bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole-genome analysis of a rare G15P[21] group A rotavirus detected at a dairy cattle farm
Authors: Karayel-Hacioglu Ilke , Timurkan Mehmet Ozkan , Pellegrini Francesco , Marton Szilvia , Gul Buket , Bányai Krisztián , Martella Vito , Alkan Feray
Published: November 2022

Group A rotaviruses (RVAs) are a major cause of severe enteritis in humans and animals. RVAs have been identified in several animal species and their genetic diversity, the segmented nature of their RNA genome and the ability to spill over from one species to another can generate new RVA strains. In this study, we investigated the genome constellations of an unusual, rare, bovine RVA strain, G15P[21], identified from a farm with neonatal diarrhoea of calves in 2006. In parallel, the genome constellations of other RVA strains with different G/P types identified from the same farm in the same time span (2006–2008) were analysed. The genome constellation of strain K53 was G15-P[21]-I2-R2-C2-M2-A13-N2-T9-E2-H3 and was similar, overall, to that of the other bovine RVA strains (G6/10-P[11]-I2-R2-C2-M2-A13-N2-T6-E2-H3) with the exception of the NSP3 segment (T9 vs T6). This study describes RVA genomes with different genotype combinations isolated at a farm and also contributes to the understanding of the diversity and evaluation of rotavirus in a global context.
Distinct evolutionary trajectories in the Escherichia coli pangenome occur within sequence types
Authors: Cummins Elizabeth A. , Hall Rebecca J. , Connor Chris , McInerney James O. , McNally Alan
Published: November 2022

The

Escherichia coli

species contains a diverse set of sequence types and there remain important questions regarding differences in genetic content within this population that need to be addressed. Pangenomes are useful vehicles for studying gene content within sequence types. Here, we analyse 21

E. coli

sequence type pangenomes using comparative pangenomics to identify variance in both pangenome structure and content. We present functional breakdowns of sequence type core genomes and identify sequence types that are enriched in metabolism, transcription and cell membrane biogenesis genes. We also uncover metabolism genes that have variable core classification, depending on which allele is present. Our comparative pangenomics approach allows for detailed exploration of sequence type pangenomes within the context of the species. We show that ongoing gene gain and loss in the

E. coli

pangenome is sequence type-specific, which may be a consequence of distinct sequence type-specific evolutionary drivers.
ShaPRS: Leveraging shared genetic effects across traits or ancestries improves accuracy of polygenic scores
Authors: Kelemen M. , Vigorito E. , Fachal L. , Anderson C. A. , Wallace C.
Published: November 2022

We present shaPRS, a novel method that leverages widespread pleiotropy between traits, or shared genetic effects across ancestries, to improve the accuracy of polygenic scores. The method uses genome-wide summary statistics from two diseases or ancestries to improve the genetic effect estimate and standard error at SNPs where there is homogeneity of effect between the two datasets. When there is significant evidence of heterogeneity, the genetic effect from the disease or population closest to the target population is maintained. We show via simulation and a series of real-world examples that shaPRS substantially enhances the accuracy of PRS for complex diseases and greatly improves PRS performance across ancestries. shaPRS is a PRS pre-processing method that is agnostic to the actual PRS generation method and, as a result, it can be integrated into existing PRS generation pipelines and continue to be applied as more performant PRS methods are developed over time.
A CNN-Transformer Deep Learning Model for Real-time Sleep Stage Classification in an Energy-Constrained Wireless Device
Authors: Yao Zongyan , Liu Xilin
Published: November 2022

This paper proposes a deep learning (DL) model for automatic sleep stage classification based on single-channel EEG data. The DL model features a convolutional neural network (CNN) and transformers. The model was designed to run on energy and memory-constrained devices for real-time operation with local processing. The Fpz-Cz EEG signals from a publicly available Sleep-EDF dataset are used to train and test the model. Four convolutional filter layers were used to extract features and reduce the data dimension. Then, transformers were utilized to learn the time-variant features of the data. To improve performance, we also implemented a subject specific training before the inference (i.e., prediction) stage. With the subject specific training, the F1 score was 0.91, 0.37, 0.84, 0.877, and 0.73 for wake, N1-N3, and rapid eye movement (REM) stages, respectively. The performance of the model was comparable to the state-of-the-art works with significantly greater computational costs. We tested a reduced-sized version of the proposed model on a low-cost Arduino Nano 33 BLE board and it was fully functional and accurate. In the future, a fully integrated wireless EEG sensor with edge DL will be developed for sleep research in pre-clinical and clinical experiments, such as real-time sleep modulation.
Comparison of LIAISON QuantiFERON-TB Gold Plus with QuantiFERON-TB Gold Plus
Authors: Kadkhoda Kamran , Dee Matthew , Simeone John
Published: November 2022

With the large global burden of latent tuberculosis (TB) infection (LTBI), screening for LTBI for various reasons has become standard practice including the low-prevalence settings.

The results showed acceptable intra- and inter-run precision as well as cutoff verification across the two analyzers at the afore-mentioned levels (Table 1). Overall, the LIAISON QFT-Plus showed better inter- and intra-run precision compared with QFT-Plus when comparing low-positive TB1/2 samples; however, coefficient of variation (CVs) less than 20% are generally acceptable for any automated test. Cutoff verification showed CVs for QFT-Plus TB1 and TB2, QFT-Plus LIAISON TB1 and TB2 of 5.2%, 4.1%, 5.2%, 5.4%, respectively, demonstrating robustness around the cutoffs.

Altogether, the two methods were highly comparable. LIAISON QFT-Plus is a suitable alternative to batch testing (e.g., using DSX) in high-volume laboratories.
Inability to work following COVID-19 vaccination among healthcare workers - an important aspect for future booster vaccinations
Authors: Reusch Julia , Wagenhäuser Isabell , Gabel Alexander , Höhn Anna , Lâm Thiên-Trí , Krone Lukas B. , Frey Anna , Schubert-Unkmeir Alexandra , Dölken Lars , Frantz Stefan , Kurzai Oliver , Vogel Ulrich , Krone Manuel , Petri Nils
Published: November 2022

Background

COVID-19 vaccination is a key prevention strategy to reduce the spread and severity of SARS-CoV-2 infections, especially among highly exposed healthcare workers (HCWs). However, vaccine-related inability to work among HCWs could overstrain healthcare systems.

Methods

This study examined sick leave and intake of pro re nata (PRN) medication after the first, second and third COVID-19 vaccination in HCWs. Subgroup analyses were performed for different vaccines, gender, healthcare professions, and for HCWs aged at least 30 years. Data was collected by using an electronic questionnaire.

Findings

Among 1,704 HCWs enrolled, in total 595 (34·9%) HCWs were on sick leave following at least one COVID-19 vaccination, leading to a total number of 1,550 sick days. Both the absolute sick days and the rate of HCWs on sick leave significantly increased with each subsequent vaccination. Comparing BNT162b2mRNA and mRNA-1273 the difference in sick leave was not significant after the second dose, but mRNA-1273 induced a significantly longer and more frequent sick leave after the third.

Interpretation

A considerable number of HCWs have been on sick leave after COVID-19 vaccination, staff absences increase with each additional dose, depend on the vaccine, and vary between HCWs’ gender, and profession. In the light of further COVID-19 infection waves and booster vaccinations, there is a risk of additional staff shortages due to post-vaccination inability to work, which could acutely overload healthcare systems and jeopardise patient care. These findings will aid further vaccination campaigns to minimise the impact of staff absences on the healthcare system.

Funding

This study was funded by the Federal Ministry for Education and Science (BMBF) via a grant provided to the University Hospital of Wuerzburg by the Network University Medicine on COVID-19 (B-FAST, grant-No 01KX2021) as well as by the Free State of Bavaria with COVID-research funds provided to the University of Wuerzburg, Germany. Nils Petri is supported by the German Research Foundation (DFG) funded scholarship UNION CVD.
Expanding the Huntington’s disease research toolbox; validated subdomain protein constructs for biochemical and structural investigation of huntingtin
Authors: Alteen Matthew G. , Deme Justin C. , Alvarez Claudia P. , Loppnau Peter , Hutchinson Ashley , Seitova Alma , Chandrasekaran Renu , Ramos Eduardo Silva , Secker Christopher , Alqazzaz Mona , Wanker Erich E. , Lea Susan M. , Arrowsmith Cheryl H , Harding Rachel J.
Published: November 2022

Huntington’s disease is characterised by CAG expansion in the huntingtin gene above a critical threshold of~35 repeats, resulting in polyglutamine expansion of the huntingtin protein (HTT). The biological role of wildtype HTT and the associated mechanisms of disease pathology caused by expanded HTT remain incompletely understood, in part, due to challenges characterising interactions between HTT and putative binding partners. Here we describe a biochemical toolkit of rationally designed, high-quality recombinant HTT subdomains; one spanning the N-terminal HEAT and bridge domains (NTD) and the second spanning the C-terminal HEAT domain (CTD). Using biophysical methods and cryo-electron microscopy, we show these smaller subdomains are natively folded and can associate to reconstitute a functional full-length HTT structure capable of forming a near native-like complex with 40 kDa HTT-associated protein (HAP40). We report biotin-tagged variants of these subdomains, as well as full-length HTT, that permit immobilisation of each protein for quantitative biophysical assays without impacting protein quality. We demonstrate the CTD alone can form a stable complex when co-expressed with HAP40, which can be structurally resolved. The CTD-HAP40 complex binds the NTD, with a dissociation constant of approximately 10 nM as measured by bio-layer interferometry. We validate the interaction between the CTD and HAP40 using a luciferase two-hybrid assay and use subdomain constructs to demonstrate their respective stabilization of HAP40 in cells. These open-source biochemical tools will enable the wider HD community to study fundamental HTT biology, discover new macromolecular or small-molecule binding partners and map interaction sites across this very large protein.
SnRK1 inhibits anthocyanin biosynthesis through both transcriptional regulation and direct phosphorylation and dissociation of the MYB/bHLH/TTG1 MBW complex
Authors: Broucke Ellen , Vi Dang Thi Tuong , Li Yi , Hulsmans Sander , Van Leene Jelle , De Jaeger Geert , Hwang Ildoo , Van den Ende Wim , Rolland Filip
Published: November 2022

Plants have evolved an extensive specialized secondary metabolism. The colorful flavonoid anthocyanins, for example, not only stimulate flower pollination and seed dispersal but also protect different tissues against high light, UV- and oxidative stress. Their biosynthesis is highly regulated by environmental and developmental cues and induced by high sucrose levels. Expression of the biosynthetic enzymes involved is controlled by a transcriptional MBW complex, comprising (R2R3) MYB- and bHLH-type transcription factors (TF) and the WD40 repeat protein TTG1. Anthocyanin biosynthesis is obviously useful but also carbon- and energy-intensive and non-vital. Consistently, the SnRK1 protein kinase, a metabolic sensor activated in carbon- and energy-depleting stress conditions, represses anthocyanin biosynthesis. Here we show thatArabidopsisSnRK1 represses MBW complex activity both at the transcriptional and post-translational level. In addition to repressing expression of the key transcription factor MYB75/PAP1, SnRK1 activity triggers MBW complex dissociation, associated with loss of target promoter binding, MYB75 protein degradation and nuclear export of TTG1. We also provide evidence for direct interaction with and phosphorylation of multiple MBW complex proteins. These results indicate that repression of expensive anthocyanin biosynthesis is an important strategy to save energy and redirect carbon flow to more essential processes for survival in metabolic stress conditions.
Isolated catatonia-like executive dysfunction in mice with forebrain-specific loss of myelin integrity
Authors: Arinrad Sahab , Depp Constanze , Siems Sophie B. , Sasmita Andrew Octavian , Eichel Maria A. , Ronnenberg Anja , Hammerschmidt Kurt , Lüders Katja A. , Werner Hauke B. , Ehrenreich Hannelore , Nave Klaus-Armin
Published: November 2022

A key feature of advanced brain aging includes structural defects of intracortical myelin that are associated with secondary neuroinflammation. A similar pathology is seen in specific myelin mutant mice that model ‘advanced brain aging’ and exhibit a range of behavioral abnormalities. However, the cognitive assessment of these mutants is problematic because myelin-dependent motor-sensory functions are required for quantitative behavioral readouts. To better understand the role of cortical myelin integrity for higher brain functions, we generated mice lackingPlp1, encoding the major integral myelin membrane protein, selectively in ventricular zone stem cells of the mouse forebrain. In contrast to conventionalPlp1null mutants, subtle myelin defects were restricted to the cortex, hippocampus and underlying callosal tracts. Moreover, forebrain-specificPlp1mutants exhibited no defect of basic motor-sensory performance at any age tested. Surprisingly, several behavioral alterations reported for conventionalPlp1null mice (Gould et al., 2018) were absent and even social interactions appeared normal. However, with novel behavioral paradigms, we determined catatonia-like symptoms and isolated executive dysfunction in both genders. This suggests that loss of myelin integrity has an impact on cortical connectivity and underlies specific defects of executive function. These observations are likewise relevant for human neuropsychiatric conditions and other myelin-related diseases.
Comprehensive glycoprofiling of oral tumours associatesN-glycosylation with lymph node metastasis and patient survival
Authors: Carnielli Carolina Moretto , Melo de Lima Morais Thayná , Malta de Sá Patroni Fábio , Prado Ribeiro Ana Carolina , Brandão Thaís Bianca , Sobroza Evandro , Matos Leandro Luongo , Kowalski Luiz Paulo , Paes Leme Adriana Franco , Kawahara Rebeca , Thaysen-Andersen Morten
Published: November 2022

While altered protein glycosylation is regarded a trait of oral squamous cell carcinoma (OSCC), its heterogeneous glycoproteome and dynamics with disease progression remain unmapped. To this end, we here employ an integrated multi-omics approach comprising unbiased and quantitative glycomics and glycoproteomics applied to a valuable cohort of resected tumour tissues from OSCC patients with (n = 19) and without (n = 12) lymph node metastasis. While all tumour tissues displayed uniformN-glycome profiles suggesting relatively stable globalN-glycosylation during lymph node metastasis, glycoproteomics and advanced correlation analysis notably uncovered altered site-specificN-glycosylation and previously unknown associations with several key clinicopathological features. Importantly, focused analyses of the multi-omics data unveiled twoN-glycans and threeN-glycopeptides that were closely associated with patient survival. This study provides novel insight into the complex OSCC tissueN-glycoproteome forming an important resource to further explore the underpinning disease mechanisms and uncover new prognostic glyco-markers for OSCC.

Teaser

Deep survey of the dynamic landscape of complex sugars in oral tumours paves a way for new prognostic disease markers.
Reducing brain kynurenic acid synthesis precludes kynurenine-induced sleep disturbances
Authors: Rentschler Katherine M. , Milosavljevic Snezana , Baratta Annalisa M. , Wright Courtney J. , Piroli Maria V. , Tentor Zachary , Valafar Homayoun , O’Reilly Christian , Pocivavsek Ana
Published: November 2022

Patients with neurocognitive disorders often battle sleep disturbances. Kynurenic acid (KYNA) is a tryptophan metabolite of the kynurenine pathway implicated in the pathology of these illnesses. Modest increases in KYNA, an antagonist at glutamatergic and cholinergic receptors, result in cognitive impairments and sleep dysfunction. We explored the hypothesis that inhibition of the KYNA synthesizing enzyme, kynurenine aminotransferase II (KAT II), may alleviate sleep disturbances. At the start of the light phase, adult male and female Wistar rats received systemic injections of either i) vehicle, ii) kynurenine (100mg/kg; i.p.), iii) the KAT II inhibitor, PF-04859989 (30 mg/kg; s.c.), or iv) PF-04859989 and kynurenine in combination. Kynurenine and KYNA levels were evaluated in the plasma and brain. Separate animals were implanted with electroencephalogram (EEG) and electromyogram (EMG) telemetry devices to record polysomnography and evaluate vigilance states wake, rapid eye movement sleep (REMS) and non-REM sleep (NREMS) following each treatment. Kynurenine challenge increased brain KYNA and resulted in reduced REMS duration, NREMS delta power and sleep spindles. PF-04859989 reduced brain KYNA formation when given prior to kynurenine, prevented disturbances in REM sleep and sleep spindles, and enhanced NREM sleep. Our findings suggest that reducing KYNA in conditions where the kynurenine pathway is activated may serve as a potential strategy for improving sleep dynamics.
Cholecystokinin from the Rhinal Cortex Facilitates Motor Skill Learning
Authors: Li Hao , Feng Jingyu , Chen Mengying , Xin Min , Chen Xi , Wang Kuan Hong , He Jufang
Published: November 2022

Cholecystokinin (CCK) is an essential modulator for neuroplasticity in sensory and emotional domains. Here, we investigated the role of CCK in motor learning using a single pellet reaching task in mice. Mice with a knockout ofcckgene (CCK-/-) or blockade of CCK-B receptor (CCKBR) showed defective motor learning ability; the success rate of retrieving reward remained at the baseline level compared to the wildtype mice with significantly increased success rate. We observed no long-term potentiation (LTP) upon high-frequency stimulation (HFS) in the motor cortex of CCK-/-mice, indicating a possible association between motor learning deficiency and neuronal plasticity in the motor cortex. In vivo calcium imaging demonstrated that the deficiency of CCK signalling disrupted the refinement of population neuronal activity in the motor cortex during motor skill training. Anatomical tracing revealed direct projections from CCK-expressing neurons in the rhinal cortex to the motor cortex. Inactivating the CCK neurons in the rhinal cortex using chemogenetic methods significantly suppressed motor learning, and intraperitoneal application of CCK4, a tetrapeptide CCK agonist, rescued the motor learning deficits of CCK-/-mice. In summary, our results suggest that CCK, which could be provided from the rhinal cortex, enables neuroplasticity in the motor cortex leading to motor skill learning.
AlphaFold predictions are valuable hypotheses, and accelerate but do not replace experimental structure determination
Authors: Terwilliger Thomas C. , Liebschner Dorothee , Croll Tristan I. , Williams Christopher J. , McCoy Airlie J. , Poon Billy K. , Afonine Pavel V. , Oeffner Robert D. , Richardson Jane S. , Read Randy J. , Adams Paul D.
Published: November 2022

AI-based methods such as AlphaFold have revolutionized structural biology, often making it possible to predict protein structures with high accuracy. The accuracies of these predictions vary, however, and they do not include ligands, covalent modifications or other environmental factors. Here we focus on very-high-confidence parts of AlphaFold predictions, evaluating how well they can be expected to describe the structure of a protein in a particular environment. We compare predictions with experimental crystallographic maps of the same proteins for 102 crystal structures. In many cases, those parts of AlphaFold predictions that were predicted with very high confidence matched experimental maps remarkably closely. In other cases, these predictions differed from experimental maps on a global scale through distortion and domain orientation, and on a local scale in backbone and side-chain conformation. Overall, Cαatoms in very-high-confidence parts of AlphaFold predictions differed from corresponding crystal structures by a median of 0.6 Å, and about 10% of these differed by more than 2 Å, each about twice the values found for pairs of crystal structures containing the same components but determined in different space groups. We suggest considering AlphaFold predictions as exceptionally useful hypotheses. We further suggest that it is important to consider the confidence in prediction when interpreting AlphaFold predictions and to carry out experimental structure determination to verify structural details, particularly those that involve interactions not included in the prediction.
Self-assembly of CIP4 drives actin-mediated asymmetric pit-closing in clathrin-mediated endocytosis
Authors: Yu Yiming , Yoshimura Shige H.
Published: November 2022

Clathrin-mediated endocytosis is pivotal to signal transduction pathways between the extracellular environment and the intracellular space. Evidence from live-cell imaging and super-resolution microscopy of mammalian cells suggests an asymmetric distribution of actin fibres near the clathrin-coated pit, which induces asymmetric pit-closing rather than radial constriction. However, detailed molecular mechanisms of this ‘asymmetricity’ remain elusive. Herein, we used high-speed atomic force microscopy to demonstrate that CIP4, a multi-domain protein with a classic F-BAR domain and intrinsically disordered regions, is necessary for asymmetric pit-closing. Strong self-assembly of CIP4 via intrinsically disordered regions, together with stereospecific interactions with the curved membrane and actin-regulating proteins, generates a small actin-rich environment near the pit, which deforms the membrane and closes the pit. Our results provide mechanistic insights into how disordered and structured domain collaboration promotes spatio-temporal actin polymerisation near the plasma membrane.
O-GlcNAcylation promotes YTHDF1 cytosolic localization and colorectal cancer tumorigenesis
Authors: Li Jie , Ahmad Muhammad , Sang Lei , Zhan Yahui , Wang Yibo , Yan Yonghong , Liu Yue , Mi Weixiao , Lu Mei , Dai Yu , Zhang Rou , Dong Meng-Qiu , Yang Yun-Gui , Wang Xiaohui , Sun Jianwei , Li Jing
Published: November 2022

O-linked N-acetylglucosamine (O-GlcNAc) is an emerging post-translation modification that couples metabolism with cellular signal transduction by crosstalking with phosphorylation and ubiquitination to orchestrate various biological processes. Herein we show that it modifies the N6-methyladenosine (m6A)-mRNA reader YTHDF1 and fine-tunes its nuclear translocation by the exportin protein Crm1. First we present evidence that YTHDF1 interacts with the sole O-GlcNAc transferase (OGT). Second, we verified the YTHDF1 O-GlcNAcylation sites to be Ser196/Ser197/Ser198, as described in previous numerous chemoproteomic studies. Then we constructed the O-GlcNAc-deficient YTHDF1-S196AS197FS198A (AFA) mutants, which significantly attentuated O-GlcNAc signals. Moreover, we revealed that YTHDF1 is a nucleocytoplasmic protein, whose nuclear export is mediated by Crm1. Furthermore, O-GlcNAcylation increases the cytosolic portion of YTHDF1 by enhancing binding with Crm1, thus upregulating the downstream target (e.g. c-Myc) expression. Molecular dynamics simulations suggest that O-GlcNAcylation at S197 might promote the binding between the nuclear export signal motif and Crm1 through increasing hydrogen bonding. Mouse xenograft assays further demonstrate that YTHDF1-AFA mutants decreased the colon cancer mass and size via decreasing c-Myc expression. In sum, we found that YTHDF1 is a nucleocytoplasmic protein, whose cytosolic localization is dependent on O-GlcNAc modification. We propose that the OGT-YTHDF1-c-Myc axis might underlie colorectal cancer tumorigenesis.
The impact of threshold decision mechanisms of collective behaviour on disease spread
Authors: Morsky Bryce , Magpantay Felicia , Day Troy , Akçay Erol
Published: November 2022

Humans are a hyper social species, which greatly impacts the spread of infectious diseases. How do social dynamics impact epidemiology? How does public health policy best take into account these impacts? Here we develop a model of disease transmission that incorporates human behaviour and social dynamics. We use a “tipping-point” dynamic, previously used in the sociological literature, where individuals adopt a behaviour given a sufficient frequency of the behaviour in the population. The thresholds at which individuals adopt behaviours is modulated by the perceived risks of infection, i.e. the disease prevalence and transmission rate, and the behaviour of others. Social conformity creates a type of “stickiness” whereby individuals are resistant to changing their behaviour due to the population’s inertia. In this model, the epidemic attack rate is sensitive to the timing of the behavioural response. Near the optimal response, small errors can result in large increases in the total number infected during the epidemic. And, more surprisingly, we observe a non-monotinicity in the attack rate as a function of various biological and social parameters such as the transmission rate, efficacy of social distancing, the costs to social distancing, the weight of social consequences of shirking the norm, and the degree of heterogeneity in the population.
Antigenic evidence of lymphatic filariasis transmission in infection persistent endemic districts of Central Nepal during post mass drug administration
Authors: Mehta Pramod Kumar , Maharjan Mahendra
Published: November 2022

Background

In Nepal, out of 75, 61 districts were endemic with lymphatic filariasis (LF) and completed 6 to 11 rounds of mass drug administration (MDA) with diethylcarbamazine (DEC) and albendazole from 2007 to 2017 in almost all endemic districts of Central Nepal with the aim of eliminating lymphatic filariasis by 2020 but due to fail in transmission assessment Survey (TAS) in some Terai districts of Nepal, aim of elimination was extended to 2030. Antigenemia prevalence have been consistently <2% in all sentinel and check spot sites since 2017 and transmission assessment survey passed in 2018 but in some foci there was low level persistent of infection ofW. bancroftiwas seen in 4 endemic districts of central Nepal so present study has been carried out with the aim of assessing antigenic prevalence in children borne after MDA program to understand evidence of new infection of LF in selected districts

Methodology and principal findings

Antigenemia survey was carried out in communities children whose borne after MDA program from selected districts of central Nepal. Two study districts had significantly improved infection to the prior study but two other districts had drastic change. Few hydrocele cases were found but no any children found antigen positive with hydrocele cases.

Conclusions

These results indicates thatW. bancroftitransmission was near to break point in one hilly district (Lalitpur) and one Terai district (Bara) while other two districts from Terai (Mahottari) and hills (Dhading) may requires further intervention. Targeted testing and treatment along with comparative study of children with adult should be required similarly number of MDA rounds should be increased.

Author summary

Lymphatic filariasis is neglected tropical disease which cause the disability to human beings which is caused by filarial nematode and transmitted by mosquitoes. Nepal government was completed 6-11 rounds of antifilarial medicine with DEC and albendazole between 2007 to 2017 in all endemic districts of central Nepal. TAS report showed low level of infection in all study sites. The present study reports assessed antigenic prevalence of 4 infection persistent endemic districts of central Nepal with high signals than prior study in 2 areas while other 2 areas showed in elimination phase so further investigation along with number of MDA rounds should be required to interrupt transmission in high antigenic prevalence districts. Our results suggest that further xenomonitoring and microfilaremia study should be required for informed decision, targeted test and treatment should required.
The attributable fraction of respiratory syncytial virus among patients of different age with influenza-like illness and severe acute respiratory illness in a high HIV prevalence setting, South Africa, 2012-2016
Authors: Moyes Jocelyn , Tempia Stefano , Walaza Sibongile , McMorrow Meredith L. , Cohen Adam L. , Treurnicht Florette , Hellferscee Orienka , Wolter Nicole , Gottberg Anne Von , Dawood Halima , Variava Ebrahim , Kahn Kathleen , Madhi Shabir A. , Cohen Cheryl
Published: November 2022

Introduction

The detection of respiratory syncytial virus (RSV) in upper airway samples does not necessarily infer causality of illness. Calculating the attributable fraction (AF) of RSV in clinical syndromes could refine disease burden estimates.

Methods

Using unconditional logistic regression models, we estimated the AF of RSV-associated influenza-like illness (ILI) and severe-acute respiratory illness (SARI) cases by comparing RSV-detection prevalence among ILI and SARI cases to those of healthy controls in South Africa, 2012-2016. The analysis, stratified by HIV serostatus, was conducted in the age categories <1, 1-4, 5-24, 25-44, 45-64, ≥65 years.

Results

We included 12,048 individuals: 2,687 controls, 5,449 ILI cases and 5,449 SARI cases. RSV-AFs for ILI were significant in <1, 1-4, 5-24, 25-44-year age groups: 84.9%(95% confidence interval (CI) 69.3%-92.6%), 74.6%(95%CI 53.6%-86.0%), 60.8%(95%CI 21.4%-80.5%) and 64.1%(95%CI 14.9%-84.9%), respectively. Similarly, significant RSV-AFs for SARI were 95.3%(95%CI 91.1%-97.5) and 83.4%(95%CI 70.9-90.5) in the <1 and 1-4-year age groups respectively. In HIV-infected persons, RSV was significantly associated with ILI cases versus controls in individuals aged 5-44 years.

Conclusion

High RSV-AFs in young children confirm RSV detection is associated severe respiratory illness in South African children, specifically infants. These estimates will assist with refining burden estimates and cost effectiveness models.

Key point

The attributable fraction of illness is key to accurate burden estimates, specifically in the presents of sensitive PCR testing. Burden and cost burden estimates are key to cost-effectiveness model for new prevention technologies in the pipeline for respiratory syncytial virus.
Host translation machinery is not a barrier to phages that infect both CPR and non-CPR bacteria
Authors: Liu Jett , Jaffe Alexander L. , Chen LinXing , Bor Batbileg , Banfield Jillian F.
Published: November 2022

Within human microbiomes, Gracilibacteria, Absconditabacteria, and Saccharibacteria, members of Candidate Phyla Radiation (CPR), are increasingly correlated with human oral health and disease. We profiled the diversity of CRISPR-Cas systems in the genomes of these bacteria and sought phages that are capable of infecting them by comparing their spacer inventories to large phage sequence databases. Gracilibacteria and Absconditabacteria recode the typical TGA stop codon to glycine and are infected by phages that share their host’s alternate genetic code. Unexpectedly, however, other predicted phages of Gracilibacteria and Absconditabacteria do not use an alternative genetic code. Some of these phages are predicted to infect both alternatively coded CPR bacteria and standard coded bacteria. These phages rely on other stop codons besides TGA, and thus should be capable of producing viable gene products in either bacterial host type. Interestingly, we predict that phages of Saccharibacteria can replicate in Actinobacteria, which have been shown to act as episymbiotic hosts for Saccharibacteria. Overall, the broad host range of some CPR phages may be advantageous for the production of these phages for microscopic characterization or use as therapy agents, given the current difficulty of CPR cultivation. Absconditabacteria phages and Gracilibacteria phages may have avoided acquisition of in-frame stop codons to increase the diversity of bacteria in which they can replicate.
Identifying Biomarkers of Retinal Pigment Epithelial Cell Stem Cell-derived RPE Cell Heterogeneity and Transplantation Efficacy
Authors: Farjood Farhad , Manos Justine D. , Wang Yue , Williams Anne L. , Zhao Cuiping , Borden Susan , Alam Nazia , Prusky Glen , Temple Sally , Stern Jeffrey H. , Boles Nathan C.
Published: November 2022

Transplantation of retinal pigment epithelial (RPE) cells holds great promise for patients with retinal degenerative diseases such as age-related macular degeneration. In-depth characterization of RPE cell product identity and critical quality attributes are needed to enhance efficacy and safety of replacement therapy strategies. Here we characterized an adult RPE stem cell-derived (RPESC-RPE) cell product using bulk and single cell RNA sequencing (sc-RNA-seq), assessing functional cell integrationin vitrointo a mature RPE monolayer andin vivoefficacy by vision rescue in the Royal College of Surgeons rats. scRNA-seq revealed several distinct subpopulations in the RPESC-RPE product, some with progenitor markers. We identified RPE clusters expressing genes associated within vivoefficacy and increased cell integration capability. Gene expression analysis revealed a lncRNA (TREX) as a predictive marker ofin vivoefficacy. TREX knockdown decreased cell integration while overexpression increased integrationin vitroand improved vision rescue in the RCS rats.
Fission yeast Swi2 designates cell-type specific donor and stimulates Rad51-driven strand exchange
Authors: Maki Takahisa , Thon Geneviève , Iwasaki Hiroshi
Published: November 2022

A haploid of the fission yeastSchizosaccharomyces pombeexpresses either the P or M matingtype, determined by the active, euchromatic,mat1cassette. Mating-type is switched by Rad51-driven gene conversion ofmat1using a heterochromatic donor cassette,mat2-Pormat3-M. The Swi2-Swi5 complex, a mating-type switching factor, is central to this process by designating a preferred donor in a cell-type-specific manner. Swi2-Swi5 selectively enables one of twocisacting recombination enhancers,SRE2adjacent tomat2-PorSRE3adjacent tomat3-M. Here, we identified two functionally important motifs in Swi2, a Swi6 (HP1 homolog)-binding site and two DNA-binding AT-hooks. Genetic analysis demonstrated that the AT-hooks were required for Swi2 localization atSRE3to select themat3-Mdonor in P cells, while the Swi6-binding site was required for Swi2 localization atSRE2to selectmat2-Pin M cells. In addition, the Swi2-Swi5 complex promoted Rad51-driven strand exchangein vitro. Taken together, our results show how the Swi2-Swi5 complex would localize to recombination enhancers through a cell-type specific binding mechanism and stimulate Rad51-driven gene conversion at the localization site.
Insights into the biosynthesis of icumazole unveiling a distinctive family of crotonyl-CoA carboxylase/reductase
Authors: Xie Feng , Kiefer Alexander F. , Hirsch Anna K. H. , Kalinina Olga , Fu Chengzhang , Müller Rolf
Published: November 2022

Icumazoles are potent antifungal polyketides with intriguing structural features. Here, we present the polyketide synthase (PKS)/nonribosomal peptide synthetase (NRPS) hybrid biosynthetic gene cluster of icumazoles. Surprisingly, an unusual non-terminal thioesterase domain divides the PKS/NRPS assembly line. The succeeding PKS modules potentially form a rare precursor 4-methyl-2-hexenoyl-ACP thus deviating from the previously proposed polyoxypeptin pathway. The 4-methyl-2-hexenoyl-ACP is further reductive carboxylated to 2-methylbutylmalonyl-ACP essential for icumazole biosynthesis by IcuL, representing a new type of crotonyl-CoA carboxylase/reductase (CCR). We characterize IcuL and its homologs TgaD and Leu10in vitro, suggesting a stricter substrate specificity of this new family of CCRs than found in canonical ones. Intriguingly, we also find that TgaD unprecedently utilizes both NADPH and NADH as cofactors with similar efficiency, diverging from the NADPH-specific characteristic of canonical CCRs. Furthermore, a sequence similarity network-based bioinformatic survey reveals that the IcuL-like CCRs are evolutionarily separated from canonical CCRs.
Mapping acute neuroinflammationin vivowith diffusion-MRI in rats given a systemic lipopolysaccharide challenge
Authors: Kim Eugene , Figueiredo Ines Carreira , Simmons Camilla , Randall Karen , Gonzalez Loreto Rojo , Wood Tobias , Ranieri Brigida , Sureda-Gibert Paula , Howes Oliver , Pariante Carmine ,   NIMA Consortium, Pasternak Ofer , Dell’Acqua Flavio , Turkheimer Federico , Cash Diana
Published: November 2022

It is becoming increasingly apparent that neuroinflammation plays a critical role in an array of neurological and psychiatric disorders. Recent studies have demonstrated the potential of diffusion MRI (dMRI) to characterize changes in microglial density and morphology associated with neuroinflammation, but these were conducted mostlyex vivoand/or in extreme, non-physiological animal models. Here, we build upon these studies by investigating the utility of well-established dMRI methods to detect neuroinflammationin vivoin a more clinically relevant animal model of sickness behavior. We show that diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) indicate widespread increases in diffusivity in the brains of rats given a systemic lipopolysaccharide challenge (n=20) vs. vehicle-treated controls (n=12). These diffusivity changes correlated with histologically measured changes in microglial morphology, confirming the sensitivity of dMRI to neuroinflammatory processes. This study marks a further step towards establishing a noninvasive indicator of neuroinflammation, which would greatly facilitate early diagnosis and treatment monitoring in various neurological and psychiatric diseases.
Efficacy of Non-invasive Brain Stimulation on Vision: A Systematic Review and Meta-analysis
Authors: Bello U.M. , Wang J. , Park A.S.Y. , Tan K.W.S. , Cheung B.W.S. , Thompson B. , Cheong A.M.Y.
Published: November 2022

Objective

Multiple studies have explored the use of non-invasive brain stimulation (NIBS) to enhance visual function. These studies vary in sample size, outcome measures, and NIBS methodology. We conducted a systematic review and meta-analyses to assess the effects of NIBS on visual functions in human participants with normal vision.

Methods

We followed the PRISMA guidelines, and a review protocol was registered with PROSPERO before study commencement (CRD42021255882). We searched Embase, Medline, PsychInfo, PubMed, OpenGrey and Web of Science using relevant keywords. The search covered the period from 1stJanuary 2000 until 1stSeptember 2021. Comprehensive meta-analysis (CMA) software was used for quantitative analysis.

Results

Forty-nine studies were included, of which 19 were included in a meta-analysis (38.8%). Meta-analysis indicated acute (Hedges’s g=0.232, 95% CI: 0.023-0.442,p=0.029) and aftereffects (0.590, 95% CI: 0.182-0.998,p=0.005) of transcranial electrical stimulation (tES, including three different stimulation protocols) on contrast sensitivity. Visual evoked potential (VEP) amplitudes were significantly enhanced immediately after tES (0.383, 95% CI: 0.110-0.665,p=0.006). Both tES (0.563, 95% CI: 0.230 to 0.896,p=0.001)] and anodal-transcranial direct current stimulation (a-tDCS) alone (0.655, 95% CI: 0.273 to 1.038,p=0.001) reduced crowding in peripheral vision. The effects of NIBS on visual acuity, motion perception and reaction time were not statistically significant.

Conclusions

There are significant effects of visual cortex NIBS on contrast sensitivity, VEP amplitude, an index of cortical excitability, and crowding among normally sighted individuals. Future studies with robust experimental designs are needed to substantiate these findings in populations with vision loss.

PROSPERO registration number

CRD42021255882

Highlights

We conducted a meta-analysis and a systematic review on the efficacy of non-invasive brain stimulation for improving on visual function

Visual cortex non-invasive brain stimulation can enhance contrast sensitivity, reduce crowding in peripheral vision and enhance visually evoked potential amplitude among normally sighted individuals.
The genetic requirements for HiVir-mediated onion necrosis byPantoea ananatis, a necrotrophic plant pathogen
Authors: Shin Gi Yoon , Dutta Bhabesh , Kvitko Brian
Published: November 2022

Pantoea ananatisis an unusual bacterial pathogen that lacks typical virulence determinants yet causes extensive necrosis in onion foliage and bulb tissues. The onion necrosis phenotype is dependent on the expression of a phosphonate toxin, pantaphos that is catalyzed by putative enzymes encoded by the HiVir gene cluster. The genetic contributions of individualhvrgenes in HiVir-mediated onion necrosis remain largely unknown except for the first genehvrA(phosphoenolpyruvate mutase,pepM) whose deletion resulted in the loss of onion pathogenicity. In this study, using gene deletion mutation and complementation, we report that of the ten remaining genes,hvrB-hvrFare also strictly required for the HiVir-mediated onion necrosis andin plantabacterial growth whereashvrG-hvrJpartially contributed to these phenotypes. As the HiVir gene cluster is a common genetic feature shared among the onion-pathogenicP. ananatisstrains, and as it could serve as a useful diagnostic marker of onion pathogenicity, we sought to understand the genetic basis of HiVir positive yet phenotypically deviant (non-pathogenic) strains. We identified and genetically characterized inactivating single nucleotide polymorphisms (SNPs) in essentialhvrgenes of six phenotypically deviantP. ananatisstrains. Finally, inoculation of the cell-free spent medium of Ptac-driven HiVir strain causedP. ananatis-characteristic red onion scale necrosis (RSN) as well as cell death symptoms in tobacco. The co-inoculation of the spent medium with essentialhvrmutant strains restored strains’in plantapopulations to the wild-type level, suggesting that necrosis is important for proliferation ofP. ananatisin onion tissue.
Artifact identification in X-ray diffraction data using machine learning methods
Authors: Yanxon Howard , Weng James , Parraga Hannah , Xu Wenqian , Ruett Uta , Schwarz Nicholas
Published: November 2022

In situ synchrotron high-energy X-ray powder diffraction (XRD) is highly utilized by researchers to analyze the crystallographic structures of materials in functional devices (e.g. battery materials) or in complex sample environments (e.g. diamond anvil cells or syntheses reactors). An atomic structure of a material can be identified by its diffraction pattern along with a detailed analysis of the Rietveld refinement which yields rich information on the structure and the material, such as crystallite size, microstrain and defects. For in situ experiments, a series of XRD images is usually collected on the same sample under different conditions (e.g. adiabatic conditions) yielding different states of matter, or is simply collected continuously as a function of time to track the change of a sample during a chemical or physical process. In situ experiments are usually performed with area detectors and collect images composed of diffraction patterns. For an ideal powder, the diffraction pattern should be a series of concentric Debye–Scherrer rings with evenly distributed intensities in each ring. For a realistic sample, one may observe different characteristics other than the typical ring pattern, such as textures or preferred orientations and single-crystal diffraction spots. Textures or preferred orientations usually have several parts of a ring that are more intense than the rest, whereas single-crystal diffraction spots are localized intense spots owing to diffraction of large crystals, typically >10 µm. In this work, an investigation of machine learning methods is presented for fast and reliable identification and separation of the single-crystal diffraction spots in XRD images. The exclusion of artifacts during an XRD image integration process allows a precise analysis of the powder diffraction rings of interest. When it is trained with small subsets of highly diverse datasets, the gradient boosting method can consistently produce high-accuracy results. The method dramatically decreases the amount of time spent identifying and separating single-crystal diffraction spots in comparison with the conventional method.
Relating protein crystal structure to ligand-binding thermodynamics
Authors: Helliwell John R.
Published: November 2022

An important interface between biophysical chemistry and biological crystal structures involves whether it is possible to relate experimental calorimetry measurements of protein ligand binding to 3D structures. This has proved to be challenging. The probes of the structure of matter, namely X-rays, neutrons and electrons, have challenges of one type or another in their use. This article focuses on saccharide binding to lectins as a theme, yet after 25 years or so it is still a work in progress to connect 3D structure to binding energies. Whilst this study involved one type of protein (lectins) and one class of ligand (monosaccharides), i.e. it was specific, it was of general importance, as measured for instance by its wide impact. The impetus for writing this update now, as a Scientific Comment, is that a breakthrough in neutron crystal structure determinations of saccharide-bound lectins has been achieved. It is suggested here that this new research from neutron protein crystallography could improve, i.e. reduce, the errors in the estimated binding energies.
Integration of outside-in and inside-out entrepreneurial marketing capabilities, marketing agility and resources for entrepreneurial firm performance
Authors: Khan Huda , Mavondo Felix , Zahoor Nadia
Published: November 2022

Purpose

The resource-based view (RBV) emphasises the importance of resources for firm performance. However, recent research argues that the focus on firm performance should also be based on inside-out (IO) and outside-in (OI) capabilities. Specifically, we study the importance of resources on product development (an IO) and market driving (an OI) entrepreneurial marketing capabilities on entrepreneurial firm performance in an emerging market. The study further investigates the moderating effects of marketing agility on the relationship between resources and capabilities.

Design/methodology/approach

The study is based on survey data of a multi-industry sample of 102 entrepreneurial firms in Pakistan.

Findings

The results show that marketing agility moderates the relationship between resource-mix flexibility on product development and market driving capabilities, but it only positively moderates the relationship between resource-mix inimitability and product development capability. Marketing driving and product development capabilities play a role as parallel mediators between resources and firm performance.

Originality/value

The study lies at the intersection of marketing and entrepreneurship literature by (1) providing a nuanced understanding of marketing agility as a boundary spanning factor for IO and OI entrepreneurial marketing capabilities; (2) integrating the resource types and product development from IO and market-driving from OI capabilities perspectives; (3) identifying the effects of IO and OI on firm performance providing guidance for entrepreneurs seeking improved firm performance.