition to carbVim also recognised human IgG-Fc showing rheumatoid factor-like reactivity. Smoke-exposed mice contained detectable amounts of carbVim and developed a broad immune response against carbamylated antigens. Although the prevalence of anti-carbamylated antibodies in smokers and non-smokers was similar, the titres of carbamylated antibodies were significantly increased in sera of smoking compared with non-smoking RA. CarbVim antibodies were observed independently of ACPAs in early phases of disease and double-positive patients for anti-mutated citrullinated vimentin (MCV) and anti-carbVim antibodies showed an extended epitope recognition pattern towards MCV.

CONCLUSIONS
Carbamylation of vimentin is inducible by cigarette smoke exposure. The polyclonal immune response against modified antigens in patients with RA is not exclusively citrulline-specific and carbamylation of antigens could be involved in the pathogenesis of disease.

TRIAL REGISTRATION NUMBER
ISRCTN36745608; EudraCT Number: 2006-003146-41.

Ospelt|Caroline|C|
Bang|Holger|H|
Feist|Eugen|E|
Camici|Giovanni|G|
Keller|Stephan|S|
Detert|Jacqueline|J|
Krämer|Anette|A|
Gay|Steffen|S|
Ghannam|Khetam|K|
Burmester|Gerd R|GR|


FOXA1 promotes proliferation, migration and invasion by transcriptional activating KRT7 in human gastric cancer cells.

Abstract: Gastric cancer (GC) is the fourth leading cause of gynecological malignancies worldwide. 5-fluorouracil (5-FU)-mediated chemotherapy is the adjuvant treatment for patients with GC following surgical resection. Many studies have indicated the cancer-type specific roles of forkhead box protein A1 (FOXA1) and keratin 7 (KRT7) in human malignancies. However, the potential mechanism underlying the involvement of FOXA1 and KRT7 in the pathogenesis and chemoresistance of GC are still not entirely clear. In our study, gain- and loss-of-function experiments proved that FOXA1 promoted cell proliferation, migration and invasion in AGS and SGC-7901 cells. Consequently, KRT7 was identified to be transcriptional activated by FOXA1 using Dual luciferase reporter assay. Our results also indicated that FOXA1 exerted its functions in enhancing viability and invasion of AGS and SGC-7901 cells through activating KRT7. Finally, interference of FOXA1 or KRT7 increased the chemosensitivity of AGS and SGC-7901 cells to 5-fluorouracil (5-Fu) treatment by suppressing cell proliferation. In conclusion, these data indicate that FOXA1 promoted proliferation, migration, invasion, and decreased chemosensitivity of GC cells to 5-Fu treatment through transcriptional activator KRT7. The present study provides a novel therapeutic strategy for the enhancement of efficacy in GC treatment and provides important insights into the molecular mechanism underlying 5-FU-mediated chemoresistance.

Liu|B L|BL|
Qin|J J|JJ|
Shen|W Q|WQ|
Liu|C|C|
Yang|X Y|XY|
Zhang|X N|XN|
Hu|F|F|
Liu|G M|GM|

D051541:Hepatocyte Nuclear Factor 3-alpha


Fear of illness recurrence and mental health anxiety in people recovering from psychosis and common mental health problems.

Abstract:
OBJECTIVES
It is well known that mental health problems can recur even after effective treatment, leading to an understandable fear of illness recurrence (FIR) and mental health anxiety (MHA). These may themselves contribute to the process of relapse. This study aims to examine whether people recovering from psychosis have greater FIR than those recovering from common mental health problems or healthy controls. The study also hypothesized that there will be a relationship between FIR and MHA and that both these constructs will be associated with maladaptive coping behaviours. Finally, the relationship between mental defeat with FIR and psychological distress (anxiety and depression) will be examined.

METHOD
A cross-sectional questionnaire design was employed. Thirty-nine participants in recovery from psychosis, eighty-two in recovery from other mental health difficulties, and sixty-one healthy controls aged 18-73 were recruited from NHS services and via social media. Self-report questionnaires measured mental defeat, mental health anxiety, fear of illness recurrence, maladaptive coping behaviours, and psychological distress.

RESULTS
Those recovering from psychosis were found to more negatively evaluate the likely consequences of relapse than those recovering from common mental health problems or healthy controls. However, the levels of FIR in common mental health problems were also significantly elevated when compared to healthy controls. There were no other differences between these groups (in terms of mental defeat, anxiety, depression, social functioning, and maladaptive coping behaviours). The hypothesized relationship between FIR and MHA was also found, and both were associated with maladaptive coping behaviours. Mental defeat was associated with FIR and psychological distress (anxiety and depression).

CONCLUSIONS
This study found that those with psychosis experienced higher FIR than those with common mental health problems. Furthermore, people defining themselves as in recovery are worried about relapse and the extent of this is linked to mental health anxiety. Given that such responses may contribute to actual relapse, it is important that these issues are better understood and interventions developed to ameliorate them.

PRACTITIONER POINTS
Following recovery, fear of relapse may be particularly high in those with experience of psychosis; it is also present in those with common mental health problems The importance of this observation lies in the issue that anxiety about relapse may initiate a self-fulfilling process, with increased anxiety worsening symptoms and vice versa. Cognitive-behavioural therapy for health anxiety may be beneficial to those experiencing high levels of mental health anxiety. Cognitions related to relapse need to be explored and addressed both in further research and, when clearly identified, may be a target during relapse-prevention planning.

mental health anxiety
psychosis
relapse
maladaptive coping behaviours
mental defeat
recovery
fear of recurrence
predictors


Effective nationwide school-based participatory extramural program on adolescent body mass index, health knowledge and behaviors.

Abstract:
BACKGROUND
Adolescent obesity is a major public health concern. Open to all high school students regardless of weight status, HealthCorps is a nationwide program offering a comprehensive high school-based participatory educational program to indirectly address obesity. We tested a hypothesis that the HealthCorps program would decrease BMI z-scores among overweight or obese students, and reduce obesity rates, and evaluated its effects on health knowledge and behaviors.

METHODS
HealthCorps aimed to improve student knowledge and behaviors regarding nutrition quality, physical activity, sleep, breakfast intake, and mental resilience. Participating students received through HealthCorps coordinators weekly or bi-weekly classroom lessons either for a semester or a year in addition to various during- and after-school health-promoting activities and mentorship. Self-reported height and weight were collected along with questionnaires assessing knowledge and behaviors during 2013-2014 academic year among 14 HealthCorps-participating New York City high schools. This quasi experimental two-arm pre-post trial included 611 HealthCorps and 221 comparison arm students for the analytic sample. Sex-specific analyses stratified by weight status were adjusted for age and Hispanic ethnicity with clustering effects of schools and students taken into account.

RESULTS
HealthCorps female overweight/obese and obese student had a significant decrease in BMI z-scores (post-pre delta BMI z-score = -0.16 (95%CI = (-0.26, -0.05), p = 0.004 for the former; and = -0.23 (-0.44, -0.03), p = 0.028, for the latter) whereas comparison female counterparts did not. The HealthCorps students, but not the comparison students, had a significant increase for all knowledge domains except for the breakfast realm, and reported a greater number of significant behavior changes including fruit and vegetable intake and physical activities.

CONCLUSIONS
The HealthCorps program was associated with reduced BMI z-score in overweight/obese and obese female adolescents, with enhanced health knowledge and behavior for both sexes. With its wide reach, this may be a promising program to help combat adolescent obesity in schools.

TRIAL REGISTRATION
This study is registered as a clinical trial at the ClinicalTrials.gov registry with trial number NCT02277496 on September 10, 2014 (Retrospectively registered).

D007722:Health Knowledge, Attitudes, Practice

Adolescent obesity
High school
HealthCorps
Health behavior


Obesity as a Risk Factor for Severe COVID-19: Summary of the Best Evidence and Implications for Health Care.

Abstract:
PURPOSE OF REVIEW
To collate the best evidence from several strands-epidemiological, genetic, comparison with historical data and mechanistic information-and ask whether obesity is an important causal and potentially modifiable risk factor for severe COVID-19 outcomes.

RECENT FINDINGS
Several hundred studies provide powerful evidence that body mass index (BMI) is a strong linear risk factor for severe COVID-19 outcomes, with recent studies suggesting ~5-10% higher risk for COVID-19 hospitalisation per every kg/m2 higher BMI. Genetic data concur with hazard ratios increasing by 14% per every kg/m2 higher BMI. BMI to COVID-19 links differ markedly from prior BMI-infection associations and are further supported as likely causal by multiple biologically plausible pathways. Excess adiposity appears to be an important, modifiable risk factor for adverse COVID-19 outcomes across all ethnicities. The pandemic is also worsening obesity levels. It is imperative that medical systems worldwide meet this challenge by upscaling investments in obesity prevention and treatments.

Genetics
Body mass Index
Activity
Diet
Epidemiology
Multimorbidity


Relationship between upper limb physical performance tests and muscle strength of scapular, shoulder and spine stabilizers: A cross-sectional study.

Abstract:
INTRODUCTION
Performance tests of the upper limb have been frequently used in the evaluation of individuals to identify risk of injury and to determine improvement in physical performance. Understanding the variables related to the performance of the tests is important for better applicability and interpretation of test results. The aim of this cross-sectional study was to investige the correlation between isometric strength of scapular, shoulder and spine muscles with physical performance test of upper limb in men and women.

EXPERIMENTAL
Forty-nine healthy and physically conditioned individuals, men (n = 24) (22,7 ± 3,2 years; 74,6 ± 8,1 Kg; 176,7 ± 7,1 cm) women (n = 25) (23 ± 2,7 years; 61,5 ± 9,1 Kg; 163,2 ± 5,6 cm), were evaluated for shoulder abductor isometric strength (S-ABD); Middle (MT) and lower (LT) trapezium; lateral shoulder rotators (S-LR); flexors (T-FLEX), lateral incliners (T-INCL), and trunk extenders (T-EXT). Evaluation of upper limb physical performance was carried out by Upper Quarter Y Balance test (YBT-UQ) and Chain upper extremity stability test (CKC-UEST). Pearson's test (r values) p ≤ 0.05 was used to analyze the correlation.

RESULTS
The results reveal strong correlations between S-ABD and CKC-UEST in male group; and strong correlations in female group between S-ABD strength with CKC-UEST; and S-LR with all YBT-UQ directions and score and between T-EXT strength with CKC-UEST.

CONCLUSION
Therefore, strength of shoulder and spine stabilizers influences performance in upper limb tests, but with different correlations as to sex. To improve test performance, it may be important to increase the strength of the shoulder and spine muscles.

Guirelli|Agnes Ramos|AR|
Dos Santos|Júlia Maria|JM|
Cabral|Estêvão Mállon Gomes|EMG|
Pinto|João Pedro Camilo|JPC|
De Lima|Gabriel Alves|GA|
Felicio|Lilian Ramiro|LR|

Upper limb
Spine
YBT-UQ
Dynamometry
Muscle strength CKC-UEST


Minimally invasive surgery procedure in isthmic spondylolisthesis.

Abstract:
PURPOSE
The aim of the study was to evaluate the efficacy and safety of the direct lateral approach to the lumbar spine in the treatment of painful isthmic spondylolisthesis in adults.

METHODS
Twenty-one patients affected by isthmic spondylolisthesis and treated with extreme lateral interbody fusion and posterior percutaneous pedicle screw fixation were enrolled. All included patients were clinically evaluated with Oswestry Disability Index, SF36 and Visual Scale Anatomy (VAS) for back pain at 1, 3 months and at 1 year.

RESULTS
The mean correction of vertebral slippage measured on lateral lumbar X-ray was 56.3% (p = 0.002). The average preoperative VAS score was 7.1, at 1 year decreasing to 2.2 (p = 0.001). The patients had an average preoperative "Oswestry Disability Index" of 36.8 and 24.1% after 1 year (p = 0.02). The preoperative Short-Form 36 Physical Health was equal to 33.8, 72.1% after 1 month, to 76.3% after 3 months and to 83.2% (p = 0.001) after 1 year of follow-up. There were no signs of implant loosening at 1-year CT scan examination in any of the patients.

CONCLUSION
The study showed that the extreme lateral approach to the lumbar spine in case of isthmic spondylolisthesis is a reliable and safe option to the most common open procedures. In the authors' opinion, XLIF procedures allow a good correction of the listhesis associated with good clinical and radiographic results. These slides can be retrieved under Electronic supplementary material.

Tamburrelli|Francesco Ciro|FC|
Meluzio|Maria Concetta|MC|
Burrofato|Aaron|A|
Perna|Andrea|A|
Proietti|Luca|L|

D019060:Minimally Invasive Surgical Procedures

Isthmic spondylolisthesis
Extreme lateral interbody fusion
XLIF
MIS
Spondylolysis


Optic neuritis in pregnancy after Tdap vaccination: Report of two cases.

Abstract: Two pregnant women developed one-eye blurring vision within three weeks after Tdap vaccination. Neurophtalmologic and MR examination confirmed an unilateral optic neuritis without evidence of underlying disease. Both patients had a full recovery, one after intravenous metilprednisolone. This is the first report of optic neuritis related with Tdap vaccination in pregnancy.

Cabrera-Maqueda|Jose M|JM|
Hernández-Clares|Rocio|R|
Baidez-Guerrero|Ana E|AE|
Pío-Rendón|Julian Ignacio Bermúdez|JIB|
Fernández|Jose J Martín|JJM|

Tdap vaccination
Pertussis vaccination
Postvaccination optic neuritis


Cryptic diversity and phylogeography of the Rhabdophis nuchalis group (Squamata: Colubridae).

Abstract: Previous studies, have found that the rapid uplift of the Tibetan plateau accelerated the diversification of species. However, there are few relevant biogeographic data for the Colubridae in this region. We conducted a comprehensive study of the Rhabdophis nuchalis Group, which presently contains four nominal species, R. nuchalis, R. pentasupralabialis, R. leonardi, and R. chiwen. Building upon previous studies with specimens we have recently examined, greater interspecific and intraspecific diversity has been revealed. Here we address three questions: (1) Do the intraspecific differences represent only geographic variation within lineages, or are there cryptic species? (2) What are the interspecific relationships among members of the R. nuchalis Group? (3) What has been the biogeographic history of this species group? To resolve these questions we used four mitochondrial gene sequences and one nuclear sequence to investigate the molecular phylogenetic and geographic relationships among populations. Our molecular analysis reveals cryptic species diversity within the R. nuchalis Group, and seven clades were identified in the analysis. Ancestral area estimation suggests that the R. nuchalis Group originated in the Hengduan Mountains approximately 6.24 Mya and expanded its range northward to the Qinling-Daba Mountains. The Sichuan Basin appears to have been a barrier to migration. Species divergence seems to have been related to the rapid uplift of the Qinghai-Tibet Plateau.

Zhu|Guangxiang|G|
Yang|Shijun|S|
Savitzky|Alan H|AH|
Cheng|Yuqi|Y|
Mori|Akira|A|
Ding|Li|L|
Rao|Dingqi|D|
Wang|Qin|Q|

Rapid uplift
Qinghai-Tibet Plateau
Classification
Genetic diversity
Natricinae
Snake


Genomic characterization of SARS-CoV-2 isolates from patients in Turkey reveals the presence of novel mutations in spike and nsp12 proteins.

Abstract: Novel mutations have been emerging in the genome of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2); consequently, the evolving of more virulent and treatment resistance strains have the potential to increase transmissibility and mortality rates. The characterization of full-length SARS-CoV-2 genomes is critical for understanding the origin and transmission pathways of the virus, as well as identifying mutations that affect the transmissibility and pathogenicity of the virus. We present an analysis of the mutation pattern and clade distribution of full-length SARS-CoV-2 genome sequences obtained from specimens tested at Gazi University Medical Virology Laboratory. Viral RNA was extracted from nasopharyngeal specimens. Next-generation sequencing libraries were prepared and sequenced on Illumina iSeq 100 platform. Raw sequencing data were processed to obtain full-length genome sequences and variant calling was performed to analyze amino acid changes. Clade distribution was determined to understand the phylogenetic background in relation to global data. A total of 293 distinct mutations were identified, of which 152 missense, 124 synonymous, 12 noncoding, and 5 deletions. The most frequent mutations were P323L (nsp12), D614G (ORF2/S), and 2421C>T (5'-untranslated region) found simultaneously in all sequences. Novel mutations were found in nsp12 (V111A, H133R, Y453C, M626K) and ORF2/S (R995G, V1068L). Nine different Pangolin lineages were detected. The most frequently assigned lineage was B.1.1 (17 sequences), followed by B.1 (7 sequences) and B.1.1.36 (3 sequences). Sequence information is essential for revealing genomic diversity. Mutations might have significant functional implications and analysis of these mutations provides valuable information for therapeutic and vaccine development studies. Our findings point to the introduction of the virus into Turkey through various sources and the subsequent spread of several key variants.

Sahin|Erdem|E|0000-0002-1389-3253
Bozdayi|Gulendam|G|0000-0002-6036-6819
Yigit|Selin|S|
Muftah|Hager|H|
Dizbay|Murat|M|
Tunccan|Ozlem G|OG|
Fidan|Isil|I|
Caglar|Kayhan|K|

D000086422:Coronavirus RNA-Dependent RNA Polymerase

SARS-CoV-2
Turkey
next-generation sequencing
full-length genome
mutation analysis
phylogenetic tree


The pharmacokinetics, pharmacodynamics and tolerability of PUR0200, a novel tiotropium formulation, in chronic obstructive pulmonary disease.

Abstract:
AIMS
PUR0200 is a tiotropium bromide formulation engineered with the iSPERSE dry powder delivery technology. PUR0200 is being developed as a bioequivalent alternative to tiotropium bromide, delivered using Spiriva® HandiHaler® (HH). We investigated the bronchodilator effects, pharmacokinetics and safety of PUR0200 in patients with chronic obstructive pulmonary disease (COPD).

METHODS
This was a randomized, placebo-controlled, crossover study using different PUR0200 doses and the comparator tiotropium HH. In vitro aerodynamic particle size distribution (aPSD) characterization of PUR0200 and tiotropium HH are presented. The main endpoints included forced expiratory volume in 1 s (FEV1 ) trough and (0-24 h) and pharmacokinetic parameters.

RESULTS
The increased fine-particle fraction of PUR0200 demonstrated by testing using the next-generation impactor increased the proportion of drug available for lung deposition compared with the tiotropium HH. There was a numerical dose-response effect for PUR0200 on FEV1 , with 3 μg demonstrating a lower effect than higher doses. The placebo-adjusted mean (95% confidence interval) increases from baseline at 24 h postdose were 150 ml (100-200), 210 ml (160-270) and 200 ml (140-250) for 3 μg, 6 μg and 9 μg doses of PUR0200, respectively. Tiotropium HH (18 μg) caused a mean 169 ml (standard deviation 157ml) improvement in trough FEV1 , which was not significantly different to the PUR0200 effects at any of the tested doses.

CONCLUSIONS
PUR0200 treatment caused bronchodilation in COPD patients that was similar in magnitude to that caused by tiotropium HH. This enabled a similar clinical effect on lung function to be achieved with PUR0200 using a lower metered dose of tiotropium compared with tiotropium HH.

Singh|Dave|D|0000-0001-8918-7075
Ravi|Arjun|A|
Kane|Katie|K|
Schmalbach|Tess|T|
Hava|David L|DL|

D029424:Pulmonary Disease, Chronic Obstructive


Electrophysiological correlates of visual attention span in Chinese adults with poor reading fluency.

Abstract: Individuals with reading fluency difficulty (RFD) show an impairment in the simultaneous processing of multiple elements, which could be reflected in their visual attention span (VAS) capacity. However, the relationship between VAS impairment and RFD is still controversial. A series of processes underlie VAS, such as the early stage of visual attentional processing and the late stage of allocating and maintaining attentional resources. Therefore, the present study explored the relationships between VAS skills and RFD through the event-related potential (ERP) technique to disentangle the contributing cognitive processes regarding VAS from a temporal perspective. Eighteen Chinese adults with poor reading fluency and 18 age-matched normal readers participated. Their VAS skills were measured by a visual one-back task with symbols as nonverbal stimuli and key pressing as nonverbal responses, while relevant electrophysiological signals were recorded. The results showed that lower d' values and abnormal electrophysiological activities (especially weak amplitudes in the N1 and P3 components) in the VAS task were observed for the nonfluent readers compared with the controls. These findings suggested that the low VAS capacity in adults with poor reading fluency could be reflected by problems both in directing selective attention to visually discriminate stimuli within a multielement string at the early processing stage and in allocating attention to further encode targets at the late processing stage. Alternative explanations were further discussed. The current results provide theoretical explanations of the VAS-RFD relationship from a temporal perspective and provide insights for future remediation of reading fluency difficulty.

Visual attention span
Chinese adult
Reading fluency difficulty
Event-related potentials (ERPs)


Feeding alters blood flow patterns in the American alligator (Alligator mississippiensis).

Abstract: The crocodilian cardiovascular design with a four-chambered heart and a left aorta that emerge from the right ventricle allows blood to be shunted away from the lungs, a right-to-left (R-L) shunt. The adaptive significance of this R-L shunt remains both poorly understood and controversial with particular debate on its putative role during digestion. Here we measure blood flow patterns in the right aorta (RAo), left aorta (LAo) and the coeliac artery (CoA) of undisturbed American alligators (Alligator mississippiensis) during fasting and throughout most of the digestive period. Digestion doubled blood flow in the RAo (10.1±0.9 to 20.7±1.5mlmin-1kg-1), whereas LAo increased approximately 3-fold (3.8±0.6 to 12.2±2.1mlmin-1kg-1). Blood flow in the CoA increased more than four-fold during digestion (3.0±0.6 to 13.3±1.6mlmin-1kg-1). The rise in blood flows was achieved by a doubling of heart rate (18.5±3.3 to 37.8±3.6mlmin-1kg-1). Maximal flows measured in all arteries and heart rate occurred in the first hour of the postprandial period and continued for the next 7h.

Findsen|Anders|A|
Crossley|Dane A|DA|
Wang|Tobias|T|

D000824:Animal Nutritional Physiological Phenomena

Left aorta
Digestion
Right aorta
Coeliac artery
Postprandial


MHJ_0461 is a multifunctional leucine aminopeptidase on the surface of Mycoplasma hyopneumoniae.

Abstract: Aminopeptidases are part of the arsenal of virulence factors produced by bacterial pathogens that inactivate host immune peptides. Mycoplasma hyopneumoniae is a genome-reduced pathogen of swine that lacks the genetic repertoire to synthesize amino acids and relies on the host for availability of amino acids for growth. M. hyopneumoniae recruits plasmin(ogen) onto its cell surface via the P97 and P102 adhesins and the glutamyl aminopeptidase MHJ_0125. Plasmin plays an important role in regulating the inflammatory response in the lungs of pigs infected with M. hyopneumoniae. We show that recombinant MHJ_0461 (rMHJ_0461) functions as a leucine aminopeptidase (LAP) with broad substrate specificity for leucine, alanine, phenylalanine, methionine and arginine and that MHJ_0461 resides on the surface of M. hyopneumoniae. rMHJ_0461 also binds heparin, plasminogen and foreign DNA. Plasminogen bound to rMHJ_0461 was readily converted to plasmin in the presence of tPA. Computational modelling identified putative DNA and heparin-binding motifs on solvent-exposed sites around a large pore on the LAP hexamer. We conclude that MHJ_0461 is a LAP that moonlights as a multifunctional adhesin on the cell surface of M. hyopneumoniae.

Jarocki|Veronica M|VM|
Santos|Jerran|J|
Tacchi|Jessica L|JL|
Raymond|Benjamin B A|BB|
Deutscher|Ania T|AT|
Jenkins|Cheryl|C|
Padula|Matthew P|MP|
Djordjevic|Steven P|SP|

D000595:Amino Acid Sequence
D000596:Amino Acids
D001426:Bacterial Proteins
D001665:Binding Sites
D006493:Heparin
D007931:Leucyl Aminopeptidase
D008565:Membrane Proteins
D008969:Molecular Sequence Data
D045705:Mycoplasma hyopneumoniae
D010958:Plasminogen
D011485:Protein Binding
D013379:Substrate Specificity

leucine aminopeptidase
adhesin
DNA-binding protein
heparin-binding protein
moonlighting protein
plasminogen-binding protein


Influence of colony traits on ectoparasite infestation in birds breeding in mixed-species colonies.

Abstract: Coloniality in birds is often associated with an increase in parasite burden, but whether the co-occurrence of several host species influences the prevalence and abundance of ectoparasites and their relationship with colony size or density remains poorly known. Here, we studied mixed-species breeding colonies formed after the provision of artificial breeding structures for restoring the lesser kestrel (Falco naumanni) population in Portugal, to investigate the influence of colony traits on ectoparasite infestation. We sampled four groups of ectoparasites (carnid flies, haematophagous mites, louse flies and chewing lice) in four hosts: lesser kestrels, European rollers (Coracias garrulus), feral pigeons (Columba livia) and spotless starlings (Sturnus unicolor). Each host species had a distinct infracommunity of ectoparasites, regardless of colony traits such as size, density or host richness. The abundance of the most common ectoparasite, Carnus hemapterus, was influenced by colony composition – number of nests of each host species – rather than by colony size or density, with its abundance being diluted with increasing numbers of less suitable hosts such as starlings. The increased contact between multiple species of hosts in breeding colonies may complexify host–parasite interactions and challenge our current knowledge on the ecological relationships between host sociality and parasitism.

haematophagous mites
louse flies
chewing lice
Carnus hemapterus
host–parasite interaction
dilution effect


Misdiagnosis of Myasthenia Gravis and Subsequent Clinical Implication: A case report and review of literature.

Abstract: The autoimmune disease, myasthenia gravis (MG), can mimic a variety of neurological disorders leading to a delay in diagnosis and treatment. On occasions, misdiagnosis of MG could lead to unnecessary and potentially harmful therapeutic interventions. We report on a 12 year-old boy, in whom MG was mistaken for meningitic sequelae and subsequently for critical neuropathy/myopathy resulting in considerable morbidity for nearly a decade. Subsequent correct diagnosis and optimal management resulted in significant improvement in his functional status. We discuss the importance of considering MG as one of the potential differential diagnoses among cases of recurrent respiratory pump failure, or unexplained bulbar symptoms where documentary proof of the previous diagnoses including work-up for MG is lacking. We also review the literature on MG misdiagnosis and highlight the potential pitfalls in MG diagnosis.

Al-Asmi|Abdullah|A|
Nandhagopal|Ramachandiran|R|
Jacob|P C|PC|
Gujjar|Arunodaya|A|

Myasthenia gravis
Case report
Bulbar palsy
Meningitis, sequelae
Oman
Pneumonia


Toxoplasma ROP16I/III ameliorated inflammatory bowel diseases via inducing M2 phenotype of macrophages.

Abstract:
BACKGROUND
Inflammatory bowel disease (IBD) is characterized by chronic and non-specific inflammation of the intestinal mucosa and mainly includes ulcerative colitis and Crohn's disease.

AIM
To explore the beneficial effect of ToxoROP16I/III-induced M2 phynotype macrophages in homeostasis of IBDs through downregulation of M1 inflammatory cells.

METHODS
RAW264.7 macrophages stimulated by lipopolysaccharide (LPS) (M1 cells) were co-cultured with Caco-2 cells as an inflammatory model of IBD in vitro. The expression of ToxoROP16I/III was observed in RAW264.7 macrophages that were transfected with pEGFP-rop16 I/III. The phenotypes of M2 and M1 macrophage cells were assessed by quantitative real-time reverse transcriptase polymerase chain reaction and the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, transforming growth factor (TGF)-β1, IL-10, inducible nitric oxide synthase (iNOS), and arginase-1 (Arg-1) was detected. The expression of iNOS, Arg-1, signal transducer and activator of transcription 3 (Stat3), p-Stat3, Stat6, p-Stat6, programmed death ligand-2 (PD-L2), caspase-3, -8, and -9 was analyzed by Western blotting, and Griess assays were performed to detect nitric oxide (NO). TNF-α, IL-1β, IL-6, TGF-β1, and IL-10 expression in the supernatants was detected by enzyme-linked immunosorbent assay, and Caco-2 cell apoptosis was determined by flow cytometry after mixing M1 cells with M2 cells in a Caco-2 cell co-culture system.

RESULTS
M1 cells exhibited significantly increased production of iNOS, NO, TNF-α, IL-1β, and IL-6, while ToxoROP16I/III induced macrophage bias to M2 cells in vitro, showing increased expression of Arg-1, IL-10 and TGF-β1 and elevated production of p-Stat3 and p-Stat6. The mixed M1 and M2 cell culture induced by ToxoROP16I/III exhibited decreased production of NO and iNOS and upregulated expression of Arg-1 and PD-L2. Accordingly, Caco-2 cells became apoptotic, and apoptosis-associated proteins such as caspase-3, -8 and -9 were dampened during co-culture of M1 and M2 cells. Flow cytometry analysis showed that co-culture of M1 cells with Caco-2 cells facilitated the apoptosis of Caco-2 cells, but co-culture of M1 and M2 cells alleviated Caco-2 cell apoptosis.

CONCLUSION
ToxoROP16I/III-induced M2 macrophages inhibited apoptosis of Caco-2 cells caused by M1 macrophages. This finding may help gain a better understanding of the underlying mechanism and represent a promising therapeutic strategy for IBDs.

Xu|Yong-Wei|YW| Xing|Rui-Xin|RX| Zhang|Wen-Hui|WH| Li|Lu|L| Wu|Yi|Y| Hu|Jing|J| Wang|Cong|C| Luo|Qing-Li|QL| Shen|Ji-Long|JL| Chen|Xi|X|

Toxoplasma ROP16I/III
Inflammatory bowel disease
Caco-2
Alternatively activated macrophages
Classically activated macrophages
Immunity


Early Graft Dysfunction in Living Donor Liver Transplantation and the Small for Size Syndrome.

Abstract: LDLT has arisen as a viable means to reduce waitlist mortality. However, its widespread embrace by the liver transplant community has been met with frustration centered on donor morbidity and small-for-size-syndrome. Focusing on the later entity, we describe the initial recognition of this early graft dysfunction, the theorized pathophysiology and solutions to remedy its emergence.

Graham|Jay A|JA|
Samstein|Benjamin|B|
Emond|Jean C|JC|

early graft dysfunction
living donor
Liver
transplantation
small-for-size-syndrome
portal hypertension