bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and Safety of Single-dose Pegfilgrastim for CD34+ Cell Mobilization in Healthy Volunteers: A Phase 2 Study
Authors: Goto Hideki , Sugita Junichi , Hasegawa Yuta , Hayasaka Koji , Sunagoya Kana , Hatase Rie , Nishida Mutsumi , Ichihashi Yuki , Odera Mitsuhiko , Senjo Hajime , Yokoyama Shota , Ara Takahide , Shiratori Souichi , Endo Tomoyuki , Hino Masayuki , Maeda Yoshinobu , Sawa Masashi , Sato Norihiro , Teshima Takanori
Published: November 2023

Background.

Pegfilgrastim, a long-acting form of granulocyte-colony stimulating factor, with a convenient single-injection dosage, is being investigated for peripheral blood stem cell (PBSC) mobilization in healthy volunteers. However, data on the adequate dose of pegfilgrastim for PBSC mobilization are limited. This phase 2, single-arm study evaluated the efficacy and safety of pegfilgrastim for PBSC mobilization in healthy volunteers.

Methods.

The study comprised 2 phases: pilot (steps 1–3, dose escalation, a single subcutaneous dose of 3.6, 7.2, and 10.8 mg pegfilgrastim, respectively) and evaluation (step 4, efficacy and safety assessments). The primary endpoint was the proportion of subjects who achieved mobilization of ≥20 × 106/L cluster of differentiation 34 positive (CD34+) cells.

Results.

Thirty-five subjects (6 each in steps 1 and 2 and 23 in step 4) were included. In the pilot phase, step 3 with a 10.8 mg dose was not conducted due to favorable outcomes in step 2 (desired CD34+ cell count), at 7.2 mg pegfilgrastim, which was identified as the optimal dose for the evaluation phase. In the evaluation phase, successful CD34+ mobilization was achieved in all 23 subjects. The mean peripheral blood CD34+ cells count peaked on day 5. Back pain, thrombocytopenia, transient elevations of alkaline phosphatase, and lactate dehydrogenase were the most common adverse events. All adverse events were mild, and none led to study discontinuation.

Conclusions.

A single-dose pegfilgrastim successfully mobilized an optimal number of CD34+ cells and was well tolerated. Pegfilgrastim could be an alternative option for PBSC mobilization in healthy volunteers. The trial was registered at www.clinicaltrials.gov (NCT03993639).
Paenibacillus polygoni sp. nov., an endophytic bacterium isolated from Polygonum lapathifolium L. in wetland
Authors: Long Yong , Li Yansheng , Wang Guanghua , Jin Jian , Mao Mengfan , Gao Lizheng , Liu Guihua , Fan Guoquan , Yu Zhenhua
Published: November 2023

A Gram-stain-positive, aerobic, rod-shaped, non-motile, yellowish and glossy strain, C31T, was isolated from a wetland plant Polygonum lapathifolium L. located south of Poyang Lake, Jiangxi Province, PR China. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain C31T showed similarity values of lower than 97.0 % to other type species belonging to the genus

Paenibacillus

. The genomic average nucleotide identity values between strain C31T and its reference type species ranged from 68.9–70.9 % and the digital DNA–DNA hybridization values were lower than 27.8 %. The genomic DNA G+C content of strain C31T was 41.9 mol%. The optimal growth temperature, pH and NaCl concentration were 37 °C, pH 7 and 0.5 %, respectively. The major cellular fatty acids (>5.0 %) of strain C31T were anteiso-C15 : 0 (73.7 %), anteiso-C17 : 0 (8.4 %) and iso-C15 : 0 (5.2 %). The polar lipids of strain C31T were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and unidentified phospholipids. The respiratory quinone was MK-7. Based on these phylogenetic and phenotypic characterizations, strain C31T represents a novel species within the genus

Paenibacillus

. Therefore, the proposed name for this newly identified species is Paenibacillus polygoni sp. nov. and the type strain is C31T (=CCTCC AB 2022349T=KCTC 43565T).
The changes of gut microbiota and metabolites in different drug-induced liver injuries
Authors: Zhu Ruirui , Gao Yinghui , Dong Jianxia , Li Zhiqin , Ren Zhigang
Published: November 2023

The increasing incidence of drug-induced liver injury (DILI) has become a major concern. Gut microbiota, as another organ of the human body, has been studied in various tumors, cardiovascular metabolic diseases, inflammatory bowel disease and human immunity. The studies mentioned above have confirmed its important impact on the occurrence and development of DILI. The gut-liver axis explains the close relationship between the gut and the liver, and it may be a pathway by which gut microbes contribute to DILI. In addition, the interaction between drugs and gut microbes affects both separately, which in turn may have positive or negative effects on the body, including DILI. There are both common and specific changes in liver injury caused by different drugs. The alteration of metabolites in DILI is also a new direction of therapeutic exploration. The application of microbiomics, metabolomics and other multi-omics to DILI has also explored new ideas for DILI. In this review, we conclude the alterations of gut microbes and metabolites under different DILI, and the significance of applying gut microbiome-metabolomics to DILI, so as to explore the metabolic characteristics of DILI and possible novel metabolic biomarkers.
Genomic analysis of Streptococcus pneumoniae serogroup 20 isolates in Alberta, Canada from 1993–2019
Authors: Williams Ashley N. , Ma Angela , Croxen Matthew A. , Demczuk Walter H. B. , Martin Irene , Tyrrell Gregory J.
Published: November 2023

In the province of Alberta, Canada, invasive disease caused by

Streptococcus pneumoniae

serogroup 20 (serotypes 20A/20B) has been increasing in incidence. Here, we characterize provincial invasive serogroup 20 isolates collected from 1993 to 2019 alongside invasive and non-invasive serogroup 20 isolates from the Global Pneumococcal Sequencing (GPS) Project collected from 1998 to 2015. Trends in clinical metadata and geographic location were evaluated, and serogroup 20 isolate genomes were subjected to molecular sequence typing, virulence and antimicrobial resistance factor mining, phylogenetic analysis and pangenome calculation. Two hundred and seventy-four serogroup 20 isolates from Alberta were sequenced, and analysed along with 95 GPS Project genomes. The majority of invasive Alberta serogroup 20 isolates were identified after 2007 in primarily middle-aged adults and typed predominantly as ST235, a sequence type that was rare among GPS Project isolates. Most Alberta isolates carried a full-length whaF capsular gene, suggestive of serotype 20B. All Alberta and GPS Project genomes carried molecular resistance determinants implicated in fluoroquinolone and macrolide resistance, with a few Alberta isolates exhibiting phenotypic resistance to azithromycin, clindamycin, erythromycin, tetracycline and trimethoprim-sulfamethoxazole, as well as non-susceptibility to tigecycline. All isolates carried multiple virulence factors including those involved in adherence, immune modulation and nutrient uptake, as well as exotoxins and exoenzymes. Phylogenetically, Alberta serogroup 20 isolates clustered with predominantly invasive GPS Project isolates from the USA, Israel, Brazil and Nepal. Overall, this study highlights the increasing incidence of invasive

S. pneumoniae

serogroup 20 disease in Alberta, Canada, and provides insights into the genetic and clinical characteristics of these isolates within a global context.
Altered placental immune cell composition and gene expression with isolated fetal spina bifida
Authors: White Marina , Abdo Hasan , Grynspan David , Van Mieghem Tim , Connor Kristin L
Published: November 2023

Problem

Maternal B vitamin deficiency increases the risk of fetal spina bifida (SB) and placental maldevelopment. It is unclear whether placental processes involving folate are altered in fetuses with SB in a contemporary cohort. We hypothesised that fetal SB would associate with reduced expression of key folate transporters (folate receptor-α [FRα], proton coupled folate receptor [PCFT], and reduced folate carrier [RFC]), and an increase in Hofbauer cell (HBC) abundance and folate receptor-β(FRβ)expression by HBCs.

Method of Study

FRα, PCFT, and RFC protein localisation and expression (immunohistochemistry) and HBC phenotypes (RNAin situhybridization) were assessed in placentae from fetuses with SB (cases; n=12) and with no congenital anomalies (controls; n=22).

Results

Cases (vs. gestational age [GA]-matched controls) had a higher proportion of placental villous cells that were HBCs (6.9% vs. 2.4%, p=0.0001) and higher averageFRβexpression by HBCs (3.2 mRNA molecules per HBC vs. 2.3, p=0.03). HBCs in cases were largely polarised to a regulatory phenotype (median 92.1% of HBCs). In sex-stratified analyses, male, but not female, cases had higher HBC levels andFRβexpression by HBCs than GA-matched controls. There were no differences between groups in the total percent of syncytium and stromal cells that were positive for FRα, PCFT, or RFC protein immunolabelling.

Conclusions

HBC abundance andFRβexpression by HBCs are increased in placentae of fetuses with isolated SB, suggesting immune-mediated dysregulation in placental development and function, and could contribute to SB-associated comorbidities, such as poor fetal growth.
Metal complexes and conjugation: Harnessing the power of cobalt complexes to curtail plasmid transfer
Authors: Alav Ilyas , Pordelkhaki Parisa , de Resende Pedro Ernesto , Partington Hannah , Gibbons Simon , Lord Rianne , Buckner Michelle M.C.
Published: November 2023

Background

Antimicrobial resistance genes (ARG), such as extended spectrum β-lactamase (ESBL) and carbapenemase genes, are commonly carried on plasmids. Plasmids can transmit between bacteria, disseminate globally, and cause clinically important resistance. Therefore, targeting plasmids could reduce ARG prevalence, and restore the efficacy of existing antibiotics. Here, we assessed the effect of four previously characterised bis(N-picolinamido)cobalt(II) complexes on the conjugative transfer of plasmids inEscherichia coliandKlebsiella pneumoniae.

Methods

Liquid broth and solid agar conjugation assays were used to measure complex activity on four plasmids inE. coli. Additionally, the effect of cobalt complexes was tested on the transmission of the fluorescently tagged extended spectrum β-lactamase encoding pCTgfpplasmid inE. coliand carbapenemase encoding pKpQILgfpplasmid inK. pneumoniae, using flow cytometry.

Results

Antimicrobial susceptibility testing of cobalt complexes revealed no antibacterial activity. The cobalt complexes significantly reduced conjugative transfer of RP4, R6K, and R388 plasmids on solid agar inE. coliand pKpQILgfptransmission inK. pneumoniae.None affected conjugative transfer of pKM101 or transmission of fluorescently tagged pCT inE. coli. The cobalt complexes had no effect on plasmid persistence, suggesting that they target conjugation rather than plasmid prevalence.

Conclusions

To the best of our knowledge, this is the first study to report reduced transmission of clinically relevant plasmids with cobalt complexes. These cobalt complexes are not cytotoxic towards mammalian cells and are not antibacterial, therefore they could be optimised and employed as conjugation inhibitors to reduce prevalence of AMR and/or virulence genes in animals and humans.

Significance

Antimicrobial resistance is a growing problem that poses a significant threat to modern medicine. Some of the most problematic resistance genes are carried on genetic elements, called plasmids, that can spread between bacteria. While our understanding of the mechanisms and drivers of gene transfer amongst bacteria is increasing, we lack effective tools to slow down/control these processes. Here we demonstrate for the first time that novel cobalt-based compounds have anti-plasmid activity on a subset ofE. coliplasmids, and are extremely potent inK. pneumoniaecarrying a clinical carbapenem-resistance plasmid, without impacting plasmid maintenance. This finding forms the foundations of a potential strategy to control the transfer of genes within Gram-negative bacteria, which has implications for AMR and virulence.
Depressive symptoms are associated with differential cognitive and neuroanatomical alterations in young and older adults
Authors: Bergmann Eyal , Harlev Daniel ,   Cam-CAN, Wolpe Noham
Published: November 2023

Objective

Depression is a heterogeneous disorder. The purpose of this article is to examine the contribution of age to this heterogeneity by characterizing the associations of depressive symptoms with cognitive performance and brain structure across the lifespan.

Methods

The authors analyzed demographic variables (age, gender, education), affective measures (Hospital Anxiety and Depression Scale), and cognitive assessments (The Addenbrooke’s Cognitive Examination Revised) from the Cambridge Centre for Ageing Neuroscience (Cam-CAN) cohort (N=2591, age 18-99). A subset of this cohort (N=647) underwent structural MRI, which was used for voxel-based brain morphometry.

Results

A linear regression model revealed a significant interaction between age and depression score, indicating that depression-related cognitive dysfunction is more severe in older adults. A comparison of different cognitive domains showed that this effect was consistent across all tested domains but significantly more prominent for fluency. A complementary voxel-based morphometry analysis, based on similar regression models, revealed age by depression interactions in several brain regions, demonstrating preferential age-related reduction in grey matter volume in the left and right hippocampi in older adults. The reciprocal contrast revealed preferential reduction in grey matter in the left superior frontal gyrus, left middle frontal gyrus, and left superior parietal lobule in younger adults.

Conclusions

These findings indicate that the associations of depression with cognitive performance and brain structure are age-dependent, suggesting that the neuropathological mechanisms underlying depression may differ between young and older adults. Recognizing these differences will support the development of better diagnostic tools and therapeutic interventions for depression across the lifespan.
Angiographic Report Generation for the 3rdAPTOS’s Competition: Dataset and Baseline Methods
Authors: Zhang Weiyi , Chotcomwongse Peranut , Chen Xiaolan , Chung Florence H.T. , Song Fan , Zhang Xueli , He Mingguang , Shi Danli , Ruamviboonsuk Paisan
Published: November 2023

Fundus angiography, including fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA), are essential examination tools for visualizing lesions and changes in retinal and choroidal vasculature. However, the interpretation of angiography images is labor-intensive and time-consuming. In response to this, we are organizing the third APTOS competition for automated and interpretable angiographic report generation. For this purpose, we have released the first angiographic dataset, which includes over 50,000 images labeled by retinal specialists. This dataset covers 24 conditions and provides detailed descriptions of the type, location, shape, size and pattern of abnormal fluorescence to enhance interpretability and accessibility. Additionally, we have implemented two baseline methods that achieve an overall score of 7.966 and 7.947 using the classification method and language generation method in the test set, respectively. We anticipate that this initiative will expedite the application of artificial intelligence in automatic report generation, thereby reducing the workload of clinicians and benefiting patients on a broader scale.
Validation of Left Ventricular High Frame Rate Echo-Particle Image Velocimetry against 4D Flow MRI in Patients
Authors: Han Yichuang , Bowen Daniel J. , Barreto Bernardo Loff , Zwaan Robert. R. , Strachinaru Mihai , van der Geest Rob J. , Hirsch Alexander , van den Bosch Annemien E. , Bosch Johan G. , Voorneveld Jason
Published: November 2023

Aims

Accurately measuring intracardiac flow patterns could provide insights into cardiac disease pathophysiology, potentially enhancing diagnostic and prognostic capabilities. This study aims to validate Echo-Particle Image Velocimetry (echoPIV) forin-vivoleft ventricular intracardiac flow imaging against 4D flow MRI.

Methods and Results

We acquired HFR contrast-enhanced ultrasound images from three standard apical views of 26 patients who required cardiac MRI. 4D flow MRI was obtained for each patient. Only echo image planes with sufficient quality and alignment with MRI were included for validation. Regional velocity, kinetic energy and viscous energy loss were compared between modalities using normalized mean absolute error, cosine similarity and Bland-Altman analysis.

Among 24 included apical view acquisitions, we observed good correspondence between echoPIV and MRI regarding spatial flow patterns and vortex traces. The velocity profile at base-level (mitral valve) cross-section had cosine similarity of 0.92 ± 0.06 and normalized mean absolute error of 14 ± 5%. Peak spatial mean velocity differed by 3 ± 6 cm/s in systole and 6 ± 10 cm/s in diastole. The kinetic energy and rate of energy loss also revealed a high level of cosine similarity (0.89 ± 0.09 and 0.91 ± 0.06) with normalized mean absolute error of 23 ± 7% and 52 ± 16%.

Conclusions

Given good B-mode image quality, echoPIV provides a reliable estimation of left ventricular flow, exhibiting spatial-temporal velocity distributions comparable to 4D flow MRI. Both modalities present respective strengths and limitations: echoPIV captured inter-beat variability and had higher temporal resolution, while MRI was more robust to patient BMI and anatomy.
Hepatitis B virus prevalence and transmission in the households of pregnant women in Kinshasa, Democratic Republic of Congo
Authors: Morgan Camille E. , Ngimbi Patrick , Boisson-Walsh Alix JN , Ntambua Sarah , Matondo Jolie , Tabala Martine , Kashamuka Melchior Mwandaglirwa , Emch Michael , Edwards Jessie K. , Powers Kimberly A. , James Linda , Mbonze Nana , Mampunza Samuel , Yotebieng Marcel , Thompson Peyton , Parr Jonathan B.
Published: November 2023

Background

Despite routine infant vaccination and blood donor screening, the Democratic Republic of Congo (DRC) has high hepatitis B virus (HBV) prevalence compared to the United States and Europe. Through the cross-sectional Horizontal and Vertical Transmission of Hepatitis B (HOVER-HBV) study, we characterized household prevalence in DRC’s capital, Kinshasa, to inform additional prevention efforts.

Methods

We introduced HBV surface antigen (HBsAg) screening alongside existing HIV screening as part of routine antenatal care (ANC) in high-volume maternity clinics in Kinshasa. We recruited households of pregnant women who were HBsAg-positive and HBsAg-negative, defining households as “exposed” and “unexposed,” respectively. Household members underwent HBsAg testing and an epidemiological survey. We evaluated HBsAg prevalence and potential transmission correlates.

Results

We enrolled 1,006 participants from 200 households (100 exposed, 100 unexposed) across Kinshasa. HBsAg prevalence was more than twice as high in exposed households (5.0%; 95% CI: 2.8%-7.1%) as in unexposed households (1.9%; 0.6%-3.2%). Exposed direct offspring had 3.3 (0.9, 11.8) times the prevalence of unexposed direct offspring. Factors associated with HBsAg-positivity included older age, marriage, and having multiple recent partners or any new sexual partners among index mothers; and older age, lower household wealth, sharing nail clippers, and using street salons among exposed offspring.

Conclusions

Vertical and horizontal HBV transmission within households is ongoing in Kinshasa. Factors associated with infection reveal opportunities for HBV prevention efforts, including perinatal prevention, protection during sexual contact, and sanitation of shared personal items.
Clinician-Trained Artificial Intelligence for Enhanced Routing of Patient Portal Messages in the Electronic Health Record
Authors: Harzand Arash , Zia ul Haq Muhammad , Hornback Andrew M. , Cowan Alison D. , Anderson Blake
Published: November 2023

Background

Increased use of electronic health records (EHR) and patient-initiated messaging has led to inefficiency, staff shortages, and provider burnout. We evaluated the impact of a natural language processing (NLP) algorithm for message routing on communication dynamics.

Methods

We developed an NLP model to accurately label inbound EHR messages from patients using a pre-trained classifier with fine-tuning based on clinician feedback. In a real-world study, the model was deployed to prospectively label and route messages sent to participating physicians at an integrated health system. A parallel control group of unrouted messages was generated for comparative analysis. The primary endpoints for assessing model performance were the time to first message interaction, the time to conversation resolution, and the total number of message interactions by staff, compared with the control group. Secondary endpoints were the precision, recall, F1 score (a measure of positive predictive value and sensitivity), and accuracy for correct message classification.

Results

The model prospectively labeled and routed 469 unique conversations over 14 days from the inbaskets of participating physicians. Compared to a control group of 402 unrouted conversations from the same time period, conversations in the routed group had an 83.3% reduction in the time to first interaction (median difference [MD], −1 hour; P<0.001), an 84.4% reduction in the time to conversation resolution (MD, −22.5 hours; P<0.001), and a 40% reduction in the total number of staff interactions after application of intervention (MD, −2.0 interactions; P<0.001). The model demonstrated high precision (>97.6%), recall (>95%), and F1 scores (>96.5%) for accurate prediction of all five message classes, with a total accuracy of 97.8%.

Conclusions

Real-time message routing using advanced NLP was associated with significantly reduced message response and resolution times.
Genomic epidemiology of SARS-CoV-2 in Sudan: A retrospective analysis 2020-2022
Authors: Mburu Maureen W. , Lambisia Arnold W. , Elnegoumi Musab , Nour Eman O. M. , Khair Osama M. M. , Abualas Elamin , Elhassan Rehab M , Adam Muatsim A. M. , Mohammed Khadija Said , Morobe John M. , Ndwiga Leonard , Moraa Edidah O. , Makori Timothy O. , Murunga Nickson , Katama Esther Nyadzua , Waruguru Dorcas W. , Mwangi Sarah , Tessema Sofonias K. , Adam Mawahib H. E. , Mahmoud Iman , Mohamed Hanan SalmanBabikir , Mustafa Yousif A. A. , Mohamed Mohamedtaha M. A. , Ahmed Rasheeda H.A. , Mohamed Nuha Y.I. , Ali Rahma H. , Ebraheem Rasha S.M. , Ahmed Huda H.H. , Abdalla Hamadelniel E. , Mukhtar Izdihar , Alla Abdalkhalig E. M. W. , Elsheikh Omer H. A. , Musa Abdualmoniem O. , Faki Mahmoud Taha , Ahmed Gada Mustfa , Ahmed Thoyba E. R. , Abdalla Mohammed A. O. , Mohamed Mujtaba O. K. , Ahmed Rayan A. A. , AwadElkarim Samah M. M. , Ahmed Basamat A. E. M. , Shumo Zainab A. I. , Ahmed Eiman N. A. , Rushwan Samia S. A. , Bejon Phillip , Nokes D. James , Ochola-Oyier Lynette Isabella , Agoti Charles N. , Githinji George , Bedri Shahinaz A.
Published: November 2023

SARS-CoV-2 was first detected in Sudan on 13thMarch 2020. Here, we describe the genomic epidemiology of SARS-CoV-2 in Sudan between May 2020 and April 2022 to understand the introduction and transmission of SARS-CoV-2 variants in the country. A total of 667 SARS-CoV-2 positive samples were successfully sequenced using the nCoV-19 Artic protocol on the Oxford Nanopore Technology (≥70% genome completeness). The genomes were compared with a select contemporaneous global dataset to determine genetic relatedness and estimate import/export events. The genomes were classified into 37 Pango lineages within theancestral strain(107 isolates across 13 Pango lineages),Eta variant of interest (VOI)(78 isolates in 1 lineage),Alpha variant of concern (VOC)(10 isolates in 2 lineages),Beta VOC(26 isolates in 1 lineage),Delta VOC(171 isolates across 8 lineages) andOmicron VOC(242 isolates across 12 lineages). We estimated a total of 144 introductions of the observed variants from different countries across the globe. Multiple introductions of the Eta VOI, Beta VOC and Omicron VOC were observed in Sudan mainly from Europe and Africa. These findings suggest a need for continuous genomic surveillance of SARS-CoV-2 to monitor their introduction and spread consequently inform public health measures to combat SARS-CoV-2 transmission.
Deep generative modeling of the human proteome reveals over a hundred novel genes involved in rare genetic disorders
Authors: Orenbuch Rose , Kollasch Aaron W. , Spinner Hansen D. , Shearer Courtney A. , Hopf Thomas A. , Franceschi Dinko , Dias Mafalda , Frazer Jonathan , Marks Debora S.
Published: November 2023

Identifying causal mutations accelerates genetic disease diagnosis, and therapeutic development. Missense variants present a bottleneck in genetic diagnoses as their effects are less straightforward than truncations or nonsense mutations. While computational prediction methods are increasingly successful at prediction for variants inknowndisease genes, they do not generalize well to other genes as the scores are not calibrated across the proteome. To address this, we developed a deep generative model, popEVE, that combines evolutionary information with population sequence data and achieves state-of-the-art performance at ranking variants by severity to distinguish patients with severe developmental disorders from potentially healthy individuals. popEVE identifies 442 genes in a cohort of developmental disorder cases, including evidence of 119 novel genetic disorders without the need for gene-level enrichment and without overestimating the prevalence of pathogenic variants in the population. By placing variants on a unified scale, our model offers a comprehensive perspective on the distribution of fitness effects across the entire proteome and the broader human population. popEVE provides compelling evidence for genetic diagnoses even in exceptionally rare single-patient disorders where conventional techniques relying on repeated observations may not be applicable. Interactive web viewer and downloads available atpop.evemodel.org.
The association between SARS-CoV-2 infections in English primary and secondary school children and staff, and infections in members of their household in the schoolyear 2020-2021: a self-controlled case-series analysis
Authors: McClenaghan Elliot , Nguipdop-Djomo Patrick , Lewin Alexandra , Warren-Gash Charlotte , Cook Sarah , Mangtani Punam
Published: November 2023

Background

The role of children and staff in SARS-CoV-2 transmission outside and within households is still not fully understood when large numbers are in regular, frequent contact in schools.

Methods

We used the self-controlled case-series method during the alpha- and delta-dominant periods to explore the incidence of infection in periods around a household member infection, relative to periods without household infection, in a cohort of primary and secondary English school children and staff from November 2020 to July 2021.

Results

We found the relative incidence of infection in students and staff was highest in the 1-7 days following household infection, remaining high up to 14 days after, with risk also elevated in the 6-12 days before household infection. Younger students had a higher relative incidence following household infection, suggesting household transmission may play a more prominent role compared with older students. The relative incidence was also higher amongst students in the alpha variant dominant period.

Conclusions

This analysis suggests SARS-CoV2 infection in children, young people and staff at English schools were more likely to be associated with within-household transmission than from outside the household, but that a small increased risk of seeding from outside is observed.

Key messages

Question: With respect to incidence of SARS-CoV-2 infection before and after household member infection, is within-household transmission more likely than community transmission amongst school children and staff?

Findings: In this self-controlled case-series analysis, the relative incidence of infection in students and staff was highest in the 1-7 days following household infection, remaining high up to 14 days after, with the highest relative incidence found in younger, primary school-aged children.

Importance: Within-household transmission is more likely than from outside the household, but a small increased risk of seeding from outside the household is observed as well as variation by age and variant dominant period.
Computational phenotyping of aberrant belief updating in individuals with schizotypal traits and schizophrenia
Authors: Mikus Nace , Lamm Claus , Mathys Christoph
Published: November 2023

Psychotic and psychotic-like experiences are thought to emerge from various patterns of disrupted belief updating. These include belief rigidity, overestimating the reliability of sensory information, and misjudging task volatility. Yet, these substrates have never been jointly addressed under one computational framework and it is not clear to what degree they reflect trait-like computational patterns. Here, we introduce a computational model that describes interindividual differences in how individuals update their beliefs about a volatile environment through noisy observations and use this model in a series of studies. In a test-retest study with healthy participants (N = 45, 4 sessions), we find that interclass correlations were moderate to high for session-level model parameters and excellent for averaged belief trajectories and learning rates estimated through hierarchical Bayesian inference. Across three studies (total N=590) we then demonstrate that two distinct computational patterns describe two different transdiagnostic categories. Higher uncertainty about the task volatility is related to schizotypal traits (N = 45, d = 0.687, P = 0.02, N = 437, d = 0.14, P = 0.032) and to positive symptoms in a sample of patients with schizophrenia (N = 108, d = 0.187, P = 0.039), when learning to gain rewards. In contrast, depressive-anxious traits were associated with more rigid beliefs about the underlying mean (N = 437, d = −0.125, P = 0.006) and outcome variance (N = 437, d = −0.111, P = 0.013), as were negative symptoms in patients with schizophrenia (d = - 0.223, P = 0.026, d = −0.298, P = 0.003), when learning to avoid losses. These findings suggest that individuals high on schizotypal traits across the psychosis continuum are less likely to learn or utilize higher-order statistical regularities of the environment and showcase the potential of clinically relevant computational phenotypes for differentiating symptom groups in a transdiagnostic manner.
RNA polymerase II transcription with partially assembled TFIID complexes
Authors: Hisler Vincent , Bardot Paul , Detilleux Dylane , Stierle Matthieu , Sanchez Emmanuel Garcia , Richard Claire , Arab Lynda Hadj , Ehrhard Cynthia , Morlet Bastien , Hadzhiev Yavor , Jung Matthieu , Le Gras Stéphanie , Négroni Luc , Müller Ferenc , Tora László , Vincent Stéphane D.
Published: November 2023

The recognition of core promoter sequences by the general transcription factor TFIID is the first step in the process of RNA polymerase II (Pol II) transcription initiation. Metazoan holo-TFIID is composed of the TATA binding protein (TBP) and of 13 TBP associated factors (TAFs). InducibleTaf7knock out (KO) results in the formation of a Taf7-less TFIID complex, whileTaf10KO leads to serious defects within the TFIID assembly pathway. Either TAF7 or TAF10 depletions correlate with the detected TAF occupancy changes at promoters, and with the distinct phenotype severities observed in mouse embryonic stem cells or mouse embryos. Surprisingly however, under eitherTaf7orTaf10deletion conditions, TBP is still associated to the chromatin, and no major changes are observed in nascent Pol II transcription. Thus, partially assembled TFIID complexes can sustain Pol II transcription initiation, but cannot replace holo-TFIID over several cell divisions and/or development.
Protein domain embeddings for fast and accurate similarity search
Authors: Iovino Benjamin Giovanni , Tang Haixu , Ye Yuzhen
Published: November 2023

Recently developed protein language models have enabled a variety of applications with the protein contextual embeddings they produce. Per-protein representations (each protein is represented as a vector of fixed dimension) can be derived via averaging the embeddings of individual residues, or applying matrix transformation techniques such as the discrete cosine transformation to matrices of residue embeddings. Such protein-level embeddings have been applied to enable fast searches of similar proteins, however limitations have been found; for example, PROST is good at detecting global homologs but not local homologs, and knnProtT5 excels for proteins of single domains but not multi-domain proteins. Here we propose a novel approach that first segments proteins into domains (or subdomains) and then applies the discrete cosine transformation to the vectorized embeddings of residues in each domain to infer domain-level contextual vectors. Our approach, called DCTdomain, utilizes predicted contact maps from ESM-2 for domain segmentation, which is formulated as adomain segmentationproblem and can be solved using arecursive cutalgorithm (RecCut in short) in quadratic time to the protein length; for comparison, an existing approach for domain segmentation uses a cubic-time algorithm. We showed such domain-level contextual vectors (termed asDCT fingerprints) enable fast and accurate detection of similarity between proteins that share global similarities but with undefined extended regions between shared domains, and those that only share local similarities.
White matter lipidome alterations in the schizophrenia brain
Authors: Senko Dmitry , Osetrova Maria , Efimova Olga , Anikanov Nikolai , Tkachev Anna , Boyko Maria , Sharaev Maksim , Morozova Anna , Zorkina Yana , Kostyuk Georgiy , Stekolshchikova Elena , Khaitovich Philipp
Published: November 2023

Numerous brain imaging studies have reported white matter alterations in schizophrenia, but the lipidome analysis of the corresponding tissue remains incomplete. In this study, we investigated the lipidome composition of six subcortical white matter regions corresponding to major axonal tracks in both control subjects and schizophrenia patients. All six regions exhibited a consistent pattern of quantitative lipidome alterations in schizophrenia, affecting specific lipid classes. These alterations partly involved myelin-forming lipid classes, particularly sphingolipids, with the extent of alterations reflecting the myelin changes previously reported in structural brain imaging studies. The other part of the schizophrenia-associated alterations, which showed a significant decrease in the disorder, involved lipid classes abundant in mitochondria. A similar significant decrease was also observed in the mitochondria-enriched membrane fraction isolated from the white matter of individuals with schizophrenia. This suggests a substantial reduction in the number of mitochondria in subcortical white matter in schizophrenia, a hypothesis supported by quantitative mitochondria staining.
Random forest classifiers trained on simulated data enable accurate short read-based genotyping of structural variants in the alpha globin region at Chr16p13.3
Authors: Hansen Nancy F. , Wang Xunde , Tegegn Mickias B. , Liu Zhi , Gouveia Mateus H. , Hill Gracelyn , Lin Jennifer C. , Okulosubo Temiloluwa , Shriner Daniel , Thein Swee Lay , Mullikin James C.
Published: November 2023

In regions where reads don’t align well to a reference, it is generally difficult to characterize structural variation using short read sequencing. Here, we utilize machine learning classifiers and short sequence reads to genotype structural variants in the alpha globin locus on chromosome 16, a medically-relevant region that is challenging to genotype in individuals. Using models trained only with simulated data, we accurately genotype two hard-to-distinguish deletions in two separate human cohorts. Furthermore, population allele frequencies produced by our methods across a wide set of ancestries agree more closely with previously-determined frequencies than those obtained using currently available genotyping software.
Sleep loss impairs myelin function by altering cholesterol metabolism in oligodendroglia
Authors: Simayi Reyila , Ficiarà Eleonora , Faniyan Oluwatomisin , Cerdán Cerdá Antonio , Aboufares El Alaoui Amina , Fiorini Rosamaria , Cutignano Adele , Piscitelli Fabiana , Andújar Pablo , Santos Alexandra , Del Gallo Federico , de Vivo Luisa , De Santis Silvia , Bellesi Michele
Published: November 2023

The increasing prevalence of sleep deprivation in modern society demands comprehension of the biological consequences of sleep loss on brain functioning. Our study reveals significant effects of sleep deprivation on myelin integrity. As a result, we identify increased conduction delays in nerve signal propagation, hindered interhemispheric synchronization, and impaired motor performance associated with sleep loss. By profiling oligodendrocyte transcriptome and lipidome, we observe sleep loss-induced endoplasmic reticulum stress and lipid metabolism disruption, particularly affecting cholesterol homeostasis. This shift in cholesterol levels alters myelin physical properties. Boosting cholesterol transport to myelin sheaths prevents sleep loss effects on nerve signal propagation and behavior. Our findings highlight the critical role of oligodendrocyte cholesterol regulation in behavioral deficits associated with sleep loss and unveil a novel target for intervention.
Exploring Relationships BetweenIn VitroAqueous Solubility and Permeability andIn VivoFraction Absorbed
Authors: Fagerholm Urban
Published: November 2023

Introduction

Solubility/dissolution and permeability are essential determinants of gastrointestinal absorption of drugs.In vitroaqueous solubility (S) and apparent permeability (Papp) are commonly used as measurements and predictors ofin vivofraction absorbed (fa) and BCS-classing in humans. The objective of this study was to explore the relationships betweenin vitroaqueous S and Dose number (Do) andin vivofaandin vitroPappandin vivofaand the predictive power ofin vitroaqueous S, Doand Papp.

Methods

In vitroandin vivodata were taken from studies in the literature and correlated.In vitroS data were produced in various laboratories and with different methodologies.In vitroPappdata were produced using Caco-2 and MDCK cells in various laboratories and Caco-2 and RRCK cells in one laboratory each. Dowas estimated as oral dose / (S • 250 mL).

Results

452 S data and 1480 Pappdata were found and used. There was no correlation (R2=0.0) betweenin vitrolog S and Dovs in vivofa, not even at S<1 mg/L or not for compounds with <90 % and <30 %in vivofa. A R2of 0.43 was found between log Caco-2 Pappandin vivofa. The corresponding R2for Caco-2 from one laboratory was 0.65. The interlaboratory R2for the Caco-2 model was 0.48. R2-estimates for Caco-2vsMDCK and Caco-2vsRRCK Pappwere 0.23 and 0.21, respectively.

Discussion and Conclusion

Aqueous S appears to have no predictive value ofin vivofain humans, not even at low S or after correction for dose. The shows that one should not base human biopharmaceutical predictions based on aqueous S. Log Caco-2 Pappexplains about half of the variance ofin vivofain humans. The poor correlations found between Caco-2 and the two other Papp-models (MDCK and RRCK) demonstrate considerable methodological differences. The unexplained variance does not appear to be explained by S and dose, but rather byin vitro-in vivodifference in permeability and poor/absent relationship betweenin vitroS andin vivodissolution potential.
Flight behaviour diverges more between seasonal forms than between species inPierisbutterflies
Authors: Kleckova Irena , Linke Daniel , Rezende Francisko De Moraes , Rauscher Luca , Le Roy Camille , Matos-Maraví Pável
Published: November 2023

In flying animals, wing morphology is typically assumed to influence flight behaviours. Whether seasonal polymorphism behaviour might be associated with divergent fore wing shapes.Pierisindividuals in the spring are small and have elongated fore wings, traits correlate with low fly speed and acceleration, and in butterfly morphology is linked to adaptive flight behaviour remains unresolved. Here we compare the flight behaviours and wing morphologies of the spring and summer forms of two closely related butterfly species,Pieris napiandP. rapae. We first quantify three-dimensional flight behaviour by reconstructing individual flight trajectories using stereoscopic high-speed videography in an experimental outdoor cage. We then measure wing size and shape, which are characteristics assumed to influence flight behaviours in butterflies. We show that seasonal, but not interspecific, differences in flight high flight curvature. Large summer individuals exhibit rounded fore wings, which correlate with high flight speed, acceleration, turning acceleration, and advance ratio. Our study provides quantitative evidence of different flight behaviours between seasonal forms ofPierisbutterflies, and these differences were better predicted by body size and forewing shape, rather than other factors (e.g., species identity, ambient temperature). This points toward a possible adaptive role of seasonal morphology determining flight behaviours, although this needs to be thoroughly investigated to distinguish the effects of microhabitat (e.g., behavioural thermoregulation, resource distribution between seasons, such as nectar and larval food plants), predator and parasitoid pressure, and possible sexual behavioural differences.
E2VD: a unified evolution-driven framework for virus variation drivers prediction
Authors: Nie Zhiwei , Liu Xudong , Chen Jie , Wang Zhennan , Liu Yutian , Si Haorui , Dong Tianyi , Xu Fan , Song Guoli , Wang Yu , Zhou Peng , Gao Wen , Tian Yonghong
Published: November 2023

The increasing frequency of emerging viral infections necessitates a rapid human response, highlighting the cost-effectiveness of computational methods. However, existing computational approaches are limited by their input forms or incomplete functionalities, preventing a unified prediction of diverse viral variation drivers and hindering in-depth applications. To address this issue, we propose a unified evolution-driven framework for predicting virus variation drivers, named E2VD, which is guided by virus evolutionary traits priors. With evolution-inspired design, E2VD comprehensively and significantly outperforms state-of-the-art methods across various virus variation drivers prediction tasks. Moreover, E2VD effectively captures the fundamental patterns of virus evolution. It not only distinguishes different types of mutations but also accurately identifies rare beneficial mutations that are critical for virus to survival, while maintains generalization capabilities on different viral lineages. Importantly, with predicted biological drivers, E2VD perceives virus evolutionary trends, in which potential high-risk mutation sites are accurately recommended. Overall, E2VD represents a unified, structure-free, and interpretable approach for analyzing and predicting viral evolutionary fitness, providing an ideal alternative to costly wet-lab measurements to accelerate responses to emerging viral infections.
Sequence-based drug design using transformers
Authors: Zhang Shengyu , Huo Donghui , Horne Robert I. , Qi Yumeng , Ojeda Sebastian Pujalte , Yan Aixia , Vendruscolo Michele
Published: November 2023

Protein-ligand interactions play central roles in biological processes and are of key importance in drug design. Deep learning-based approaches are emerging as cost-effective alternatives to high-throughput experimental methods for the screening of large libraries of ligands. Here, to predict the binding affinity between proteins and small molecules, we introduce Ligand-Transformer, a deep learning framework based on the AlphaFold2 transformer architecture. We applied Ligand-Transformer to screen inhibitors targeting the mutant EGFRLTCkinase, identifying compounds with low nanomolar potency. We then used this approach to predict the conformational population shifts induced by ABL kinase inhibitors. To show the applicability of Ligand-Transformer to disordered proteins, we explored the binding of small molecules to the Alzheimer’s Aβ peptide, identifying compounds that delayed its aggregation. Overall, Ligand-Transformer illustrates the potential of transformers in accurately predicting the interactions of small molecules with both ordered and disordered proteins, thus uncovering molecular mechanisms and facilitating the initial steps in drug discovery.
Investigating impacts of marine sponge derived mycothiazole and its acetylated derivative on mitochondrial function and aging
Authors: Dutta Naibedya , Gerke Joe A , Odron Sofia F , Morris Joseph D , Hruby Adam , Torres Toni Castro , Shemtov Sarah J , Clarke Jacqueline G , Chang Michelle C , Shaghasi Hooriya , Ray Marissa N. , Averbukh Maxim , Hoang Sally , Oorloff Maria , Alcala Athena , Vega Matthew , Mehta Hemal H , Thorwald Max A , Crews Phillip , Vermulst Marc , Garcia Gilberto , Johnson Tyler A , Higuchi-Sanabria Ryo
Published: November 2023

Small molecule inhibitors of the mitochondrial electron transport chain (ETC) hold significant promise to provide valuable insights to the field of mitochondrial research and aging biology. In this study, we investigated two molecules: mycothiazole (MTZ) - from the marine spongeC. mycofijiensisand its more stable semisynthetic analog 8-O-acetylmycothiazole (8-OAc) as potent and selective chemical probes based on their high efficiency to inhibit ETC complex I function. Similar to rotenone (Rote), a widely used ETC complex I inhibitor, these two molecules showed cytotoxicity to cancer cells but strikingly demonstrate a lack of toxicity to non-cancer cells, a highly beneficial feature in the development of anti-cancer therapeutics. Furthermore, in vivo experiments with these small molecules utilizingC.elegansmodel demonstrate their unexplored potential to investigate aging studies. We observed that both molecules have the ability to induce a mitochondria-specific unfolded protein response (UPRMT) pathway, that extends lifespan of worms when applied in their adult stage. Interestingly, we also found that these two molecules employ different pathways to extend lifespan in worms. Whereas MTZ utilize the transcription factors ATFS-1 and HSF-1, which are involved in the UPRMTand heat shock response (HSR) pathways respectively, 8-OAc only required HSF-1 and not ATFS-1 to mediate its effects. This observation underscores the value of applying stable, potent, and selective next generation chemical probes to elucidate an important insight into the functional roles of various protein subunits of ETC complexes and their regulatory mechanisms associated with aging.