bluuebunny/crossref_metadata_2025 huggingface dataset:
The Index Theorem for Toeplitz Operators as a Corollary of Bott Periodicity
Authors: Baum Paul F , Van Erp Erik
Published: January 2021

This is an expository paper about the index of Toeplitz operators, and in particular Boutet de Monvel’s theorem [5]. We prove Boutet de Monvel’s theorem as a corollary of Bott periodicity, and independently of the Atiyah-Singer index theorem.
Peripheral ulcerative keratitis in rheumatoid arthritis patients taking tocilizumab: paradoxical manifestation or insufficient efficacy?
Authors: Cohen Florian , Gabison Eric Ernest , Stéphan Sophie , Belkhir Rakiba , Nocturne Gaetane , Best Anne-Laurence , Haigh Oscar , Barreau Emmanuel , Labetoulle Marc , Seror Raphaele , Rousseau Antoine
Published: January 2021

Objectives

Peripheral ulcerative keratitis (PUK) is a severe corneal condition associated with uncontrolled RA. Tocilizumab (TCZ) is used to control RA, however, episodes of paradoxical ocular inflammation have been reported in TCZ-treated patients. We report a case series of PUK in TCZ-treated RA patients with ophthalmological and systemic findings and discuss the potential underlying mechanisms.

Methods

Four patients (six eyes), 47–62 years of age, were included. At the onset of PUK, the median duration of RA was 13 years [interquartile range (IQR) 3–13] and the median treatment with TCZ was 9 months (IQR 3–14). Two patients had active disease [28-joint DAS (DAS28) >3.2] and the disease was controlled in two patients (DAS28 ≤3.2).

Results

TCZ was initially replaced by another immunomodulatory treatment in all patients and later reintroduced in two patients without PUK recurrence. Corneal inflammation was controlled in all cases with local and systemic treatments, with severe visual loss in one eye.

Conclusion

PUK may occur in patients with long-standing RA after a switch to TCZ and can be interpreted, depending on the context, as insufficient efficacy or a paradoxical manifestation. These cases highlight the urgent need for reliable biomarkers of the efficacy and paradoxical reactions of biologics.
A Method for Tapering Antipsychotic Treatment That May Minimize the Risk of Relapse
Authors: Horowitz Mark Abie , Jauhar Sameer , Natesan Sridhar , Murray Robin M , Taylor David
Published: January 2021

The process of stopping antipsychotics may be causally related to relapse, potentially linked to neuroadaptations that persist after cessation, including dopaminergic hypersensitivity. Therefore, the risk of relapse on cessation of antipsychotics may be minimized by more gradual tapering. There is converging evidence that suggests that adaptations to antipsychotic exposure can persist for months or years after stopping the medication—from animal studies, observation of tardive dyskinesia in patients, and the clustering of relapses in this time period after the cessation of antipsychotics. Furthermore, PET imaging demonstrates a hyperbolic relationship between doses of antipsychotic and D2 receptor blockade. We, therefore, suggest that when antipsychotics are reduced, it should be done gradually (over months or years) and in a hyperbolic manner (to reduce D2 blockade “evenly”): ie, reducing by one quarter (or one half) of the most recent dose of antipsychotic, equivalent approximately to a reduction of 5 (or 10) percentage points of its D2 blockade, sequentially (so that reductions become smaller and smaller in size as total dose decreases), at intervals of 3–6 months, titrated to individual tolerance. Some patients may prefer to taper at 10% or less of their most recent dose each month. This process might allow underlying adaptations time to resolve, possibly reducing the risk of relapse on discontinuation. Final doses before complete cessation may need to be as small as 1/40th a therapeutic dose to prevent a large decrease in D2 blockade when stopped. This proposal should be tested in randomized controlled trials.
Neural Processing of Repeated Emotional Scenes in Schizophrenia, Schizoaffective Disorder, and Bipolar Disorder
Authors: Trotti Rebekah L , Abdelmageed Sunny , Parker David A , Sabatinelli Dean , Tamminga Carol A , Gershon Elliot S , Keedy Sarah K , Keshavan Matcheri S , Pearlson Godfrey D , Sweeney John A , McDowell Jennifer E , Clementz Brett A
Published: January 2021

Impaired emotional processing and cognitive functioning are common in schizophrenia, schizoaffective disorder, and bipolar disorders, causing significant socioemotional disability. While a large body of research demonstrates abnormal cognition/emotion interactions in these disorders, previous studies investigating abnormalities in the emotional scene response using event-related potentials (ERPs) have yielded mixed findings, and few studies compare findings across psychiatric diagnoses. The current study investigates the effects of emotion and repetition on ERPs in a large, well-characterized sample of participants with schizophrenia-bipolar syndromes. Two ERP components that are modulated by emotional content and scene repetition, the early posterior negativity (EPN) and late positive potential (LPP), were recorded in healthy controls and participants with schizophrenia, schizoaffective disorder, bipolar disorder with psychosis, and bipolar disorder without psychosis. Effects of emotion and repetition were compared across groups. Results displayed significant but small effects in schizophrenia and schizoaffective disorder, with diminished EPN amplitudes to neutral and novel scenes, reduced LPP amplitudes to emotional scenes, and attenuated effects of scene repetition. Despite significant findings, small effect sizes indicate that emotional scene processing is predominantly intact in these disorders. Multivariate analyses indicate that these mild ERP abnormalities are related to cognition, psychosocial functioning, and psychosis severity. This relationship suggests that impaired cognition, rather than diagnosis or mood disturbance, may underlie disrupted neural scene processing in schizophrenia-bipolar syndromes.
Effects of sleep restriction on the sleep electroencephalogram of adolescents
Authors: Campbell Ian G , Cruz-Basilio Alejandro , Darchia Nato , Zhang Zoey Y , Feinberg Irwin
Published: January 2021

Study Objectives

This report describes findings from an ongoing longitudinal study of the effects of varied sleep durations on wake and sleep electroencephalogram (EEG) and daytime function in adolescents. Here, we focus on the effects of age and time in bed (TIB) on total sleep time (TST) and nonrapid eye movement (NREM) and rapid eye movement (REM) EEG.

Methods

We studied 77 participants (41 male) ranging in age from 9.9 to 16.2 years over the 3 years of this study. Each year, participants adhered to each of three different sleep schedules: four consecutive nights of 7, 8.5, or 10 h TIB.

Results

Altering TIB successfully modified TST, which averaged 406, 472 and 530 min on the fourth night of 7, 8.5, and 10 h TIB, respectively. As predicted by homeostatic models, shorter sleep durations produced higher delta power in both NREM and REM although these effects were small. Restricted sleep more substantially reduced alpha power in both NREM and REM sleep. In NREM but not REM sleep, sleep restriction strongly reduced both the all-night accumulation of sigma EEG activity (11–15 Hz energy) and the rate of sigma production (11–15 Hz power).

Conclusions

The EEG changes in response to TIB reduction are evidence of insufficient sleep recovery. The decrease in sigma activity presumably reflects depressed sleep spindle activity and suggests a manner by which sleep restriction reduces waking cognitive function in adolescents. Our results thus far demonstrate that relatively modest TIB manipulations provide a useful tool for investigating adolescent sleep biology.
Effects of moderate sleep restriction during 8-week calorie restriction on lipoprotein particles and glucose metabolism
Authors: Sparks Joshua R , Porter Ryan R , Youngstedt Shawn D , Bowyer Kimberly P , Durstine J Larry , Wang Xuewen
Published: January 2021

Study Objectives

This study examined how glucose, glucose regulatory hormones, insulin sensitivity, and lipoprotein subclass particle concentrations and sizes change with sleep restriction during weight loss elicited by calorie restriction.

Methods

Overweight or obese adults were randomized into an 8-week calorie restriction intervention alone (CR, n = 12; 75% female; body mass index = 31.4 ± 2.9 kg/m2) or combined with sleep restriction (CR+SR, n = 16; 75% female; body mass index = 34.5 ± 3.1 kg/m2). Participants in both groups were given the same instructions to reduce calorie intake. Those in the CR+SR group were instructed to reduce their habitual time-in-bed by 30–90 minutes 5 days each week with 2 ad libitum sleep days. Fasting venous blood samples were collected at pre- and post-intervention.

Results

Differential changes were found between the two groups (p = 0.028 for group × time interaction) in glucagon concentration, which decreased in the CR group (p = 0.016) but did not change in CR+SR group. Although changes in mean HDL particle (HDL-P) size and visfatin concentration were not statistically different between groups (p = 0.066 and 0.066 for group×time interaction, respectively), mean HDL-P size decreased only in the CR+SR group (Cohen’s d = 0.50, p = 0.022); visfatin concentrations did not change significantly in either group but appeared to decrease in the CR group (Cohen’s d = 0.67, p = 0.170) but not in the CR+SR group (Cohen’s d = 0.43, p = 0.225).

Conclusion

These results suggest that moderate sleep restriction, despite the presence of periodic ad libitum sleep, influences lipoprotein subclass particles and glucose regulation in individuals undergoing calorie restriction.

Clinical trial registration: ClinicalTrials.gov (NCT02413866, Weight Outlooks by Restriction of Diet and Sleep)
The role of reproductive loss on flock performance: a comparison of nine industry flocks
Authors: Shorten Paul R , Edwards Sara J , Juengel Jenny L
Published: January 2021

The reproductive performance of a sheep flock is dependent on a multitude of complex interacting factors. Attaining optimal flock performance requires information about how the reproductive steps are linked and relate to readily available measurements of the state of the flock. The goal was to use data from nine commercial flocks (greater than 300,000 records) to investigate and model the key reproductive steps affecting flock reproductive performance. We also developed a maximum-likelihood based methodology to predict flock ovulation rate based on measurements of the number of fetuses at mid-pregnancy (detected by ultrasound-scanning). The model was used to determine how changes in premating liveweight, age, predicted ovulation rate, number of fetuses at mid-pregnancy, lamb survival and lamb growth rate affect the total lamb liveweight at weaning per ewe exposed to the ram in each flock. The data from the commercial flocks were also used to investigate the role of ewe age and premating liveweight on each reproductive step. Sensitivity analyses were conducted to identify the key reproductive steps affecting flock reproductive performance, with a focus on understanding how these steps vary between flocks. The elasticity for embryo survival was 60% of that for lamb survival for these flocks and the elasticities for ovulation rate were highly variable between flocks (0.16 to 0.50 for mature ewes). This indicates that ovulation rate was near-optimal for some flocks, whereas there was potential to significantly improve flock performance in suboptimal flocks. The elasticity for ewe premating liveweight was highly variable between flocks (−0.03 to 0.84 for mature ewes and −0.18 to 1.39 for ewe lambs), indicating that premating liveweight ranged from optimal to suboptimal between flocks. For these suboptimal farms, the opportunity exists to increase flock performance through improved management of ewe premating liveweight. Reproductive loss was significantly greater in ewe lambs than mature ewes, although the difference is dependent on the stage of reproduction and flock. Predicted ovulation rate was 25% lower for ewe lambs and there was a 30% relative decrease in the predicted embryo survival probability from ovulation to scanning for ewe lambs. There was a 10% relative decrease in lamb survival probability from birth to weaning for ewe lambs and lamb growth rate was 25% lower for ewe lambs.
Ending the ‘Cult of the Broken Home’: Divorce, Children and the Changing Emotional Dynamics of Separating British Families, c. 1945–90
Authors: Miller Ian
Published: January 2021

From the 1960s, rising divorce rates forced a re-thinking of family dynamics beyond the nuclear. Traditionally, experts and the public had presumed that children from ‘broken homes’ typically drifted into juvenile delinquency and crime. Children of divorce were blamed for a plethora of social problems. The increasingly common nature of divorce meant that this model was no longer sustainable. Post-war children of divorce were more likely to be framed as ‘emotionally vulnerable’ and studied in more nuanced ways, not least because it seemed increasingly obvious that not all affected children grew up delinquent. However, a new consensus emerged that problems could only be avoided if parents created appropriate emotional conditions while separating and divorcing, and if parents and children openly communicated their feelings throughout the process. Children themselves were actively encouraged, through a new genre of divorce manuals often aimed at them, to express their emotions with parents and friends. Using Britain as a case study, this article argues that emotions became central to discussion of divorce in the post-war period, placing onuses on breaking down families to create a positive emotional space for affected children.
High-Throughput Transcriptomics Platform for Screening Environmental Chemicals
Authors: Harrill Joshua A , Everett Logan J , Haggard Derik E , Sheffield Thomas , Bundy Joseph L , Willis Clinton M , Thomas Russell S , Shah Imran , Judson Richard S
Published: January 2021

New approach methodologies (NAMs) that efficiently provide information about chemical hazard without using whole animals are needed to accelerate the pace of chemical risk assessments. Technological advancements in gene expression assays have made in vitro high-throughput transcriptomics (HTTr) a feasible option for NAMs-based hazard characterization of environmental chemicals. In this study, we evaluated the Templated Oligo with Sequencing Readout (TempO-Seq) assay for HTTr concentration-response screening of a small set of chemicals in the human-derived MCF7 cell model. Our experimental design included a variety of reference samples and reference chemical treatments in order to objectively evaluate TempO-Seq assay performance. To facilitate analysis of these data, we developed a robust and scalable bioinformatics pipeline using open-source tools. We also developed a novel gene expression signature-based concentration-response modeling approach and compared the results to a previously implemented workflow for concentration-response analysis of transcriptomics data using BMDExpress. Analysis of reference samples and reference chemical treatments demonstrated highly reproducible differential gene expression signatures. In addition, we found that aggregating signals from individual genes into gene signatures prior to concentration-response modeling yielded in vitro transcriptional biological pathway altering concentrations (BPACs) that were closely aligned with previous ToxCast high-throughput screening assays. Often these identified signatures were associated with the known molecular target of the chemicals in our test set as the most sensitive components of the overall transcriptional response. This work has resulted in a novel and scalable in vitro HTTr workflow that is suitable for high-throughput hazard evaluation of environmental chemicals.
Genome Sequence Data of Peronophythora litchii, an Oomycete Pathogen Causing Litchi Downy Blight
Authors: Guo Hengyuan , Bao Jiandong , Lin Lianyu , Wang Zhixin , Shi Mingyue , Huang Yuting , Wang Rongbo , Li Benjin , Liu Peiqing , Chen Qinghe
Published: January 2021

Peronophythora litchii is an oomycete pathogen that exclusively infects litchi, with infection stages affecting a broad range of tissues. In this study, we obtained a near chromosome-level genome assembly of P. litchii ZL2018 from China using Oxford Nanopore Technologies long-read sequencing and Illumina short-read sequencing. The genome assembly was 64.15 Mb in size and consisted of 81 contigs with an N50 of 1.43 Mb and a maximum length of 4.74 Mb. Excluding 34.67% of repeat sequences, 14,857 protein-coding genes were identified, among which 14,447 genes were annotated. We also predicted 306 candidate RxLR effectors in the assembly. The high-quality genome assembly and annotation resources reported in this study will provide new insight into the infection mechanisms of P. litchii.

[Formula: see text] The author(s) have dedicated the work to the public domain under the Creative Commons CC0 “No Rights Reserved” license by waiving all of his or her rights to the work worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law. 2021
Management of Ralstonia solanacearum in Tomato Using ZnO Nanoparticles Synthesized Through Matricaria chamomilla
Authors: Khan Raja Asad Ali , Tang Yuanyang , Naz Ishrat , Alam Syed Sartaj , Wang Wenzhao , Ahmad Musharaf , Najeeb Saba , Rao Crist , Li Yanlin , Xie Bingyan , Li Yan
Published: January 2021

Matricaria chamomilla flower extract was used as a biocompatible material for synthesis of zinc oxide nanoparticles (ZnONPs). The synthesized NPs were evaluated for their antibacterial potential in vitro and in vivo against the Gram-negative bacterium Ralstonia solanacearum, which causes devastating bacterial wilt disease in tomato and other crops. Synthesized ZnONPs were further analyzed by UV-visible spectroscopy, Fourier transform infrared spectroscopy, x-ray diffraction, transmission electron microscopy, and scanning electron microscopy with energy-dispersive spectroscopy. The synthesized polydisperse ZnONPs were found to be in the size range of 8.9 to 32.6 nm, and at 18.0 µg ml−1 exhibited maximum in vitro growth inhibition of the pathogen R. solanacearum. Scanning electron microscopy analysis of affected bacterial cells showed morphological deformation such as disruption of the cell membrane and wall, and the leakage of cell contents. Results of in vivo studies also showed that application of ZnONPs to the artificially inoculated tomato plants with the pathogen R. solanacearum significantly enhanced the plant growth by reducing bacterial soil population and disease severity as compared with the untreated control. Biosynthesized ZnONPs could be an effective approach to control the bacterium R. solanacearum.
Genetic Structure ofPlasmodiophora brassicaePopulations Virulent on Clubroot Resistant Canola (Brassica napus)
Authors: Askarian Homa , Akhavan Alireza , González Leonardo Galindo , Hwang Sheau-Fang , Strelkov Stephen E.
Published: January 2021

Clubroot, caused by Plasmodiophora brassicae Woronin, is a significant threat to the canola (Brassica napus L.) industry in Canada. Clubroot resistance has been overcome in more than 200 fields since 2013, representing one of the biggest challenges to sustainable canola production. The genetic structure of 36 single-spore isolates derived from 12 field isolates of P. brassicae collected before and after the introduction of clubroot resistant (CR) canola cultivars (2005–2014) was evaluated by simple sequence repeat (SSR) marker analysis. Polymorphisms were detected in 32 loci with the identification of 93 distinct alleles. A low level of genetic diversity was found among the single-spore isolates. Haploid linkage disequilibrium and number of migrants suggested that recombination and migration were rare or almost absent in the tested P. brassicae population. A relatively clear relationship was found between the genetic structure and virulence phenotypes of the pathogen as defined on the differential hosts of Somé et al., Williams, and the Canadian Clubroot Differential (CCD) set. Although genetic variability within each pathotype group, as classified on each differential system, was low, significant genetic differentiation was observed among the pathotypes. The highest correlation between genetic structure and virulence was found among matrices produced with genetic data and the hosts of the CCD set, with a threshold index of disease of 50% to distinguish susceptible from resistant reactions. Genetically homogeneous single-spore isolates provided a more complete and clearer picture of the population genetic structure of P. brassicae, and the results suggest some promise for the development of pathotype-specific primers.
Effect of Ozone on Inactivation of Purified Pepper Mild Mottle Virus and Contaminated Pepper Seed
Authors: Stommel John R. , Dumm Judith M. , Hammond John
Published: January 2021

Pepper mild mottle virus (PMMoV) is a major viral pathogen of pepper (Capsicum spp.). PMMoV is readily mechanically transmitted and is seed transmissible. Trisodium phosphate (TSP) treatment is commonly used to reduce the level of viable PMMoV in contaminated seed. Ozone is efficacious in disinfecting fungal-contaminated seed and disrupting bacterial and viral pathogens on various substrates. The purpose of this study was to evaluate efficacy of ozone and chemical treatment on PMMoV viability. Treated pepper seed infectivity was evaluated via bioassay with Nicotiana benthamiana. Symptoms of PMMoV infection were not observed in bioassays of TSP-treated seed. Sufficient viable PMMoV remained on ozone-treated seed to cause infection, which was confirmed by ELISA. Neither treatment affected seed germination. Ozone treatment of purified PMMoV was assessed to determine the extent, if any, of PMMoV inactivation by ozone. At the low PMMoV concentration (0.01 mg/ml), 14-h ozone exposure eliminated infectivity as determined by N. benthamiana bioassays with ELISA confirmations. At the higher PMMoV concentration (0.1 mg/ml), ozone treatment was insufficient to prevent infection. Ozone inactivation of purified PMMoV was quantified via bioassay using the local lesion host N. glutinosa and quantitative real-time PCR. Ozone exposure reduced lesion counts and PMMoV concentration, and PMMoV degradation increased with exposure time. Although PMMoV infection was eliminated at the low PMMoV concentration, bioassays using naturally infected seed and purified PMMoV preparations at relatively higher concentrations demonstrated that ozone is not efficacious as a standard treatment to sufficiently reduce levels of infective PMMoV in contaminated pepper seed.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Vibrio aestuarianus subsp. cardii subsp. nov., pathogenic to the edible cockles Cerastoderma edule in France, and establishment of Vibrio aestuarianus subsp. aestuarianus subsp. nov. and Vibrio aestuarianus subsp. francensis subsp. nov.
Authors: Garcia Céline , Mesnil Aurélie , Tourbiez Delphine , Moussa Mirna , Dubreuil Christine , Gonçalves de Sa Amélie , Chollet Bruno , Godfrin Yoann , Dégremont Lionel , Serpin Delphine , Travers Marie-Agnès
Published: January 2021

Cockle mortality events have been reported in northern France since 2012. In the present study, we describe and investigate the implication of a potential bacterial causative agent in cockle mortality. Bacteria isolated from five different cockle mortality events were characterized and studied. Using phenotypic analysis combined with DNA–DNA hybridization (DDH) and whole genome sequencing, the isolates were shown to belong to

Vibrio aestuarianus

, a species regularly detected in France during oyster mortality events. Comparison of the strains from cockles with strains from French oysters and the type strain showed that the strains from cockles were genetically different to those from oysters and also different to the

V. aestuarianus

type strain. Moreover, the cockle and oyster strains were classified into two different, but close, groups both separated from the type strain by: (1) analyses of the ldh gene sequences; (2) DDH assays between 12/122 3T3T (LMG 31436T=DSM 109723T), a representative cockle strain, 02/041T (CIP 109791T=LMG 24517T) representative oyster strain and

V. aestuarianus

type strain LMG 7909T; (3) average nucleotide identity values calculated on the genomes; and (4) phenotypic traits. Finally, results of MALDI-TOF analyses also revealed specific peaks discriminating the three representative strains. The toxicity of representative strains of these cockle isolates was demonstrated by experimental infection of hatchery-produced cockles. The data therefore allow us to propose two novel subspecies of

Vibrio aestuarianus

:

Vibrio aestuarianus

subsp. cardii subsp. nov. for the cockle strains and

Vibrio aestuarianus

subsp.

francensis

subsp. nov. for the Pacific oyster strains, in addition to an emended description of the species

Vibrio aestuarianus

.
Clinical Validation of a Proteomic Biomarker Threshold for Increased Risk of Spontaneous Preterm Birth
Authors: Burchard Julja , Polpitiya Ashoka D. , Fox Angela C. , Randolph Todd , Fleischer Tracey C. , Dufford Max , Garite Thomas J. , Critchfield Greg C. , Boniface J. Jay , Kearney Paul E.
Published: January 2021

Preterm births are prevalent and a leading cause of neonatal death in the United States. Despite the availability of effective interventions, to date there is not a robust and widely applicable test to identify pregnancies at high risk for spontaneous preterm birth (sPTB). Previously, a sPTB predictor based on the ratio of two proteins, IBP4/SHBG, was validated as an accurate predictor of sPTB in the observational study Proteomic Assessment of Preterm Risk (PAPR). Here it is demonstrated that the same predictor threshold associated with 2-fold increased risk of sPTB, namely −1.4, is also statistically significant for predicting elevated risk of sPTB in the observational study Multicenter Assessment of a Spontaneous Preterm Birth Risk Predictor (TreeToP).
Segmentor: A tool for manual refinement of 3D microscopy annotations
Authors: Borland David , McCormick Carolyn M. , Patel Niyanta K. , Krupa Oleh , Mory Jessica T. , Beltran Alvaro A. , Farah Tala M. , Escobar-Tomlienovich Carla F. , Olson Sydney S. , Kim Minjeong , Wu Guorong , Stein Jason L.
Published: January 2021

Background

Recent advances in tissue clearing techniques, combined with high-speed image acquisition through light sheet microscopy, enable rapid three-dimensional (3D) imaging of biological specimens, such as whole mouse brains, in a matter of hours. Quantitative analysis of such 3D images can help us understand how changes in brain structure lead to differences in behavior or cognition, but distinguishing features of interest, such as nuclei, from background can be challenging. Recent deep learning-based nuclear segmentation algorithms show great promise for automated segmentation, but require large numbers of manually and accurately labeled nuclei as training data.

Results

We present Segmentor, an open-source tool for reliable, efficient, and user-friendly manual annotation and refinement of objects (e.g., nuclei) within 3D light sheet microscopy images. Segmentor employs a hybrid 2D-3D approach for visualizing and segmenting objects and contains features for automatic region splitting, designed specifically for streamlining the process of 3D segmentation of nuclei. We show that editing simultaneously in 2D and 3D using Segmentor significantly decreases time spent on manual annotations without affecting accuracy.

Conclusions

Segmentor is a tool for increased efficiency of manual annotation and refinement of 3D objects that can be used to train deep learning segmentation algorithms, and is available athttps://www.nucleininja.org/andhttps://github.com/RENCI/Segmentor.
Clinical evaluation of BCL-2/XL levels pre- and post- HER2-targeted therapy
Authors: Zoeller Jason J. , Press Michael F. , Selfors Laura M. , Dering Judy , Slamon Dennis J. , Hurvitz Sara A. , Brugge Joan S.
Published: January 2021

Our previous pre-clinical work defined BCL-2 induction as a critical component of the adaptive response to lapatinib-mediated inhibition of HER2. To determine whether a similar BCL-2 upregulation occurs in lapatinib-treated patients, we evaluated gene expression within tumor biopsies, collected before and after lapatinib or trastuzumab treatment, from the TRIO-B-07 clinical trial (NCT#00769470). We detected BCL-2 mRNA upregulation in both HER2+/ER- as well as HER2+/ER+ patient tumors treated with lapatinib or trastuzumab. To address whether mRNA expression correlated with protein expression, we evaluated pre- and post-treatment tumors for BCL-2 via immunohistochemistry. Despite BCL-2 mRNA upregulation within HER2+/ER- tumors, BCL-2 protein levels were undetectable in most of the lapatinib- or trastuzumab-treated HER2+/ER- tumors. BCL-2 upregulation was evident within the majority of lapatinib-treated HER2+/ER+ tumors and was often coupled with increased ER expression and decreased proliferation. Comparable BCL-2 upregulation was not observed within the trastuzumab-treated HER2+/ER+ tumors. Together, these results provide clinical validation of the BCL-2 induction associated with the adaptive response to lapatinib and support evaluation of BCL-2 inhibitors within the context of lapatinib and other HER2-targeted receptor tyrosine kinase inhibitors.
Immune response to SARS-CoV-2 in the nasal mucosa in children and adults
Authors: Koch Clarissa M , Prigge Andrew D , Anekalla Kishore R , Shukla Avani , Do-Umehara Hanh Chi , Setar Leah , Chavez Jairo , Abdala-Valencia Hiam , Politanska Yuliya , Markov Nikolay S , Hahn Grant R , Heald-Sargent Taylor , Sanchez-Pinto L Nelson , Muller William J , Misharin Alexander V , Ridge Karen M , Coates Bria M
Published: January 2021

Rationale

Despite similar viral load and infectivity rates between children and adults infected with SARS-CoV-2, children rarely develop severe illness. Differences in the host response to the virus at the primary infection site are among the proposed mechanisms.

Objectives

To investigate the host response to SARS-CoV-2, respiratory syncytial virus (RSV), and influenza virus (IV) in the nasal mucosa in children and adults.

Methods

Clinical outcomes and gene expression in the nasal mucosa were analyzed in 36 children hospitalized with SARS-CoV-2 infection, 24 children with RSV infection, 9 children with IV infection, 16 adults with mild to moderate SARS-CoV-2 infection, and 7 healthy pediatric and 13 healthy adult controls.

Results

In both children and adults, infection with SARS-CoV-2 leads to an interferon response in the nasal mucosa. The magnitude of the interferon response correlated with the abundance of viral reads and was comparable between symptomatic children and adults infected with SARS-CoV-2 and symptomatic children infected with RSV and IV. Cell type deconvolution identified an increased abundance of immune cells in the samples from children and adults with a viral infection. Expression of ACE2 and TMPRSS2 – key entry factors for SARS-CoV-2 – did not correlate with age or presence or absence of viral infection.

Conclusions

Our findings support the hypothesis that differences in the immune response to SARS-CoV-2 determine disease severity, independent of viral load and interferon response at the primary infection primary site.
The Addiction Risk Factor: A Unitary Genetic Vulnerability Characterizes Substance Use Disorders and Their Associations with Common Correlates
Authors: Hatoum Alexander S. , Johnson Emma C. , Colbert Sarah M.C. , Polimanti Renato , Zhou Hang , Walters Raymond , Gelernter Joel , Edenberg Howard J. , Bogdan Ryan , Agrawal Arpana
Published: January 2021

Substance use disorders commonly co-occur with one another and with other psychiatric disorders. They share common features including high impulsivity, negative affect, and lower executive function. We tested whether a common genetic factor undergirds liability to problematic alcohol use (PAU), problematic tobacco use (PTU), cannabis use disorder (CUD), and opioid use disorder (OUD) by applying genomic structural equation modelling to genome-wide association study summary statistics for individuals of European ancestry (Total N = 1,019,521; substance specific Ns range: 82,707-435,563), while adjusting for the genetics of substance use (Ns = 184,765-632,802). We also tested whether shared liability across SUDs is associated with behavioral constructs (risk taking, executive function, neuroticism; Ns = 328,339-427,037) and non-substance use psychopathology (psychotic, compulsive, and early neurodevelopmental disorders). Shared genetic liability to PAU, PTU, CUD, and OUD was characterized by a unidimensional addiction risk factor (termed The Addiction-Risk-Factor, independent of substance use. OUD and CUD demonstrated the largest loadings, while problematic tobacco use showed the lowest loading. The Addiction-Risk-Factor was associated with risk taking, neuroticism, executive function, and non-substance psychopathology, but retained specific variance before and after accounting for genetics of substance use. Thus, a common genetic factor partly explains susceptibility for alcohol, tobacco, cannabis, and opioid use disorder. The Addiction-Risk-Factor has a unique genetic architecture that is not shared with normative substance use or non-substance psychopathology, suggesting that addiction is not the linear combination of substance use and psychopathology.
Prevalence of chronic kidney disease in the general population in Latin America and the Caribbean: Protocol for a systematic review and meta-analysis
Authors: Sequeiros-Buendia Diego A , Villa-Ato Camila S , Weiss-Carlini Marlies , Carrillo-Larco Rodrigo M
Published: January 2021

Background

Chronic kidney disease (CKD) is a global health issue with a general prevalence of 9%. Although the most affected populations are in low- and middle-income countries, the epidemiology of CKD in these countries remains poorly understood and prevalence estimates come from global efforts informed by data from high-income countries; these prevalence estimates need to be compared –and if needed updated–with local estimates.

Objective

To estimate the prevalence of CKD in adults in Latin America and the Caribbean (LAC).

Methods

Systematic review and meta-analysis. We will search Embase, Medline, Global Health (these three through Ovid), Scopus and LILACS. No date or language restrictions will be set. We seek observational studies with a random sample of the general population. We will screen titles and abstracts, we will then study the selected reports. Both phases will be done by two reviewers independently. Data extraction will be performed by two researchers independently using a pre-specified Excel form. We will evaluate the risk of bias with the scale proposed by Hoy et al. for prevalence studies. We will conduct a meta-analysis of prevalence estimates, if there are at least three reports homogeneous enough to be pooled; we will use a random-effects model.

Conclusions

This systematic review and meta-analysis will provide the prevalence of CKD in adults in countries of LAC. Currently, information regarding CKD in the region is limited. This work will provide evidence to elucidate the magnitude of CKD prevalence in LAC. In so doing, we will provide evidence to inform the scientific community about the burden of CKD in LAC so that research, policies and health interventions can be planned accordingly.
Foveal vision at the time of microsaccades
Authors: Mostofi Naghmeh , Intoy Janis , Rucci Michele
Published: January 2021

Humans use rapid eye movements (saccades) to inspect stimuli with the foveola, the region of the retina where receptors are most densely packed. It is well established that visual sensitivity is generally attenuated during these movements, a phenomenon known as saccadic suppression. This effect is commonly studied with large, often peripheral, stimuli presented during instructed saccades. However, little is known about how saccades modulate the foveola and how the resulting dynamics unfold during natural visual exploration. Here we measured the foveal dynamics of saccadic suppression in a naturalistic high-acuity task, a task designed after primate’s social grooming, which—like most explorations of fine patterns—primarily elicits minute saccades (microsaccades). Leveraging on recent advances in gaze-contingent display control, we were able to systematically map the peri-saccadic time-course of sensitivity across the foveola. We show that contrast sensitivity is not uniform across this region and that both the extent and dynamics of saccadic suppression vary within the foveola. Suppression is stronger and faster in the most central portion, where sensitivity is generally higher and selectively rebounds at the onset of a new fixation. These results shed new light on the modulations experienced by foveal vision during the saccade-fixation cycle and explain some of the benefits of microsaccades.
Nonlinear visuoauditory integration in the mouse superior colliculus
Authors: Ito Shinya , Si Yufei , Litke Alan M. , Feldheim David A.
Published: January 2021

Sensory information from different modalities is processed in parallel, and then integrated in associative brain areas to improve object identification and the interpretation of sensory experiences. The Superior Colliculus (SC) is a midbrain structure that plays a critical role in integrating visual, auditory, and somatosensory input to assess saliency and promote action. Although the response properties of the individual SC neurons to visuoauditory stimuli have been characterized, little is known about the spatial and temporal dynamics of the integration at the population level. Here we recorded the response properties of SC neurons to spatially restricted visual and auditory stimuli using large-scale electrophysiology. We then created a general, population-level model that explains the spatial, temporal, and intensity requirements of stimuli needed for sensory integration. We found that the mouse SC contains topographically organized visual and auditory neurons that exhibit nonlinear multisensory integration. We show that nonlinear integration depends on properties of auditory but not visual stimuli. We also find that a heuristically derived nonlinear modulation function reveals conditions required for sensory integration that are consistent with previously proposed models of sensory integration such as spatial matching and the principle of inverse effectiveness.
A trigger phosphodiesterase modulates the global c-di-GMP pool, motility and biofilm formation inVibrio parahaemolyticus
Authors: Martínez-Méndez Raquel , Camacho-Hernández Diego A. , Sulvarán-Guel Elizabeth , Zamorano-Sánchez David
Published: January 2021

Vibrio parahaemolyticuscells transit from free swimming to surface adapted lifestyles, such as swarming colonies and three-dimensional biofilms. These transitions are regulated by sensory modules and regulatory networks that involve the second messenger cyclic dimeric guanosine monophosphate (c-di-GMP). In this work, we show that a previously uncharacterized c-di-GMP phosphodiesterase (VP1881) fromV. parahaemolyticusplays an important role in modulating the c-di-GMP pool. We found that the product of VP1881 promotes its own expression when the levels of c-di-GMP were low or when the phosphodiesterase was catalytically inactive. This behavior has been observed in a class of c-di-GMP receptors called Trigger phosphodiesterases, hence we named the product of VP1881 TpdA, for Trigger phosphodiesterase A. The absence oftpdAshowed a negative effect on swimming motility while its overexpression from an IPTG inducible promoter showed a positive effect on both swimming and swarming motility, and a negative effect on biofilm formation. Changes in TpdA abundance altered the expression of representative polar and lateral flagellar genes as well as the biofilm related genecpsA. Our results also revealed that autoactivation of the native PtpdApromoter is sufficient to alter c-di-GMP signaling responses such as swarming and biofilm formation inV. parahaemolyticus, an observation that could have important implications in the dynamics of this social behaviors.

Importance

C-di-GMP trigger phosphodiesterases (PDEs) could play a key role in controlling the heterogeneity of biofilm-matrix composition, a property that endows characteristics that are potentially relevant for sustaining integrity and functionality of biofilms in a variety of natural environments. Trigger PDEs are not always easy to identify based on their sequence, hence not many examples of these type of signaling proteins have been reported in the literature. Here we report on the identification of a novel trigger PDE inV. parahaemolyticusand provide evidence suggesting that its autoactivation could play an important role in the progression of swarming motility and biofilm formation, multicellular behaviors that are important for the survival and dissemination of this environmental pathogen.
TheGASAGene Family inTheobroma cacao: Genome wide Identification and Expression Analysis
Authors: Abdullah  , Faraji Sahar , Mehmood Furrukh , Malik Hafiz Muhammad Talha , Ahmed Ibrar , Heidari Parviz , Poczai Peter
Published: January 2021

The gibberellic acid-stimulatedArabidopsis(GASA/GAST) gene family is widely distributed in plants. The role of theGASAgene family has been reported previously in various physiological and biological processes, such as cell division, root and seed development, stem growth, and fruit ripening. These genes also provide resistance to abiotic and biotic stresses including antimicrobial, antiviral, and antifungal. Here, we report 17tcGASAgenes inTheobroma cacaoL. distributed on six chromosomes. The gene structure, promoter-region sequences, protein structure, and biochemical properties, expression, and phylogenetics of alltcGASAs were analyzed. Phylogenetic analyses divided tcGASA proteins into five groups. The nine segmentally duplicating genes form four pairs and cluster together in phylogenetic tree. Purifying selection pressure was recorded ontcGASA, including duplicated genes. Several stress/hormone-responsive cis-regulatory elements were also recognized in the promoter region oftcGASAs.Differential expression analyses revealed that most of thetcGASAgenes showed elevated expression in the seeds (cacao food), implying their role in seed development. The black rod disease of genusPhytophthoracaused up to 20–25% loss (700,000 metric tons) in world cacao production. The role oftcGASAgenes in conferring fungal resistance was also explored based on RNAseq data againstPhytophthora megakarya. The differential expression oftcGASAgenes was recorded between the tolerant and susceptible cultivars of cacao plants, which were inoculated with the fungus for 24h and 72h. This differential expression indicating possible role oftcGASAgenes to fungal resistant in cacao. Our findings provide new insight into the function, evolution, and regulatory system of theGASAfamily genes inT.cacao and provide new target genes for development of fungi-resistant cacao varieties in breeding programs.
Unique Protein Interaction Networks Define The Chromatin Remodeling Module of The NuRD Complex
Authors: Tabar Mehdi Sharifi , Giardina Caroline , Feng Yue Julie , Francis Habib , Sani Hakimeh Moghaddas , Low Jason K. K. , Mackay Joel P. , Bailey Charles G. , Rasko John E.J.
Published: January 2021

The combination of four proteins and their paralogues including MBD2/3, GATAD2A/B, CDK2AP1, and CHD3/4/5, which we refer to as the MGCC module, form the chromatin remodeling module of the Nucleosome Remodeling and Deacetylase (NuRD) complex, a gene repressor complex. Specific paralogues of the MGCC subunits such as MBD2 and CHD4 are amongst the key repressors of adult-stage fetal globin and provide important targets for molecular therapies in beta (β)-thalassemia. However, mechanisms by which the MGCC module acquires paralogue-specific function and specificity have not been addressed to date. Understanding the protein-protein interaction (PPI) network of the MGCC subunits is essential in defining underlying mechanisms and developing treatment strategies. Therefore, using pulldown followed by mass spectrometry analysis (PD-MS) we report a proteome-wide interaction network of the MGCC module in a paralogue-specific manner. Our data also demonstrate that the disordered C-terminal region of CHD3/4/5 is a gateway to incorporate remodeling activity into both the ChAHP (CHD4, ADNP, HP1γ) and NuRD complexes in a mutually exclusive manner. We define a short aggregation prone region (APR) within the C-terminal segment of GATAD2B that is essential for the interaction of CHD4 and CDK2AP1 with the NuRD complex. Finally, we also report an association of CDK2AP1 with the Nuclear Receptor Co-Repressor (NCOR) complex. Overall, this study provides insight into the possible mechanisms through which the MGCC module can achieve specificity and diverse biological functions.
Arabidopsis inositol polyphosphate kinases IPK1 and ITPK1 modulate crosstalks between SA-dependent immunity and phosphate-starvation responses
Authors: Gulabani Hitika , Goswami Krishnendu , Walia Yashika , Noor Jewel Jameeta , Ingole Kishor D. , Roy Abhisha , Laha Debabrata , Schaaf Gabriel , Bhattacharjee Saikat
Published: January 2021

The propensity for polyphosphorylation makesmyo-inositol derivatives, the inositol polyphosphates (InsPs), especially phytic acid or inositol hexakisphosphate (InsP6) the major form of phosphate storage in plants. Acts of pyrophosphorylation on InsP6generates InsP7or InsP8containing high-energy phosphoanhydride bonds that are harnessed during energy requirements of a cell. Also implicated as co-factors for several phytohormone signaling networks, InsP7/InsP8modulate key developmental processes. With recent identification as the common moeity for transducing both jasmonic acid (JA) and phosphate-starvation responses (PSR), InsP8is the classic example of a metabolite that may moonlight crosstalks to different cellular pathways during diverse stress adaptations. We show here thatArabidopsis thalianaINOSITOL PENTAKISPHOSPHATE 2-KINASE (IPK1), INOSITOL 1,3,4-TRISPHOSPHATE 5/6-KINASE 1 (ITPK1), and DIPHOSPHOINOSITOL PENTAKISPHOSPHATE KINASE 2 (VIH2), but not other InsP-kinases, suppress basal salicylic acid (SA)-dependent immunity. Inipk1, itpk1orvih2mutants, elevated endogenous SA levels and constitutive activation of defense signaling lead to enhanced resistance against the virulentPseudomonas syringae pvtomato DC3000 (PstDC3000) strain. Our data reveal that activated SA-signaling sectors in these mutants modulate expression amplitudes of phosphate-starvation inducible (PSI)-genes, reported earlier. In turn, via mutualism the heightened basal defenses in these mutants require upregulated PSI-gene expressions likely highlighting the increased demand of phosphates required to support immunity. We demonstrate that SA is induced in phosphate-deprived plants, however its defense-promoting functions are likely diverted to PSR-supportive roles. Overall, our investigations reveal selective InsPs as crosstalk mediators among diverse signaling networks programming stress-appropriate adaptations.