bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterisation of heterogeneous microstructure in large forged products using nonlinear ultrasonic method
Authors: Abraham Saju T. , Shivaprasad S. , Das C.R. , Albert S. K. , Venkatraman B. , Balasubramaniam Krishnan
Published: February 2020

A comparative study between the ultrasonic attenuation and the nonlinearity is presented for the characterisation of microstructure in large dimension forgings. Results are provided for two austenitic stainless steel forgings of AISI type 304L with a diameter 200 mm, where microscopic observations reveal abnormal grain growth near the surface of one of the forgings. Frequency dependence of the nonlinearity parameter is used to discern variations in grain size in these forgings more precisely than attenuation measurements. The distribution of grain size is shown to have a significant influence on the nonlinearity parameter. Relative changes in the nonlinearity parameter with applied frequency were correlative with the microstructural variations in both the forgings.
In vivo stress granule misprocessing evidenced in a FUS knock-in ALS mouse model
Authors: Zhang Xue , Wang Fengchao , Hu Yi , Chen Runze , Meng Dawei , Guo Liang , Lv Hailong , Guan Jisong , Jia Yichang
Published: February 2020

Many RNA-binding proteins, including TDP-43, FUS, and TIA1, are stress granule components, dysfunction of which causes amyotrophic lateral sclerosis (ALS). However, whether a mutant RNA-binding protein disrupts stress granule processing in vivo in pathogenesis is unknown. Here we establish a FUS ALS mutation, p.R521C, knock-in mouse model that carries impaired motor ability and late-onset motor neuron loss. In disease-susceptible neurons, stress induces mislocalization of mutant FUS into stress granules and upregulation of ubiquitin, two hallmarks of disease pathology. Additionally, stress aggravates motor performance decline in the mutant mouse. By using two-photon imaging in TIA1-EGFP transduced animals, we document more intensely TIA1-EGFP-positive granules formed hours but cleared weeks after stress challenge in neurons in the mutant cortex. Moreover, neurons with severe granule misprocessing die days after stress challenge. Therefore, we argue that stress granule misprocessing is pathogenic in ALS, and the model we provide here is sound for further disease mechanistic study.
A Systematic Review and Meta-analysis of Paediatric Inflammatory Bowel Disease Incidence and Prevalence Across Europe
Authors: Roberts S E , Thorne K , Thapar N , Broekaert I , Benninga M A , Dolinsek J , Mas E , Miele E , Orel R , Pienar C , Ribes-Koninckx C , Thomson M , Tzivinikos C , Morrison-Rees S , John A , Williams J G
Published: February 2020

Background and Aims

Inflammatory bowel disease [IBD] is often one of the most devastating and debilitating chronic gastrointestinal disorders in children and adolescents. The main objectives here were to systematically review the incidence and prevalence of paediatric IBD across all 51 European states.

Methods

We undertook a systematic review and meta-analysis based on PubMed, CINAHL, the Cochrane Library, searches of reference lists, grey literature and websites, covering the period from 1970 to 2018.

Results

Incidence rates for both paediatric Crohn’s disease [CD] and ulcerative colitis [UC] were higher in northern Europe than in other European regions. There have been large increases in the incidence of both paediatric CD and UC over the last 50 years, which appear widespread across Europe. The largest increases for CD have been reported from Sweden, Wales, England, the Czech Republic, Denmark and Hungary, and for UC from the Czech Republic, Ireland, Sweden and Hungary. Incidence rates for paediatric CD have increased up to 9 or 10 per 100 000 population in parts of Europe, including Scandinavia, while rates for paediatric UC are often slightly lower than for CD. Prevalence reported for CD ranged from 8.2 per 100 000 to approximately 60 and, for UC, from 8.3 to approximately 30.

Conclusions

The incidence of paediatric IBD continues to increase throughout Europe. There is stronger evidence of a north–south than an east–west gradient in incidence across Europe. Further prospective studies are needed, preferably multinational and based on IBD registries, using standardized definitions, methodology and timescales.
Spatial architecture of tumour-infiltrating lymphocytes as a prognostic parameter in resected non-small-cell lung cancer
Authors: Bocchialini Giovanni , Lagrasta Costanza , Madeddu Denise , Mazzaschi Giulia , Marturano Davide , Sogni Francesco , Silini Enrico Maria , Gnetti Letizia , Becchi Gabriella , Rusca Michele , Carbognani Paolo , Ventura Luigi , Braggio Cesare , Tiseo Marcello , Quaini Federico , Ampollini Luca
Published: February 2020

OBJECTIVES

Tumour-infiltrating lymphocytes (TILs) are critically implicated in the clinical outcome and response to immunotherapy in non-small-cell lung cancer (NSCLC) patients. The functional competence of lymphocyte subpopulations is strongly conditioned by their spatial arrangement within the tumour immune microenvironment. The aim of this study was to determine whether the tissue localization of specific TIL subpopulations might have an impact on the risk of recurrence in surgically resected NSCLC.

METHODS

High-speed scanning of whole slide images was performed on immunohistochemically stained tissue sections from 97 NSCLC patients to assess the number and ratio of CD3+, CD8+ and PD-1+ T-lymphocytes. TIL distribution was computed considering the intratumoural (proximal or distal) and peripheral (invasive margin) localization as well as their location within the fibrotic tissue (immune excluded). The tumour proliferative index was assessed by Ki67 labelling. The impact of TILs number and distribution on clinical-pathological characteristics and outcomes were statistically analysed.

RESULTS

High density and percentage of proximal CD8+ TILs and low PD-1-to-CD8 ratio had a positive impact on disease-free-survival (P = 0.03) and overall survival (P = 0.003). An inverse correlation was observed between the abundance of intratumoural CD8+ TILs carrying PD-1 inhibitory receptor and cancer cell proliferation. Cases with high compared to low fraction of immune excluded CD8+ TILs had significantly reduced 5-year overall survival (n events: 22 vs 12; P = 0.04) and disease-free survival (n events: 24 vs 16; P = 0.03) rates while the amount of CD3+ and CD8+ TILs located at the invasive margin had a favourable effect on the clinical course.

CONCLUSIONS

Mapping TIL subpopulations may implement the definition of prognostic parameters in surgically resected NSCLC.
Distinct mechanisms shape soil bacterial and fungal co-occurrence networks in a mountain ecosystem
Authors: Li Jiabao , Li Chaonan , Kou Yongping , Yao Minjie , He Zhili , Li Xiangzhen
Published: February 2020

Understanding microbial network assembly is a promising way to predict potential impacts of environmental changes on ecosystem functions. Yet, soil microbial network assembly in mountain ecosystems and its underlying mechanisms remain elusive. Here, we characterized soil microbial co-occurrence networks across 12 altitudinal sites in Mountain Gongga. Despite differences in habitats, soil bacterial networks separated into two different clusters by altitude, namely the lower and higher altitudes, while fungi did not show such a pattern. Bacterial networks encompassed more complex and closer relationships at the lower altitudes, while fungi had closer relationships at the higher altitudes, which could be attributed to niche differentiation caused by high variations in soil environments and plant communities. Both abiotic and biotic factors (e.g. soil pH and bacterial community composition) shaped bacterial networks. However, biotic factors played more important roles than the measured abiotic factors for fungal network assembly. Further analyses suggest that multiple mechanisms including niche overlap/differentiation, cross-feeding and competition between microorganisms could play important roles in shaping soil microbial networks. This study reveals microbial co-occurrence networks in response to different ecological factors, which provides important insights into our comprehensive understanding of microbial network assembly and their functional potentials in mountain ecosystems.
Biofilms: hot spots of horizontal gene transfer (HGT) in aquatic environments, with a focus on a new HGT mechanism
Authors: Abe Kimihiro , Nomura Nobuhiko , Suzuki Satoru
Published: February 2020

Biofilms in water environments are thought to be hot spots for horizontal gene transfer (HGT) of antibiotic resistance genes (ARGs). ARGs can be spread via HGT, though mechanisms are known and have been shown to depend on the environment, bacterial communities and mobile genetic elements. Classically, HGT mechanisms include conjugation, transformation and transduction; more recently, membrane vesicles (MVs) have been reported as DNA reservoirs implicated in interspecies HGT. Here, we review the current knowledge on the HGT mechanisms with a focus on the role of MVs and the methodological innovations in the HGT research.
Aesthetic Elisions: The Ruins of Palmyra and the “Good Life” of Liberal Multiculturalism
Authors: Kalaycioglu Elif
Published: February 2020

Palmyra's capture and destruction by ISIS resonated widely with an international audience. Drawing on Lefebvre's theory of the production of space and affect theory's key insights on object attachment, this article argues that the attachment to Palmyra manifests desire for a particular “good life” of an idealized liberal multiculturalism: a virtuous cycle of trade and tolerance represented by aesthetic flourishing. This widely circulated representation is grounded on excisions of power and inequality. I analyze the political stakes of such excision through the invisibility of Tadmor, positioned as a neighboring town rather than an afterlife of Palmyra in this representation. Through Tadmor, we see Palmyra as entangled in economic inequality and consolidation of power and complicit in their elision through its aesthetic representation as a multicultural haven. At stake is the question of what it means to attach the desire for coexistence to this representation of Palmyra at the detriment of places like Tadmor. While this paper makes its key intervention into the affective terrain and limits of a current global political moment, my argument also contributes to discussions of the global production and circulation of affect, bringing into view its attachment to sites and spaces.
Terminological Entrepreneurs and Discursive Shifts in International Relations: How a Discipline Invented the “International Regime”
Authors: Steffek Jens , Müller Marcus , Behr Hartmut
Published: February 2020

The disciplinary history of international relations (IR) is usually told as a succession of theories or “isms” that are connected to academic schools. Echoing the increasing criticism of this narrative, we present in this article a new perspective on the discipline. We introduce concepts from linguistics and its method of digital discourse analysis (DDA) to explore discursive shifts and terminological entrepreneurship in IR. DDA directs attention away from schools of thought and “heroic figures” who allegedly invented new theories. As we show exemplarily with the rise of “regime theory,” there were entire generations of IR scholars who (more or less consciously) developed new vocabularies to frame and address their common concerns. The terminological history of “international regime” starts in nineteenth century international law, in which French authors already used “régime” to describe transnational forms of governance that were more than a treaty but less than an international organization. Only in the 1980s, however, was an explicit definition of “international regime” forged in American IR, which combined textual elements already in use. We submit that such observations can change the way in which we understand, narrate, and teach the discipline of IR. DDA decenters IR theory from its traditional focus on schools and individuals and suggests unlearning established taxonomies of “isms.” The introduction of corpus linguistic methods to the study of academic IR can thus provide new epistemological directions for the field.
Detection of Drugs in Oral Fluid Samples Using a Commercially Available Collection Device: Agreement with Urine Testing and Evaluation of A and B Samples Obtained from Employees at Different Workplace Settings with Uncontrolled Sampling Procedures
Authors: Zheng Yufang , Sparve Erik , Sparring Stefan , Bergström Mats
Published: February 2020

The use of oral fluid tests to detect drugs is of growing interest in various areas, including treatment centers, roadside and workplace testing. In this study, we investigated drug detection in oral fluid samples collected using a commercially available device, Oral Eze. Drug detection in oral fluid was compared to paired urine samples, which were simultaneously collected. We also evaluated the collection device by comparing A and B oral fluid samples. Finally, we studied the stability of various drugs in samples stored for at least 1 year. The drug profile was investigated by comparing the drugs detected in oral fluid samples with paired urine samples collected in a treatment center. A total of 113 paired oral fluid and urine samples were investigated for the presence of drugs in the following groups: amphetamines, benzodiazepines, opiates and opioids, cocaine and cannabis. A and B samples were collected from different workplaces through an uncontrolled sampling procedure (n = 76). The stability of drugs in A samples was assessed after storage at −20°C for 1 year. Generally, there was a good correlation between drugs detected in oral fluid samples and urine samples. The heroin metabolite, 6-MAM, was more frequently detected in oral fluid samples than in urine samples, while cannabis was better detected in urine samples. Drugs in oral fluid samples were stable when stored at −20°C for at least 1 year. However, in many positive A and B oral fluid samples, there was significant variation in the concentrations obtained. Hence, the collection device may need to be further standardized and improved.
Evidence of Natural GHB Presence in Energy Drinks: Caution in Data Interpretation in Suspected DFSA Cases
Authors: Vaiano Fabio , Ronchi Federica Umani
Published: February 2020

Gamma-hydroxybutyric acid (GHB), usually reported as rape drug in drug-facilitated sexual assaults (DFSA), is an endogenous substance in human body and is also found in many beverages. This may lead to data misinterpretation in forensic cases. Herein, we aimed to collect evidence about natural GHB presence in 13 energy drinks (ED). After a liquid–liquid extraction with acidic ethyl acetate, samples were derivatized with BSTFA 1% TMCS. Analyses were carried out by a GC–MS system in SIM mode (GHB, 233, 234, 143 and 147 m/z; GHB-d6, 239, 240, 120 and 206 m/z). GHB was present in all the samples at very low concentrations ranging from 98 to 197 ng/mL. Thus, GHB presence in ED is not exclusively related to exogenous addition. Since the GHB levels are far lower than the minimum active dose (i.e., 0.5 g), it is not expected to induce any effect.
PD-L1 expression and response to pembrolizumab in patients with EGFR-mutant non-small cell lung cancer
Authors: Miyawaki Eriko , Murakami Haruyasu , Mori Keita , Mamesaya Nobuaki , Kawamura Takahisa , Kobayashi Haruki , Omori Shota , Wakuda Kazushige , Ono Akira , Kenmotsu Hirotsugu , Naito Tateaki , Takahashi Toshiaki
Published: February 2020

Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer is less likely to express programmed death-ligand 1 (PD-L1) than tumors with wild-type EGFR and is associated with poor response to pembrolizumab. To understand the relationship between EGFR mutation and PD-L1 expression in pembrolizumab response, we retrospectively evaluated the factors contributing to the high tumor proportion score in 155 EGFR-mutant non-small cell lung cancer cases and their associated response to pembrolizumab. Uncommon EGFR mutations were significantly associated with a PD-L1 tumor proportion score ≥ 50% compared to common EGFR mutations. The objective response rate to pembrolizumab of 14 patients was 36%, including 22% in patients with common EGFR mutations, 60% in patients with uncommon EGFR mutations and 75% in patients with both uncommon mutations and a PD-L1 tumor proportion score ≥ 50%. A PD-L1 tumor proportion score ≥ 50% was more frequent in non-small cell lung cancer patients harboring uncommon EGFR mutations and was associated with pembrolizumab efficacy.
Evaluation of different blends of medium-chain fatty acids, lactic acid, and monolaurin on nursery pig growth performance12
Authors: Thomas Lori L , Woodworth Jason C , Tokach Mike D , Dritz Steve S , DeRouchey Joel M , Goodband Robert D , Williams Hayden E , Hartman Ashley R , Mellick Dillon J , McKilligan Denny M , Jones Aaron M
Published: February 2020

A total of 710 pigs (Line 400 × 200, DNA, Columbus, net energy (NE)) were used in two experiments (Exp. 1: initially, 6.3 ± 0.05 kg; Exp. 2: initially, 6.8 ± 0.05 kg) to evaluate the effects of two medium-chain fatty acid (MCFA) based products on nursery pig growth performance. Following their arrival at the nursery facility, pigs were randomized to pens (five pigs per pen) and allowed a 4-d acclimation period. Thereafter, pens of pigs were blocked by initial weight and randomized to dietary treatment. In Exp. 1, the dietary treatments were a dose titration of: 0%, 0.5%, 1.0%, or 2.0% MCFA-based additive, as well as a diet including 1.0% MCFA from a 1:1:1 blend of C6:0, C8:0, and C10:0. In Exp.2, dietary treatments consisted of a basal diet containing no MCFA (control), the control diet with a 1.0% inclusion of four different blends of MCFA, lactic acid, and monolaurin or a diet with 1.0% added MCFA (a 1:1:1 blend of C6:0, C8:0, and C10:0). The four blends consisted of 50% C6:0, 20% lactic acid, and increasing levels of monolaurin (0%, 10%, 20%, and 30%) at the expense of C12:0 (30%, 20%, 10%, and 0%). Treatment diets were formulated and manufactured in two dietary phases. Data were analyzed as a randomized complete block design with pen as the experimental unit. In Exp. 1, overall (days 0–34), increasing CaptiSURE increased (linear, P ≤ 0.014) average daily gain (ADG) and average daily feed intake (ADFI). Feed efficiency improved (quadratic, P = 0.002) with increasing CaptiSURE up to 1.0% of the diet with no benefit thereafter. There was no evidence for differences between pigs fed 1.0% CaptiSURE and pigs fed the 1.0% MCFA blend of C6:0, C8:0, and C10:0. In Exp. 2, overall (days 0–35), pigs fed the 1.0% 1:1:1 MCFA blend had increased (P < 0.034) ADFI and ADG resulting in 0.9 kg greater final weight (P = 0.014) compared with the control group. There was no evidence that the mean performance of pigs fed the four blends of MCFA, lactic acid, and monolaurin were different from the pigs fed the control diet. In summary, the addition of a 1.0% 1:1:1 blend of C6:0, C8:0, and C10:0 in nursery pig diets improved ADG, ADFI, and gain to feed ratio (G:F) compared with pigs fed the control diet. In addition, providing nursery pigs with the MCFA product CaptiSURE, up to 2% of the diet, resulted in linear improvements in ADG and ADFI. Altering the C12:0 to monolaurin ratio and adding lactic acid did not improve growth performance compared with pigs fed the control diet.
The Swollen Parotid Gland
Authors: Cohen-Addad Dan Isaac , Farooq Zerwa , Smoker Wendy , Reede Deborah L.
Published: February 2020

Several systemic diseases and local inflammatory processes can cause diffuse enlargement of the parotid gland. Clinical information regarding the patient's age, localization (including laterality), duration, clinical course of the disease, and presence of associated symptoms can aid in determining the diagnosis. CT and MRI features that help narrow the differential diagnosis include the appearance of the gland (homogeneous, single, or multiple masses); inflammatory changes in, or adjacent to, the parotid gland; pattern of disease spread to adjacent spaces; and the presence of lymphadenopathy. In some cases, imaging is used to monitor treatment response, progression of disease, and identify complications. Some of the diseases/conditions that produce diffuse enlargement of a parotid gland include Sjögren syndrome, sarcoidosis, IgG4 disease, benign lymphoepithelial lesions of HIV, sialolithiasis, sialosis, and Rosai-Dorfman syndrome.
Gut microbiota: closely tied to the regulation of circadian clock in the development of type 2 diabetes mellitus
Authors: Ding Lu , Xiao Xin-Hua
Published: February 2020

Type 2 diabetes mellitus (T2DM), a worldwide epidemic disease, has caused tremendous economic and social burden, but the pathogenesis remains uncertain. Nowadays, the impact of unrhythmic circadian clock caused by irregular sleep and unhealthy diet on T2DM has be increasingly studied. However, the contribution of the endogenous circadian clock system to the development of T2DM has not yet been satisfactorily explored. It is now becoming clear that the gut microbiota and the circadian clock interact with each other to regulate the host metabolism. Considering all these above, we reviewed the literature related to the gut microbiota, circadian clock, and T2DM to elucidate the idea that the gut microbiota is closely tied to the regulation of the circadian clock in the development of T2DM, which provides potential for gut microbiota-directed therapies to ameliorate the effects of circadian disruptions linked to the occurrence and development of T2DM.
Breast cancer immunology and immunotherapy: targeting the programmed cell death protein-1/programmed cell death protein ligand-1
Authors: Zhao Jing , Huang Jian
Published: February 2020

Historically, breast cancer has been regarded as an immunogenic “cold” tumor. However, the discovery of immune checkpoint inhibitors has made immunotherapy becoming an emerging new treatment modality for breast cancer. This review discusses the immune system, immune features of breast cancer, and the programmed cell death protein-1/programmed cell death protein ligand-1 (PD-1/PD-L1) inhibitors used in the treatment of breast cancer. High T lymphocyte infiltration and mutation burden were observed in triple-negative breast cancer and human epidermal growth factor receptor 2 positive breast cancer. Increasing breast cancer immunogenicity and modulating the tumor microenvironment has been reported to improve the therapeutic efficacy of immunotherapy. Recent clinical trials involving PD-1/PD-L1 inhibitors monotherapy in breast cancer has revealed little efficacy, which highlights the need to develop combinations of PD-1/PD-L1 inhibitors with chemotherapy, molecularly targeted therapies, and other immunotherapies to maximize the clinical efficacy. Collectively, the immunotherapy might be a promising therapeutic strategy for breast cancer and several clinical trials are still on-going.
Creating a Safe Space for Nursing Students' Spiritual Reflection
Authors: Briggs Crista L. , Lartey Grace , Eagle Susan
Published: February 2020

In an effort to improve students' comfort level and confidence with spiritual care, nursing faculty initiated a classroom activity to encourage students to think about and reflect upon 10 questions. Students responded by answering whether they had ever thought about the question being asked, then writing a short narrative response. Topics included issues about life, death, afterlife, spiritual well-being, truth, and God. Although 88.8% of participants (n = 107) considered themselves to be religious or spiritual, results revealed many had never thought about the questions being asked. Based on these findings, nurse educators should consider including a similar classroom reflection exercise to better prepare students for providing spiritual care prior to beginning clinical rotations.
Clinical Evaluation of 225 Sub-SMAS Facelifts with No Temporal Incision
Authors: Swanson Eric
Published: February 2020

Background:

Despite their name, “short scar” procedures leave scars in the temples and the postauricular scar often requires extension. Redraping the orbicularis muscle for periorbital rejuvenation increases the risk of facial nerve injury. This retrospective cohort study was undertaken to clinically evaluate a surgical approach that eliminates the temporal incision.

Methods:

A sub-superficial musculoaponeurotic system (SMAS) facelift was used, incorporating a triple-vector platysmaplasty and fat injection for periorbital rejuvenation. From 2009 to 2019, 225 consecutive outpatients underwent a sub-SMAS facelift with a triple-vector (superior, lateral, medial) platysmaplasty, either alone or in combination with fat injection, laser resurfacing, blepharoplasties, endoscopic forehead lift, and other cosmetic procedures. Release of the retaining ligaments optimized SMAS mobilization. A temporal incision was not used. Fat (mean volume 32 ml) was injected into the undissected subcutaneous tissue plane. The mean follow-up time was 28 months.

Results:

The most frequent complication was a neuropraxia (7.6%), usually affecting a frontal nerve branch, and always temporary. Two deep venous thromboses were detected by ultrasound surveillance. No significant correlation was detected between complications and age, sex, body mass index, smoking history, or a previous facelift. Sixteen patients (7%) returned for a secondary facelift (mean interval, 3.5 years).

Conclusions:

A sub-SMAS facelift and triple-vector platysmaplasty with fat injection combine effective neckline rejuvenation with facial volume restoration. Avoiding a temporal incision eliminates a telltale scar. Orbicularis preservation avoids additional dissection, possibly reducing the risk of neuropraxia. Fat injection provides a net increase in facial volume. Long-term measurement studies are recommended.
Clinical Significance of TARP Expression in Pediatric Acute Myeloid Leukemia
Authors: Depreter Barbara , De Moerloose Barbara , Vandepoele Karl , Uyttebroeck Anne , Van Damme An , Denys Barbara , Dedeken Laurence , Dresse Marie‐Françoise , Van der Werff Ten Bosch Jutte , Hofmans Mattias , Kerre Tessa , Vandekerckhove Bart , Philippé Jan , Lammens Tim
Published: February 2020

Supplemental Digital Content is available in the text
TOXICITY AND EFFICACY OF INTRAVITREAL MELPHALAN FOR RETINOBLASTOMA
Authors: Liao Albert , Hsieh Terry , Francis Jasmine H. , Lavery Jessica A. , Mauguen Audrey , Brodie Scott E. , Abramson David H.
Published: February 2020

Purpose:

To compare retinal toxicity as measured by electroretinogram, ocular, and patient survival in retinoblastoma treated with intravitreal melphalan at two concentrations (25 vs. 30 µg).

Methods:

Single-center, retrospective analysis of retinoblastoma eyes receiving 25-µg or 30-µg intravitreal melphalan from September 2012 to January 2019. Ocular toxicity was measured by electroretinogram of evaluable injections in 449 injections in 136 eyes. A repeated-measures linear mixed model with a random intercept and slope was applied to account for repeated measures for each eye.

Results:

Average decline in electroretinogram after each additional injection was −4.9 µV (95% confidence interval −6.3 to −3.4); electroretinogram declined by −4.6 µV (95% confidence interval −7.0 to −2.2) after 25-µg injections and −5.2 µV (95% confidence interval −6.6 to −3.8) after 30-µg injections (P = 0.66). Injection at a new clock site hour was associated with a −3.91-µV lower average (95% confidence interval −7.8 to −0.04).

Conclusion:

Electroretinogram-measured toxicity in retinoblastoma eyes treated with intravitreal injections was not found to be different across 25-µg and 30-µg injections. There were no cases of extraocular extension or metastatic deaths in our patient population.
A cohort-based comprehensive characterization of different patterns of very short-term, within-visit, blood pressure variability
Authors: Papaioannou Theodore G. , Protogerou Athanase D. , Stamatelopoulos Kimon S. , Alexandraki Krystallenia I. , Vrachatis Dimitrios , Argyris Antonios , Papaioannou Vasilios , Vavuranakis Manolis , Stefanadis Christodoulos , Tousoulis Dimitrios
Published: February 2020

Aim

To characterize different patterns of variability of three repeated within-visit blood pressure (BP) readings and to determine the prevalence of specific variation trends in systolic (SBP), diastolic (DBP) blood pressure and pulse pressure (PP).

Methods

Data from 53 737 subjects from the National Health and Nutrition Examination Survey were analyzed. In each subject, three consecutive BP measurements were performed with a minimum time-interval of at least 30 s. We propose three patterns of within-visit BP variability (separately for SBP, DBP and PP): (1) increasing trend (BP3 > BP2 > BP1); (2) decreasing trend (BP1 > BP2 > BP3) and (3) no trend (BP3 ≈ BP2 ≈ BP1). A threshold of minimum change (ΔP > 3 mmHg) between BP1-BP2 and BP2-BP3 was also applied as a prerequisite for the definition of these trends.

Results

An increasing trend was observed among three consecutive measurements of SBP, DBP and PP in 7.4, 10.4 and 10.2%, respectively. When a minimum threshold of 3 mmHg was set the respective increasing trends were observed in 1.8, 2.9 and 4.4%, respectively. There was a higher prevalence of decreasing trend within three consecutive SBP, DBP and PP readings: 17, 13.1 and 16.2%, respectively, whereas using a threshold of ΔP >3 mmHg the respective prevalence was 6.3, 4.1 and 7.7%. A maximum absolute difference >10 mmHg within triplicate of SBP/DBP/PP readings was observed in 12.9, 13 and 29.4%, respectively. In the era of personalized medicine, these patterns are well worth further investigation concerning their pathophysiologic and clinical relevance.
Transient receptor potential vanilloid 1 antagonism in neuroinflammation, neuroprotection and epigenetic regulation: potential therapeutic implications for severe psychiatric disorders treatment
Authors: Escelsior Andrea , Sterlini Bruno , Belvederi Murri Martino , Valente Pierluigi , Amerio Andrea , di Brozolo Manfredo Radicati , da Silva Beatriz Pereira , Amore Mario
Published: February 2020

Transient receptor potential vanilloid 1 (TRPV1) is a polymodal cation channel gated by a large array of chemical and physical stimuli and distributed across different brain regions on neuronal and glial cells. Preclinical studies indicate that TRPV1 might be a target for the treatment of anxiety, depression and addictive disorders. The aim of this narrative review is to focus on studies examining the effects of TRPV1 antagonism on neuroinflammation, neuroprotection and epigenetic regulation. Results suggest that TRPV1 modulation leads to pro- or anti-inflammatory effects depending on the cytokine environment and that the TRPV1 antagonism can switch the microglia towards an anti-inflammatory phenotype. Moreover, TRPV1 inhibitors have neuroprotective properties through the regulation of calcium levels. Finally, TRPV1 antagonism exerts regulatory effects on genes involved in synaptic and cognitive functions through histone deacetylase 2 inhibition. These findings highlight different mechanisms that may underlie the efficacy of TRPV1 antagonists in animal models of severe psychiatric disorders.
Whole-exome sequencing in a family with a monozygotic twin pair concordant for schizophrenia and a follow-up case-control study of identified de-novo variants
Authors: Hoya Satoshi , Watanabe Yuichiro , Nunokawa Ayako , Otsuka Ikuo , Shibuya Masako , Igeta Hirofumi , Hishimoto Akitoyo , Someya Toshiyuki
Published: February 2020

Whole-exome sequencing (WES) studies have shown that de-novo variants contribute to the genetic etiology of schizophrenia. WES studies of families with a monozygotic twin pair concordant or discordant for a disease may be fruitful for identifying de-novo pathogenic variants. Here, we performed WES in six individuals from one family (affected monozygotic twins, their unaffected parents, and two siblings) and identified three de-novo missense variants (CPT2 Ala283Thr, CPSF3 Val584Ile, and RNF148 Val210Ile) in the monozygotic twin pair concordant for schizophrenia. These three missense variants were not found in 1760 patients with schizophrenia or schizoaffective disorder or 1508 healthy controls. Our data do not support the role of the three missense variants in conferring risk for schizophrenia.
TWIRLS, an automated topic-wise inference method based on massive literature, suggests a possible mechanism via ACE2 for the pathological changes in the human host after coronavirus infection
Authors: Ji Xiaoyang , Zhang Chunming , Zhai Yubo , Zhang Zhonghai , Zhang Chunli , Xue Yiqing , Tan Guangming , Niu Gang
Published: February 2020

Faced with the current large-scale public health emergency, collecting, sorting, and analyzing biomedical information related to the “coronavirus” should be done as quickly as possible to gain a global perspective, which is a basic requirement for strengthening epidemic control capacity. However, for human researchers studying the viruses and the hosts, the vast amount of information available cannot be processed effectively and in a timely manner, particularly when the scientific understanding may be limited, which can further lower the information processing efficiency. We present TWIRLS, a method that can automatically acquire, organize, and classify information. Additionally, independent functional data sources can be added to build an inference system using a machine-based approach, which can provide relevant knowledge to help human researchers quickly establish subject cognition and to make more effective decisions. TWIRLS can automatically analyze more than three million words in more than 14,000 literature articles in only 4 hours. Combining with generalized gene interaction databases creates a data interface that can help researchers to further analyze the information. Using the TWIRLS system, we found that an important regulatory factor angiotensin-converting enzyme 2 (ACE2) may be involved in the host pathological changes on binding to the coronavirus after infection. After triggering functional changes in ACE2/AT2R, an imbalance in the steady-state cytokine regulatory axis involving the Renin-Angiotensin System and IP-10 leads to a cytokine storm.
Machine Learning Assisted Intraoperative Assessment of Brain Tumor Margins Using HRMAS NMR Spectroscopy
Authors: Cakmakci Doruk , Karakaslar Emin Onur , Ruhland Elisa , Chenard Marie-Pierre , Proust Francois , Piotto Martial , Namer Izzie Jacques , Cicek A. Ercument
Published: February 2020

Complete resection of the tumor is important for survival in glioma patients. Even if the gross total resection was achieved, left-over micro-scale tissue in the excision cavity risks recurrence. High Resolution Magic Angle Spinning Nuclear Magnetic Resonance (HRMAS NMR) technique can distinguish healthy and malign tissue efficiently using peak intensities of biomarker metabolites. The method is fast, sensitive and can work with small and unprocessed samples, which makes it a good fit for real-time analysis during surgery. However, only a targeted analysis for the existence of known tumor biomarkers can be made and this requires a technician with chemistry background, and a pathologist with knowledge on tumor metabolism to be present during surgery. Here, we show that we can accurately perform this analysis in real-time and can analyze the full spectrum in an untargeted fashion using machine learning. We work on a new and large HRMAS NMR dataset of glioma and control samples (n = 568), which are also labeled with a quantitative pathology analysis. Our results show that a random forest based approach can distinguish samples with tumor cells and controls accurately and effectively with a mean AUC of 85.6% and AUPR of 93.4%. We also show that we can further distinguish benign and malignant samples with a mean AUC of 87.1% and AUPR of 96.1%. We analyze the feature (peak) importance for classification to interpret the results of the classifier. We validate that known malignancy biomarkers such as creatine and 2-hydroxyglutarate play an important role in distinguish tumor and normal cells and suggest new biomarker regions. The code is released at http://github.com/ciceklab/HRMAS_NC.
Oxytocin Acts on Astrocytes in the Central Amygdala to Promote a Positive Emotional State
Authors: Wahis Jérôme , Kerspern Damien , Althammer Ferdinand , Baudon Angel , Goyon Stéphanie , Hagiwara Daisuke , Lefèvre Arthur , Boury-Jamot Benjamin , Bellanger Benjamin , Abatis Marios , da Gouveia Miriam Silva , Benusiglio Diego , Eliava Marina , Rozov Andrej , Weinsanto Ivan , Knobloch-Bollmann Hanna Sophie , Wang Hong , Pertin Marie , Inquimbert Perrine , Pitzer Claudia , Siemens Jan , Goumon Yannick , Boutrel Benjamin , Darbon Pascal , Lamy Christophe Maurice , Stern Javier E. , Décosterd Isabelle , Chatton Jean-Yves , Young W. Scott , Stoop Ron , Poisbeau Pierrick , Grinevich Valery , Charlet Alexandre
Published: February 2020

Oxytocin orchestrates social and emotional behaviors through modulation of neural circuits in brain structures such as the central amygdala (CeA). The long-standing dogma is that oxytocin signaling in the central nervous system occurs exclusively via direct actions on neurons. However, several findings over the last decades showed that astrocytes actively participate in the modulation of neuronal circuits. Here, we investigate the degree of astrocytes’ involvement in oxytocin functions. Using astrocyte’ specific gain and loss of function approaches, we demonstrate that CeA astrocytes not only directly respond to oxytocin, but are actually necessary for its effects on neuronal circuits and ultimately behavior. Our work identifies astrocytes as a crucial cellular substrate underlying the promotion of a positive emotional state by oxytocin. These results further corroborate that astrocytes are key regulators of neuronal circuits activity by responding to specific neuropeptidergic inputs, and opens up new perspectives to understand how neuromodulators gate brain functions.
Creative destruction: Sparse activity emerges on the mammal connectome under a simulated communication strategy with collisions and redundancy
Authors: Hao Yan , Graham Daniel
Published: February 2020

Signal interactions in brain network communication have been little studied. We describe how nonlinear collision rules on simulated mammal brain networks can result in sparse activity dynamics characteristic of mammalian neural systems. We tested the effects of collisions in “information spreading” (IS) routing models and in standard random walk (RW) routing models. Simulations employed synchronous agents on tracer-based mesoscale mammal connectomes at a range of signal loads. We find that RW models have high average activity that increases with load. Activity in RW models is also densely distributed over nodes: a substantial fraction is highly active in a given time window, and this fraction increases with load. Surprisingly, while IS models make many more attempts to pass signals, they show lower net activity due to collisions compared to RW, and activity in IS increases little as function of load. Activity in IS also shows greater sparseness than RW, and sparseness decreases slowly with load. Results hold on two networks of the monkey cortex and one of the mouse whole-brain. We also find evidence that activity is lower and more sparse for empirical networks compared to degree-matched randomized networks under IS, suggesting that brain network topology supports IS-like routing strategies.
Modular biomaterials vaccine technology protects against multiple pathogens and septic shock
Authors: Super Michael , Doherty Edward J. , Cartwright Mark J. , Seiler Benjamin T. , White Des A. , Langellotto Fernanda , Stafford Alexander G. , Dimitrakakis Nikolaos , Karkada Mohan , Graveline Amanda R. , Horgan Caitlin L. , Lightbown Kayla R. , Urena Frank R. , Yeager Chyenne D. , Rifai Sami A. , Dellacherie Maxence O. , Li Aileen W. , Jiang Amanda R. , Chandrasekhar Vasanth , Scott Justin M. , Lightbown Shanda L. , Ingber Donald E. , Mooney David J.
Published: February 2020

Broad spectrum vaccines could provide a solution to the emergence of antibiotic resistant microbes, pandemics and engineered biothreat agents. Here, we describe a modular vaccine (composite infection vaccine technology (ciVAX)) which can be rapidly assembled and in which 4 of the 5 components are already approved for human use. ciVAX consists of an injectable biomaterial scaffold with factors to recruit and activate dendritic cells (DC)in vivoand microbeads conjugated with the broad-spectrum opsonin Fc-Mannose-binding Lectin (FcMBL) that is pre-bound to polysaccharide-rich cell wall antigens, such as the pathogen-associated molecular patterns (PAMPs) fractions, captured from whole inactivated bacteria. Vaccination of mice and rabbits with ciVAX generates potent humoral and T cell responses to PAMPs isolated from native antibiotic-resistantE. coliandS. aureus, and ciVAX protects mice and pigs against lethalE colichallenge in sepsis and septic shock models. In addition to the efficacy of ciVAX against homologous challenge, PAMPS isolated from an infected animal protects other animals against infection by heterologous challenge using differentE. coliserotypes – demonstrating the potential for use of ciVAX in controlling pandemics. The advantage of the ciVAX technology is the strong immunogenicity with limited reactogenicity, the use of inactivated pathogens, and the modular manufacture using cGMP approved products which can be stockpiled ready for the next pandemic.

One Sentence Summary

Biomaterial vaccine induces strong immunogenicity, weak reactogenicity, and protects fromE. colisepsis in rodents and pigs, and MRSA skin abscess.
TheDrosophila FUSorthologcabezapromotes adult founder myoblast selection by Xrp1-dependent regulation of FGF signaling
Authors: Catinozzi Marica , Mallik Moushami , Frickenhaus Marie , Been Marije , Sijlmans Céline , Kulshrestha Divita , Alexopoulos Ioannis , Weitkunat Manuela , Schnorrer Frank , Storkebaum Erik
Published: February 2020

The number of adult myofibers inDrosophilais determined by the number of founder myoblasts selected from a myoblast pool, a process governed by fibroblast growth factor (FGF) signaling. Here, we show that loss ofcabeza(caz) function results in a reduced number of adult founder myoblasts, leading to a reduced number and misorientation of adult dorsal abdominal muscles. Genetic experiments revealed that loss ofcazfunction in both adult myoblasts and neurons contributes tocazmutant muscle phenotypes. Selective overexpression of the FGF receptor Htl or the FGF receptor-specific signaling molecule Stumps in adult myoblasts partially rescuedcazmutant muscle phenotypes, and Stumps levels were reduced incazmutant founder myoblasts, indicating FGF pathway deregulation. In both adult myoblasts and neurons,cazmutant muscle phenotypes were mediated by increased expression levels of Xrp1, a DNA-binding protein involved in gene expression regulation. Xrp1-induced phenotypes were dependent on the DNA-binding capacity of its AT-hook motif, and increased Xrp1 levels in founder myoblasts reduced Stumps expression. Thus, control of Xrp1 expression by Caz is required for regulation of Stumps expression in founder myoblasts, resulting in correct founder myoblast selection.

Author Summary

Skeletal muscles mediate movement, and therefore, proper structure and function of skeletal muscles is required for respiration, locomotion, and posture. Adult muscles arise from fusion of muscle precursor cells during development. In the fruit flyDrosophila melanogaster, muscle precursor cells come in two flavors: founder cells and fusion-competent cells. The number of founder cells selected during development corresponds to the number of adult muscles formed. Here, we report that inactivation of theDrosophila cazgene results in muscle developmental defects. Loss ofcazfunction in both muscle precursor cells and the nerve cells that innervate muscles contributes to the muscle developmental defect. At the molecular level, loss ofcazfunction leads to increased levels of Xrp1. Xrp1 regulates the expression of many other genes, including genes that produce components of the FGF signaling pathway, which is known to be involved in founder cell selection. In all, we uncovered a novel molecular mechanism that regulates founder cell selection during muscle development.
Immune reactivity to neurofilaments and dipeptide repeats in ALS progression
Authors: Puentes Fabiola , Lombardi Vittoria , Lu Ching-Hua , Yildiz Ozlem , Kang Angray , Nissim Ahuva , Fratta Pietro , Isaacs Adrian , Bobeva Yoana , Malaspina Andrea
Published: February 2020

Objective

To test antibody response and formation of immune-complexes to neurofilaments and dipeptide-repeats, the translational products of the mutated C9orf72 gene, as potential biomarkers for clinical stratification of amyotrophic lateral sclerosis (ALS).

Methods

Using neurofilament protein isoforms plasma expression as reference, antibodies and immune-complexes against neurofilament-light, medium and heavy chain and poly-(GP)-GR dipeptide-repeats were tested in blood from 105 fast and slow progressing ALS patients, 26 C9orf72 mutation carriers (C9+ve) ALS patients and 77 healthy controls (HC) using single-molecule and immune-capture assays. Longitudinal antibody/immune-complex responses were measured in serial blood samples from 37 (including 11 C9+ve) patients.

Results

Antibodies and immune-complex reactivity was higher in ALS patients than HC, particularly in C9+ve ALS patients, and modestly correlated with total neurofilament protein isoforms (r:0.24p=0.002; r:0.18p=0.02 respectively). Neurofilament-light immune-complexes and neurofilament-heavy antibodies had the best diagnostic performances distinguishing ALS subtypes from HC (AUC=0.68p<0.01; AUC=0.68p<0.001 respectively). Neurofilament-light immune-complexes (AUC=0.69p<0.01) and poly-(GP) dipeptide-repeats antibodies (AUC=0.71p<0.001) separated C9+ve from C9-ve patients. Multivariate mortality hazard ratio and Kaplan-Meier analyses showed low neurofilament-heavy antibody levels associated with increased survival. Longitudinal analysis identified raising levels of antibodies against neurofilaments in fast progressing ALS and of neurofilament-light immune-complexes in C9+ve patients.

Interpretation

C9+ve and fast progressing ALS patients have a distinct neurofilament and dipeptide-repeat immuno-phenotype, with increasing levels of blood neurofilament-light immune-complexes and neurofilament antibodies with disease progression. The study of the expression of these biomarkers in the natural history of ALS may shed light on disease initiation and progression and provide novel pharmacodynamic biomarkers in emerging C9orf72 gene silencing therapies.