bluuebunny/crossref_metadata_2025 huggingface dataset:
A Double-Blind, Placebo-Controlled, Phase 3b Study of ATX-101 for Reduction of Mild or Extreme Submental Fat
Authors: Glogau Richard G. , Glaser Dee Anna , Callender Valerie D. , Yoelin Steve , Dover Jeffrey S. , Green Jeremy B. , Breshears Laura , Bowen Beta
Published: April 2019

BACKGROUND

ATX-101 (deoxycholic acid injection) is approved for reduction of moderate or severe submental fat (SMF).

OBJECTIVE

To evaluate the efficacy and safety of ATX-101 in subjects with mild or extreme SMF.

PATIENTS AND METHODS

Adults with mild or extreme SMF (based on clinician assessment) were randomized to receive ≤6 treatments with ATX-101 or placebo. Efficacy end points, evaluated at 12 weeks after last treatment, included percentage of subjects who achieved ≥1-grade improvement in SMF from baseline based on both clinician and patient assessment (composite CR-1/PR-1 response) as well as multiple subject-reported outcomes. Safety end points included change in skin laxity and incidence of adverse events.

RESULTS

Overall, 61.3% of ATX-101–treated subjects versus 6.7% of placebo-treated subjects with mild SMF and 89.3% versus 13.3% of subjects, respectively, with extreme SMF achieved a composite CR-1/PR-1 response (p < .001 for both). ATX-101–treated subjects also reported higher levels of satisfaction and greater reductions in the psychological impact of SMF versus placebo-treated subjects regardless of baseline SMF severity. Skin laxity was unchanged or improved in most of the subjects. Adverse events were mainly mild/moderate, transient, and associated with the injection site.

CONCLUSION

ATX-101 was efficacious and well tolerated for reduction of mild or extreme SMF.
Ovarian Reserve Testing: A Review of the Options, Their Applications, and Their Limitations
Authors: ULRICH NICOLE D. , MARSH ERICA E.
Published: April 2019

Ovarian reserve refers to the number of oocytes remaining in a woman’s ovaries that have the potential to yield a pregnancy. This is a concept based on the fact that the number of oocytes within a woman’s ovaries and her ability to achieve pregnancy decline over time. There are 2 overlapping but distinct interpretations and utilizations of ovarian reserve testing (ORT)—biological and clinical. Given the increasing incorporation of ORT into clinical practice, care must be taken to ensure that patients and providers understand the limitations affecting ORT interpretation. Here, we will review commonly used tests of ovarian reserve and offer guidance on interpretation (biology) and application (clinical practice) of results.
Vestibular Aqueduct Morphology Correlates With Endolymphatic Sac Pathologies in Menière's Disease—A Correlative Histology and Computed Tomography Study
Authors: Bächinger David , Luu Ngoc-Nhi , Kempfle Judith S. , Barber Samuel , Zürrer Daniel , Lee Daniel J. , Curtin Hugh D. , Rauch Steven D. , Nadol Joseph B. , Adams Joe C. , Eckhard Andreas H.
Published: April 2019

Hypothesis:

The vestibular aqueduct (VA) in Menière's disease (MD) exhibits different angular trajectories depending on the presenting endolymphatic sac (ES) pathology, i.e., 1) ES hypoplasia or 2) ES degeneration.

Background:

Hypoplasia or degeneration of the ES was consistently found in inner ears affected by MD. The two etiologically distinct ES pathologies presumably represent two disease “endotypes,” which may be associated with different clinical traits (“phenotypes”) of MD. Recognizing these endotypes in the clinical setting requires a diagnostic tool.

Methods:

1) Defining the angular trajectory of the VA (ATVA) in the axial plane. 2) Measuring age-dependent normative data for the ATVA in postmortem temporal bone histology material from normal adults and fetuses. 3) Validating ATVA measurements from normative CT imaging data. 4) Correlating the ATVA with different ES pathologies in histological materials and CT imaging data from MD patients.

Results:

1) The ATVA differed significantly between normal adults and MD cases with ES degeneration, as well as between fetuses and MD cases with ES hypoplasia; 2) a strong correlation between ATVA measurements in histological sections and CT imaging data was found; 3) a correlation between the ATVA, in particular its axial trajectory in the opercular region (angle α
exit), with degenerative (α
exit < 120°) and hypoplastic ES pathology (α
exit > 140°) was demonstrated.

Conclusion:

We established the ATVA as a radiographic surrogate marker for ES pathologies. CT-imaging-based determination of the ATVA enables endotyping of MD patients according to ES pathology. Future studies will apply this method to investigate whether ES endotypes distinguish clinically meaningful subgroups of MD patients.
Primary Petrous Apex Epidermoids With Skull Base Erosion
Authors: Casazza Geoffrey C. , McCrary Hilary C. , Shelton Clough , Gurgel Richard K.
Published: April 2019

Objective:

To describe the clinical course and treatment outcomes for patients with petrous apex epidermoid with skull base erosion.

Study Design:

Retrospective case series.

Setting:

Tertiary-care academic center.

Patients:

Patients surgically managed for petrous apex epidermoids at a single-tertiary care institution from 2001 to 2017.

Interventions:

Surgical management of primary petrous apex epidermoids.

Main Outcome Measures:

The presenting symptoms, imaging, pre- and postoperative clinical course, and complications were reviewed.

Results:

Seven patients were identified. The most common presenting symptoms included: sudden sensorineural hearing loss (n = 3), headaches (n = 1), vertigo (n = 2), and facial paralysis/paresis (n = 2). An epidermoid was discovered in two patients as an incidental finding after a head trauma and one patient after admission for altered mental status and meningitis. Two patients presented with complete facial paralysis (House–Brackmann 6/6). Preoperative normal hearing (pure-tone average < 25 db) was identified in three patients and serviceable hearing (pure-tone average 25–60 dB) in one patient. Three patients with nonserviceable hearing underwent a transcochlear or transotic approach. The remaining four patients underwent an attempted hearing preservation approach. Postoperatively, one patient developed delayed facial paralysis, improving within 3 months. Hearing was preserved in three patients. Two patients developed recurrence of disease within 4 and 7 years respectively.

Conclusions:

Surgical management of aggressive petrous apex epidermoid is effective to preserve facial function and prevent recurrence. In our series different surgical approaches were used with variable outcomes.
Clusters of Psychological Symptoms in Breast Cancer
Authors: Guimond Anne-Josée , Ivers Hans , Savard Josée
Published: April 2019

Background

Breast cancer patients tend to experience numerous concurrent psychological symptoms that form clusters. It has been proposed that a common psychological mechanism may underlie the membership of symptoms in a given cluster, but this hypothesis has never been investigated. Maladaptive emotion regulation (ER) is one possible common mechanism.

Objective

This study examined cross-sectional and prospective relationships between subjective (experiential avoidance, expressive suppression, and cognitive reappraisal) and objective (high-frequency heart rate variability) measures of ER and clusters of psychological symptoms among women receiving radiation therapy for breast cancer.

Method

A total of 81 women completed a battery of self-report scales before (T1) and after (T2) radiotherapy, including measures of anxiety, depression, fear of cancer recurrence, insomnia, fatigue, pain, and cognitive impairments. Resting high-frequency heart rate variability was measured at T1.

Results

Latent profile analyses identified between 2 and 3 clusters of patients with similar levels of symptoms at T1 and T2 and with a similar profile of symptom changes between T1 and T2. Discriminant analyses showed that higher levels of avoidance and suppression predicted membership in symptom clusters that included more severe symptoms cross-sectionally at T1 and at T2 (both P values < .0001). However, ER at T1 did not significantly predict membership in clusters of symptom changes between T1 and T2 (P = .15).

Conclusion

Maladaptive ER strategies, more particularly suppression and avoidance, are a possible psychological mechanism underlying clusters of cancer-related psychological symptoms.

Implications for Practice

Psychological interventions targeting maladaptive ER strategies have the potential to treat several psychological symptoms simultaneously.
EWSR1-NFATC2 Translocation-associated Sarcoma Clinicopathologic Findings in a Rare Aggressive Primary Bone or Soft Tissue Tumor
Authors: Wang Grace Y. , Thomas Dafydd G. , Davis Jessica L. , Ng Tony , Patel Rajiv M. , Harms Paul W. , Betz Bryan L. , Schuetze Scott M. , McHugh Jonathan B. , Horvai Andrew E. , Cho Soo-Jin , Lucas David R.
Published: April 2019

In recent years, a novel small round cell sarcoma harboring EWSR1-NFATC2 translocation with immunomorphologic overlap with Ewing sarcoma (ES), myoepithelial tumors, and extraskeletal myxoid chondrosarcoma has emerged. There has not been a case series devoted to describing its detailed clinicopathologic and immunohistochemical characteristics. Six sarcomas harboring EWSR1-NFATC2 fusion transcripts by reverse transcription polymerase chain reaction and amplification of the fusion gene by fluorescence in situ hybridization were identified. The patients were 5 adult men and 1 adult woman. Three were primary bone tumors of the radius and 3 were primary soft tissue tumors. Most tumors showed monomorphic round to epithelioid cells in anastomosing cords and abundant myxohyaline to collagenous extracellular matrix. Two tumors had large areas of a solid, matrix-poor histomorphology. All tumors stained for CD99 and NKX2.2; while EMA, dot-like cytokeratin, and focal WT-1 and SMA were present in some tumors. All but 1 tumor showed poor histologic and radiologic responses to neoadjuvant ES-specific chemotherapy. Local or distant recurrences happened in 4 cases. EWSR1-NFATC2 sarcoma is a novel translocation-associated sarcoma. It presents as either a primary bone or soft tissue tumor, usually exhibits distinctive histopathologic features, and has predilection for long bones of adult men. It consistently shows recurrent fusion gene amplification readily detectable by EWSR1 breakapart fluorescence in situ hybridization, which serves as a diagnostic surrogate. It has potential for local and distant recurrence and histologic progression, and is resistant to Ewing sarcoma-specific chemotherapy.
Increased Testing and Health Care Costs for Pediatric Cannabis Exposures
Authors: Bashqoy Ferras , Heizer Justin W. , Reiter Pamela D. , Wang George S. , Borgelt Laura M.
Published: April 2019

Objectives

This study aimed to evaluate the process of identifying marijuana exposure in a children's hospital emergency department and compare the cost of diagnostic testing and procedures.

Methods

A retrospective chart review was performed on patients 31 days to 20 years old with a positive marijuana toxicology screen result between November 2009 and December 2014. Primary outcomes included time to provider recognition of marijuana exposure, number of diagnostic tests and procedures performed, and length of hospital stay. Patients were analyzed based on time of exposure recognition (forthcoming compared with not forthcoming of marijuana exposure) and age (children <12 years compared with adolescents >12 years).

Results

There were 37 children and 38 adolescents included. Mean time to exposure recognition was 2.3 ± 4.3 hours in children compared with 0.4 ± 0.9 hours in adolescents (P = 0.02). Patients who were not forthcoming of marijuana exposure experienced more than twice as many diagnostic tests or procedures compared with children who were forthcoming of marijuana exposure (mean, 8.91 vs 4 tests, P < 0.0001) and more than a 4-fold higher cost of potentially avoidable diagnostic tests/procedures. Length of hospital stay was significantly longer in children (18.34 ± 2.39 hours) compared with adolescents (4.22 ± 0.52 hours; P ≤ 0.0001). Few parents or guardians were able to disclose characteristics of the marijuana product.

Conclusion

Delay in recognition of marijuana exposure is associated with high resource utilization, unnecessary medical costs, and prolonged length of stay.
Dental Infection Cause of Flap Loss in Cleft Palate Repair
Authors: Jagtap Rasika , Deshpande Gaurav
Published: April 2019

Flap necrosis is a very common complication encountered after cleft palate repair, especially in uni-pedicled flaps. Many causes have been attributed to this complication but very limited data is available in the literature on dental infection as the cause of flap necrosis. This report of a case describes loss of flap caused due to a periapical granuloma of dental origin impinging on the pedicle causing suspected thrombosis of the pedicle resulting in flap necrosis. Since this is an important cause that can be easily prevented, it is reported.
Surgical Treatment Strategy for Severe Rhinophyma With Bilateral Pedicled Nasolabial Flaps
Authors: Cui Meng-Ying , Guo Shu , Wang Chen-Chao , Lv Meng-Zhu , Jin Shi-Feng
Published: April 2019

Background:

Rhinophyma is a rare disease characterized by chronic inflammation and hypertrophy of sebaceous glands, blood vessels, and fibrous tissue, associated with end-stage severe acne rosacea. There are multiple approaches to treatment and repair, including dermal shaving, secondary intention healing, free skin graft, and skin flaps. However, these methods have various disadvantages, such as prolonged healing, obvious scarring, and skin texture mismatch. Therefore, the authors adopted surgical excision with bilateral pedicled nasolabial flaps, which have better color, texture, thickness, and symmetry.

Methods:

The authors present a case of severe nasal tip rhinophyma successfully treated by excision and repair with bilateral pedicled nasolabial flaps. This procedure combines deep excision of the focal lesion and coverage with bilateral nasolabial flaps.

Results:

The bilateral pedicled nasolabial flaps were used for severe rhinophyma in a patient. After the operation, the flaps survived uneventfully in this study. Both functional and aesthetic results were satisfactory at 3 months.

Conclusion:

The authors offer an effective method for surgical treatment of rhinophyma. Excision of hypertrophic nasal tissue is an acknowledged effective treatment for patients with severe rhinophyma. After excision, reconstruction with nasolabial flaps results in satisfactory outcomes both functionally and aesthetically. Therefore, this approach should be considered an appropriate alternative in cases of severe rhinophyma.
TUDCA Ameliorates Liver Injury Via Activation of SIRT1–FXR Signaling in a Rat Hemorrhagic Shock Model
Authors: Sun Silei , Zhao Bing , Qi Mengzhi , Yao Yi , Xu Lili , Ji Ran , Chen Weiwei , Wang Jinlong , Huang Shunwei , Ma Li , Chen Ying , Yang Zhitao , Sheng Huiqiu , Fei Jian , Chen Erzhen , Mao Enqiang
Published: April 2019

Objective:

The aim of this study was to investigate the changes of bile acids in the liver during hemorrhagic shock (HS) and their potential to attenuate liver injury via activation of SIRT1 (sirtuin 1)–FXR (farnesoid X receptor) signaling.

Methods:

A Sprague–Dawley (SD) rat HS model was established, whereas HepG2 cells were hypoxically cultured to simulate HS in vitro. Liver bile acids (BA) were profiled with ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). FXR expression was detected by western blot and immunohistochemistry. The mRNA levels of SIRT1 and FXR were detected by polymerase chain reaction. Protein expression of SIRT1, FoxM1, NF-κB, acetyl-NF-κB, p53, and acetyl-p53 was analyzed by western blot. Hepatocyte apoptosis and proliferation were measured by TUNEL assay and Ki-67 staining, respectively. Serum and supernatant cytokines were analyzed using ELISA assays. Liver injury was also assessed. To investigate the possible mechanisms, SIRT1 agonist (SRT1720), SIRT1 inhibitor (EX527), and FXR inhibitor (Z-guggulsterone) were used.

Results:

Tauroursodeoxycholic acid (TUDCA) in the liver decreased significantly after HS. SIRT1 and FXR expression was time-dependently downregulated by HS or hypoxia condition. TUDCA upregulated SIRT1–FXR activity, which inhibited expression and acetylation of NF-κB and p53 and increased FoxM1 expression, leading to decreased inflammatory response and apoptosis and increased proliferative capacity in hepatocytes, and attenuation of liver injury. EX527 pretreatment reversed the protective effect of TUDCA. Moreover, Z-guggulsterone supplementation decreased the protective effect of TUDCA in vitro.

Conclusion:

TUDCA in the liver decreased during HS. TUDCA supplementation might attenuate HS-induced liver injury by upregulating SIRT1–FXR signaling.
Preliminary Studies of the Impact of CXCL12 on the Foreign Body Reaction to Pancreatic Islets Microencapsulated in Alginate in Nonhuman Primates
Authors: Sremac Marinko , Lei Ji , Penson Madeline F.E. , Schuetz Christian , Lakey Jonathan R.T. , Papas Klearchos K. , Varde Pushkar S. , Hering Bernhard , de Vos Paul , Brauns Timothy , Markmann James , Poznansky Mark C.
Published: April 2019

Background.

We previously demonstrated that the incorporation of the chemokine CXCL12 into alginate microbeads supported long-term survival of microencapsulated auto-, allo-, and xenogeneic islets in murine models of diabetes without systemic immune suppression. The purpose of this study was to test whether CXCL12 could abrogate foreign body responses (FBRs) against alginate microbeads which were empty or contained autologous islets in healthy nonhuman primates (NHPs; n = 4).

Methods.

Two NHPs received intraperitoneal implants of 400 000 alginate microbeads with or without CXCL12, and postimplantation immunological and histopathological changes were evaluated up to 6 months postimplantation. A similar evaluation of autologous islets in CXCL12-containing alginate microbeads was performed in NHPs (n = 2).

Results.

CXCL12-containing alginate microbeads were associated with a markedly reduced FBR to microbeads. Host responses to microbead implants were minimal, as assessed by clinical observations, blood counts, and chemistry. Evaluation of encapsulated islets was limited by the development of necrotizing pancreatitis after hemipancreatectomy in 1 NHP. A limited number of functioning islets were detectable at 6 months posttransplantation in the second NHP. In general, empty microbeads or islet-containing beads were found to be evenly distributed through the intraperitoneal cavity and did not accumulate in the Pouch of Douglas.

Conclusions.

Inclusion of CXCL12 in alginate microbeads minimized localized FBR. The NHP autologous islet implant model had limited utility for excluding inflammatory/immune responses to implanted islets because of the complexity of pancreatic surgery (hemipancreatectomy) before transplantation and the need to microencapsulate and transplant encapsulated autologous islets immediately after pancreatectomy and islet isolation.
Domestication ofCampylobacter jejuniNCTC 11168
Authors: Pascoe Ben , Williams Lisa K. , Calland Jessica K. , Méric Guillaume , Hitchings Matthew D. , Dyer Myles , Ryder Joseph , Shaw Sophie , Lopes Bruno S. , Chintoan-Uta Cosmin , Allan Elaine , Vidal Ana , Fearnley Catherine , Everest Paul , Pachebat Justin A. , Cogan Tristan A. , Stevens Mark P. , Humphrey Thomas J. , Wilkinson Thomas S. , Cody Alison J. , Colles Frances M. , Jolley Keith A. , Maiden Martin C. J. , Strachan Norval , Pearson Bruce M. , Linton Dennis , Wren Brendan W. , Parkhill Julian , Kelly David J. , van Vliet Arnoud H. M. , Forbes Ken J. , Sheppard Samuel K.
Published: April 2019

Reference and type strains of well-known bacteria have been a cornerstone of microbiology research for decades. The sharing of well-characterised isolates among laboratories has parallelised research efforts and enhanced the reproducibility of experiments, leading to a wealth of knowledge about trait variation in different species and the underlying genetics.Campylobacter jejunistrain NCTC 11168, deposited at the National Collection of Type Cultures in 1977, has been adopted widely as a reference strain by researchers worldwide and was the firstCampylobacterfor which the complete genome was published (in 2000). In this study, we collected 23C. jejuniNCTC 11168 reference isolates from laboratories across the UK and compared variation in simple laboratory phenotypes with genetic variation in sequenced genomes. Putatively identical isolates identified previously to have aberrant phenotypes varied by up to 281 SNPs (in 15 genes) compared to the most recent reference strain. Isolates also display considerable phenotype variation in motility, morphology, growth at 37°C, invasion of chicken and human cell lines and susceptibility to ampicillin. This study provides evidence of ongoing evolutionary change amongC. jejuniisolates as they are cultured in different laboratories and highlights the need for careful consideration of genetic variation within laboratory reference strains.

Impact statement

In this paper, we comment on the changing role of laboratory reference strains. While the model organism allows basic comparison within and among laboratories, it is important to remember the effect even small differences in isolate genomes can have on the validity and reproducibility of experimental work. We quantify differences in 23 referenceCampylobactergenomes and compare them with observable differences in common laboratory phenotypes.

Data summary

Short read data are archived on the NCBI SRA associated with BioProject accession PRJNA517467 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA517467).

All assembled genomes are also available on FigShare (doi: 10.6084/m9.figshare.7849268). Phylogeny visualised on microreact:https://microreact.org/project/NCTC11168.

Repositories

Short read data are archived on the NCBI SRA repository, associated with BioProject accession PRJNA517467 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA517467;Table S1).

The authors confirm all supporting data, code and protocols have been provided within the article or through supplementary data files.
Analyses of rare and common alleles in parent-proband trios implicate rare missense variants in SLC6A1 in schizophrenia and confirm the involvement of loss of function intolerant and neurodevelopmental disorder genes
Authors: Rees Elliott , Han Jun , Morgan Joanne , Carrera Noa , Escott-Price Valentina , Pocklington Andrew J. , Duffield Madeleine , Hall Lynsey , Legge Sophie E. , Pardiñas Antonio F. , Richards Alexander L. , Roth Julian , Lezheiko Tatyana , Kondratyev Nikolay , Golimbet Vera , Parellada Mara , González-Peñas Javier , Arango Celso ,   GROUP Investigators, Gawlik Micha , Kirov George , Walters James T. R. , Holmans Peter , O’Donovan Michael C. , Owen Michael J.
Published: April 2019

Schizophrenia is a highly polygenic disorder with important contributions coming from both common and rare risk alleles, the latter including CNVs and rare coding variants (RCVs), sometimes occurring as de novo variants (DNVs). We performed DNV analysis in whole exome-sequencing data obtained from a new sample of 613 schizophrenia trios, and combined this with published data for a total of 3,444 trios. Loss-of-function (LoF) DNVs were significantly enriched among 3,488 LoF intolerant genes in our new trio data (rate ratio (RR) (95% CI) = 2.23 (1.31, 3.79); p = 2.2 × 10−3), supporting previous findings. In the full dataset, genes associated with neurodevelopmental disorders (NDD; n=160) were significantly enriched for LoF DNVs (RR (95% CI) = 3.32 (2.0, 5.21); p = 7.4 × 10−6). Within this set of NDD genes, SLC6A1, encoding a gamma-aminobutyric acid transporter, was associated with missense-damaging DNVs (p = 5.2 × 10−5). Using data from a subset of 1,122 trios for which we had genome-wide common variant data, schizophrenia polygenic risk was significantly over-transmitted to probands (p = 2.6 × 10−60), as was bipolar disorder common variant polygenic risk (p = 5.7 × 10−17). We defined carriers of candidate schizophrenia-related DNVs as those with LoF or deletion DNVs in LoF intolerant or NDD genes. These individuals had significantly less over-transmission of common risk alleles than non-carriers (p = 3.5 × 10−4), providing robust support for the hypothesis that this set of DNVs is enriched for those related to schizophrenia.
No evidence forWolbachiaas a nutritional co-obligate endosymbiont in the aphidPentalonia nigronervosa
Authors: Manzano-Marín Alejandro
Published: April 2019

Obligate symbiotic associations are present in a wide variety of animals with a nutrient-restricted diet. Aphids (hemiptera: Aphididae) almost-universally hostBuchnera aphidicolabacteria in a specialised organs (called bacteriomes). These bacteria supply the aphid with essential nutrients lacking from their diet (i.e. essential amino acids and some B vitamins). Some aphid lineages, such as species from the Lacninae subfamily, have evolved co-obligate associations with secondary endosymbionts, deriving from a loss of biotin-and riboflavin-biosynthetic genes. In this study I re-analyse previously published sequencing data from the banana aphidPentalonia nigronervosa. I show that the metabolic inference results from De Clercket al.(2015) are incorrect and possibly arise from the use of inadequate methods. Additionally, I discuss how the biased interpretation of their antibiotic treatment analyses together with the incorrect metabolic inference resulted in the erroneous suggestion “that a co-obligatory symbiosis betweenB. aphidicolaandWolbachiaoccurs in the banana aphid”.
A novel deep learning scheme for morphology-based classification of mycobacterial infection in unstained macrophages
Authors: Zhao Xinzhuo , Bao Yanqing , Wang Lin , Qian Wei , Sun Jianjun
Published: April 2019

Objective

Mycobacterium tuberculosis (Mtb) is an airborne, contagious bacterial pathogen that causes widespread infections in humans. Using Mycobacterium marinum (Mm), a surrogate model organism for Mtb research, the present study develops a deep learning-based scheme that can classify the Mm-infected and uninfected macrophages in tissue culture solely based on morphological changes.

Methods

A novel weak-and semi-supervised learning method is developed to detect and extract the cells, firstly. Then, transfer learning and fine-tuning from the CNN is built to classify the infected and uninfected cells.

Results

The performance is evaluated by accuracy (ACC), sensitivity (SENS) and specificity (SPEC) with 10-fold cross-validation. It demonstrates that the scheme can classify the infected cells accurately and efficiently at the early infection stage. At 2 hour post infection (hpi), we achieve the ACC of 0.923 ± 0.005, SENS of 0.938 ± 0.020, and SPEC of 0.905 ± 0.019, indicating that the scheme has detected significant morphological differences between the infected and uninfected macrophages, although these differences are hardly visible to naked eyes. Interestingly, the ACC at 12 and 24 hpi are 0.749 ± 0.010 and 0.824 ± 0.009, respectively, suggesting that the infection-induced morphological changes are dynamic throughout the infection. Finally, deconvolution with guided propagation maps the key morphological features contributing to the classification.

Significance

This proof-of-concept study provides a novel venue to investigate bacterial pathogenesis in a macroscopic level and has a great promise in diagnosis of bacterial infections.
Laminin-driven Epac/Rap1 regulation of epithelial barriers on decellularized matrix
Authors: Young Bethany M. , Shankar Keerthana , Tho Cindy K. , Pellegrino Amanda R. , Heise Rebecca L.
Published: April 2019

Decellularized tissues offer a unique tool for developing regenerative biomaterials orin vitroplatforms for the study of cell-extracellular matrix (ECM) interactions. One main challenge associated with decellularized lung tissue is that ECM components can be stripped away or altered by the detergents used to remove cellular debris. Without characterizing the composition of lung decellularized ECM (dECM) and the cellular response caused by the altered composition, it is difficult to utilize dECM for regeneration and specifically, engineering the complexities of the alveolar-capillary barrier. This study takes steps towards uncovering if dECM must be enhanced with lost ECM proteins to achieve proper epithelial barrier formation. To achieve this, epithelial barrier function was assessed on dECM coatings with and without the systematic addition of several key basement membrane proteins. After comparing barrier function on collagen, fibronectin, laminin, and dECM in varying combinations as anin vitrocoating, the alveolar epithelium exhibited superior barrier function when dECM was supplemented with laminin as evidenced by trans-epithelial electrical resistance (TEER) and permeability assays. Increased barrier resistance with laminin addition was associated with upregulation of Claudin-18, E- cadherin, and junction adhesion molecule (JAM)-A, and stabilization of zonula occludens (ZO)-1 at junction complexes. The Epac/Rap1 pathway was observed to play a role in the ECM-mediated barrier function determined by protein expression and Epac inhibition. These findings reveal potential ECM coatings and molecular therapeutic targets for improved regeneration with decellularized scaffolds or edema related pathologies.
In vivo FirreandDxz4deletion elucidates roles for autosomal gene regulation
Authors: Andergassen Daniel , Smith Zachary D. , Lewandowski Jordan P. , Gerhardinger Chiara , Meissner Alexander , Rinn John L.
Published: April 2019

Recent evidence has determined that the conserved X chromosome “mega-structures” controlled by theFirreandDxz4alleles are not required for X chromosome inactivation (XCI) in cell lines. Here we determined thein vivocontribution of these alleles by generating mice carrying a single or double deletion ofFirreandDxz4. We found that these mutants are viable, fertile and show no defect in random or imprinted XCI. However, the lack of these elements results in many dysregulated genes on autosomes in an organ-specific manner. By comparing the dysregulated genes between the single and double deletion, we identified superloop, megadomain, andFirrelocus dependent gene sets. The largest transcriptional effect was observed in all strains lacking theFirrelocus, indicating that this locus is the main driver for these autosomal expression signatures. Collectively, these findings suggest that these X-linked loci are involved in autosomal gene regulation rather than XCI biology.
Lactobacillus rhamnosusLcr35®as an effective treatment for preventingCandida albicansinfection in preclinical models: first mechanistical insights
Authors: Poupet Cyril , Saraoui Taous , Veisseire Philippe , Bonnet Muriel , Dausset Caroline , Gachinat Marylise , Camarès Olivier , Chassard Christophe , Nivoliez Adrien , Bornes Stéphanie
Published: April 2019

The increased recurrence ofCandida albicansinfections is associated with greater resistance to antifungal drugs. This involves the establishment of alternative therapeutic protocols such as the probiotic microorganisms whose antifungal potential has already been demonstrated using preclinical models (cell cultures, laboratory animals). Understanding the mechanisms of action of probiotic microorganisms has become a strategic need for the development of new therapeutics for humans. In this study, we investigated the prophylactic anti-Candida albicansproperties ofLactobacillus rhamnosusLcr35®using thein vitroCaco-2 cells model and thein vivo Caenorhabditis elegansmodel. On Caco-2 cells, we showed that the strain Lcr35®significantly inhibited the growth of the pathogen (~2 log CFU.mL−1) and its adhesion (150 to 6,300 times less). Moreover, on the top of having a prolongevity activity in the nematode, Lcr35®protects the animal from the fungal infection even if the yeast is still detectable in its intestine. At the mechanistic level, we noticed the repression of genes of the p38 MAPK signaling pathway and genes involved in the antifungal response induced by Lcr35®suggesting that the pathogen no longer appears to be detected by the worm immune system. However, the DAF-16 / FOXO transcription factor, implicated in the longevity and antipathogenic response ofC. elegans, is activated by Lcr35®. These results suggest that the probiotic strain acts by stimulating its host via DAF-16, but also by suppressing the virulence of the pathogen.
Droplet-based combinatorial indexing for massive scale single-cell epigenomics
Authors: Lareau Caleb A. , Duarte Fabiana M. , Chew Jennifer G. , Kartha Vinay K. , Burkett Zach D. , Kohlway Andrew S. , Pokholok Dmitry , Aryee Martin J. , Steemers Frank J. , Lebofsky Ronald , Buenrostro Jason D.
Published: April 2019

While recent technical advancements have facilitated the mapping of epigenomes at single-cell resolution, the throughput and quality of these methods have limited the widespread adoption of these technologies. Here, we describe a droplet microfluidics platform for single-cell assay for transposase accessible chromatin (scATAC-seq) for high-throughput single-cell profiling of chromatin accessibility. We use this approach for the unbiased discovery of cell types and regulatory elements within the mouse brain. Further, we extend the throughput of this approach by pairing combinatorial indexing with droplet microfluidics, enabling single-cell studies at a massive scale. With this approach, we measure chromatin accessibility across resting and stimulated human bone marrow derived cells to reveal changes in the cis- and trans- regulatory landscape across cell types and upon stimulation conditions at single-cell resolution. Altogether, we describe a total of 502,207 single-cell profiles, demonstrating the scalability and flexibility of this droplet-based platform.
Cell-type specific concentration regulation of the basal transcription factor TFIIH
Authors: Donnio Lise-Marie , Miquel Catherine , Vermeulen Wim , Giglia-Mari Giuseppina , Mari Pierre-Olivier
Published: April 2019

The basal transcription/repair factor TFIIH is a ten sub-unit complex essential for RNA polymerase II (RNAP2) transcription initiation and DNA repair. In both these processes TFIIH acts as a DNA helix opener (by the enzymatic activity of the XPB and XPD helicases), required for promoter escape of RNAP2 in transcription initiation, and to set the stage for strand incision within the Nucleotide Excision Repair (NER) pathway. We generated a knock-in mouse model that endogenously expresses a fluorescent version of XPB. Here we demonstrate, via confocal imaging of ex vivo tissues and cells derived from this mouse model, that TFIIH steady state levels are tightly regulated at the single cell level, thus keeping nuclear TFIIH concentrations remarkably constant in a cell type dependent manner. Moreover, we show that individual cellular TFIIH levels are proportional to the speed of mRNA production, hence to a cell’s transcriptional activity, which we can correlate to proliferation status. Importantly, cancer tissue presents a higher TFIIH than normal healthy tissues. Taken together, these results show that TFIIH cellular concentration might be used as a bona-fide marker of transcriptional activity and proliferation.

Significance

Using a mouse model expressing a fluorescently version of TFIIH, we showed that TFIIH concentration is tightly controlled and that this concentration is proportional to the cellular transcriptional activity and proliferation capacity.
Single-Cell Data Analysis Using MMD Variational Autoencoder for a More Informative Latent Representation
Authors: Zhang Chao
Published: April 2019

Abstract

Variational Autoencoder (VAE) is a generative model from the computer vision community; it learns a latent representation of images and generates new images in an unsupervised way. Recently, Vanilla VAE has been applied to single-cell data analysis, in the hope of harnessing the representation power of latent space to evade the “curse of dimensionality” of the original dataset. However, Vanilla VAE is suffering from the issue of less informative latent space, which raises a question concerning the reliability of Vanilla VAE latent space in representing the high-dimensional single-cell datasets. Therefore I set up such a study to examine this issue from the multiple perspectives.

This paper confirms the issue of Vanilla VAE by comparing it with MMD-VAE, a variant of VAE which has claimed to have overcome this issue based on image data, across a series of single-cell RNAseq and mass cytometry datasets. The result indicates that MMD-VAE is superior to Vanilla VAE in retaining the information not only in the latent space but also the reconstruction space, which suggests that MMD-VAE be a better option for single-cell data analysis than Vanilla VAE.
Small-angle scattering by supported nanoparticles: exact results and useful approximations
Authors: Gommes Cedric J. , Asset Tristan , Drnec Jakub
Published: April 2019

In functional materials, nanoparticles are often dispersed in a porous support for the purpose of stabilizing them. This makes their characterization by small-angle scattering challenging because the signal comprises contributions from the nanoparticles of interest, from the inert support and from their cross-correlation. Exact analytical expressions for all three contributions are derived in the case of a Gaussian-field model of the porous support, with nanoparticles randomly distributed over the surface. For low nanoparticle loading, the expressions simplify to the addition of properly scaled support and particle scattering. For higher loadings, however, the cross-correlation cannot be ignored. Two approximations are introduced, which capture correlation effects in cases where the pores of the support are much larger or only slightly larger than the nanoparticles. The methods of the paper are illustrated with the small-angle X-ray scattering analysis of hollow metallic nanoparticles supported on porous carbon.
Constructing social networks and mobilizing social capital
Authors: Zhang Donghui
Published: April 2019

Purpose

The purpose of this paper is to examine the life worlds of Tibetan students who participate in China’s inland boarding programs and seek to understand the social networks they develop in the Han-culture dominant school settings.

Design/methodology/approach

This study is based on ethnographic fieldwork with two Tibetan students (Dorji and Lhamo) in a Beijing inland boarding high school.

Findings

This study found that the Tibetan students are capable social actors who construct two kinds of social networks, the “we” group (co-ethnics) vs the “they” group (cross-ethnics), and mobilize different social capitals strategically. The former provides them with emotional support, cultural affinity and a sense of belonging, while the latter helps them achieve instrumental outcomes, such as Mandarin proficiency, academic improvement and broadened horizons.

Research limitations/implications

However, the group boundary they draw between the two kinds of networks reflects the futility of government efforts to promote interethnic integration through the inland schools.

Originality/value

The issue of minority students as active agents in constructing social networks and mobilizing social capital in unfamiliar sociocultural settings is a relatively new research area (Reynolds, 2007; Holland et al., 2007), whereas the Tibetan students in China are among the least known in the existing scholarship.
Social customer relationship management (s-CRM) among
small- and medium-sized enterprises (SMEs) in Malaysia
Authors: Hassan Siti Hasnah , Mohamed Haniba Noor Mohamed , Ahmad Noor Hazlina
Published: April 2019

Purpose

In this twenty-first century, the emergence of social media has been integral
in business-related processes, especially in small- and medium-sized
enterprises (SMEs), which allows businesses to interact and build a
relationship with customers to improve their sustainable service quality.
Concisely, this study aims to examine the benefits of social customer
relationship management (s-CRM) performance from the perceptive of SMEs
owned by Muslims.

Design/methodology/approach

A survey method was used and the data were gathered from 135 SMEs which
participated in Halfest (Halal Fiesta Malaysia) trade show in Kuala Lumpur,
Malaysia.

Findings

Interestingly, the results revealed that the adoption of information and
communications technology (ICT) has both direct and indirect impacts on
s-CRM performance. On the other hand, the perceived value of s-CRM mediates
the relationship between customer information management and performance of
s-CRM. In this context, the perceived value was ascertained to be an
influential factor for both ICT adoption and customer information
management.

Research
limitations/implications

With a connection to the results, this study concludes that to enhance
business performance to sustain in the marketplace, the establishment of
s-CRM is crucial, as it has significant implication in marketing, customer
service and sales department of SMEs.

Originality/value

This paper provides new insight into the importance of s-CRM to SMEs to
improve interactions with the key stakeholders and convey meaningful insight
to instil customer-centric practices.
A novel alarm signal in aquatic prey: Familiar minnows coordinate group defences against predators through chemical disturbance cues
Authors: Bairos‐Novak Kevin R. , Ferrari Maud C. O. , Chivers Douglas P.
Published: April 2019

Animal signalling systems outside the realm of human perception remain largely understudied. These systems consist of four main components: a signalling context, a voluntary signal, receiver responses and resulting fitness benefits to both the signaller and receiver(s). It is often most difficult to determine incidental cues from voluntary signals. One example is chemical disturbance cues released by aquatic prey during predator encounters that may serve to alert conspecifics of nearby risk and initiate tighter shoaling.

We aimed to test whether disturbance cues are released incidentally (i.e. as a cue) or are produced voluntarily depending on a specific signalling context such as the audience surrounding the individual, and thus constitute a signal. We hypothesized that if receivers use disturbance cues to communicate risk among themselves, they would produce more (or more potent) disturbance cues when present in a group of conspecifics rather than when they are isolated (presence/absence of an audience) and use disturbance cues more when present alongside familiar rather than unfamiliar conspecifics (audience composition effect).

We placed fathead minnows (Pimephales promelas) in groups with familiar fish, unfamiliar fish or as isolated individuals with no audience present, and then simulated a predator chase to evoke disturbance cues. We used bioassays with independent receivers to assess whether the disturbance cues produced differed depending on the signallers’ audience.

We found evidence of voluntary signalling, as minnows responded to disturbance cues from groups of fish with tighter shoaling while disturbance cues from isolated minnows did not evoke a significant shoaling response (presence/absence audience effect). Receivers also increased shoaling, freezing and dashing more in response to disturbance cues from familiar groups compared to disturbance cues from unfamiliar groups or isolated minnows (audience composition effect).

Together, these findings support our hypothesis that disturbance cues are used as an antipredator signal to initiate coordinated group defences among familiar conspecifics involving shoaling, freezing and dashing. This study represents the strongest evidence to date that chemicals released by aquatic prey upon disturbance by predators serve as voluntary signals rather than simply cues that prey have evolved to detect when assessing their risk of predation.
Risk factors for neutropenia and febrile neutropenia following prophylactic pegfilgrastim
Authors: Lee Mirinae , Yee Jeong , Kim Jae Youn , Kim Ju Young , An Sook Hee , Lee Kyung Eun , Gwak Hye Sun
Published: April 2019

Aim

Neutropenia is a common side effect of myelosuppressive chemotherapy. Administration of granulocyte colony‐stimulating factor is being used for neutropenia prophylaxis, but there are patients who develop neutropenia or febrile neutropenia despite prophylaxis. We attempted to identify potential risk factors for chemotherapy‐induced neutropenia in patients with pegfilgrastim prophylaxis.

Methods

This was a single‐center, retrospective, observational study of patients with breast cancer or diffuse large B‐cell lymphoma. We obtained patients’ data from electronic medical records, including baseline demographics and clinical characteristics regarding diseases, treatments and laboratory values. The outcome measures assessed were the incidence of neutropenia and febrile neutropenia.

Results

There were a total of 127 patients, including 77 patients with diffuse large B‐cell lymphoma (DLBCL) and 50 patients with breast cancer, and we analyzed 722 chemotherapy cycles. We found 88 cases (12.2%) of grade 3 or 4 neutropenia and 39 cases of febrile neutropenia (5.4%). In the univariate analysis, variables associated with both grade 3 or 4 neutropenia and febrile neutropenia were age, cancer type, cancer stage, radiotherapy and platelet count. A multivariate logistic regression model revealed that age, radiotherapy and platelet count were significant factors in severe neutropenia, whereas platelet count was the only statistically significant factor in febrile neutropenia. Platelet counts of less than 150 000/mm3 increased the risk of neutropenia and febrile neutropenia approximately fourfold. In the subgroup analysis of patients with DLBCL, it was found that platelet count was a significant factor for both neutropenia and febrile neutropenia.

Conclusion

Among cancer patients with pegfilgrastim prophylaxis, advanced age, absence of radiation therapy and low platelet count were independent predictors of neutropenia, and low platelet count was the predictor of febrile neutropenia.
Valence, Elections, and Legislative Institutions
Authors: Patty John W. , Schibber Constanza F. , Penn Elizabeth Maggie , Crisp Brian F.
Published: April 2019

To the degree that voters care about competence, expertise, and other valence characteristics of their representatives and political parties care about winning elections, parties have an incentive to signal that their legislators have such characteristics. We construct a model of parties, motivated by both reelection and by policy, that attempt to signal individual incumbents' valences to voters through the assignment of these members to positions of authority. The model illustrates how electorally motivated party leaders will have an incentive to promote less competent incumbents than they would if voters did not make inferences from promotion decisions. We derive the model's empirical implications and test them with original data on the careers of Chilean senators serving between 1998 and 2013. In support of the model's insights, we find that promotion to a leadership position is an effective signal to voters only if the promoted incumbent has extreme views relative to the party.