bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficient overexpression and purification of SARS-CoV-2 Nucleocapsid proteins inEscherichia coli
Authors: Brudenell Emma L , Pohare Manoj B , Zafred Domen , Phipps Janine , Hornsby Hailey R , Darby John , Dai Junxiao , Liggett Ellen , Cain Kathleen , Barran Perdita E. , de Silva Thushan I , Sayers Jon R
Published: January 2024

The fundamental biology of Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein (Ncap), its use in diagnostic assays and its potential application as a vaccine component have received considerable attention since the outbreak of the Covid19 pandemic in late 2019. Here we report the scalable expression and purification of soluble, immunologically active, SARS-CoV-2 Ncap inEscherichia coli. Codon-optimised synthetic genes encoding the original Ncap sequence and four common variants with an N-terminal 6His affinity tag (sequence MHHHHHHG) were cloned into an inducible expression vector carrying a regulated bacteriophage T5 synthetic promoter controlled bylacoperator binding sites. The constructs were used to express Ncap proteins and protocols developed which allow efficient production of purified Ncap with yields of over 200 mg per litre of culture media. These proteins were deployed in ELISA assays to allow comparison of their responses to human sera. Our results suggest that there was no detectable difference between the 6His-tagged and untagged original Ncap proteins but there may be a slight loss of sensitivity of sera to other Ncap isolates.
Annotations of four high-quality indigenous chicken genomes identify more than one thousand missing genes in sub-telomeric regions with high G/C contents
Authors: Wu Siwen , Dou Tengfei , Yuan Sisi , Yan Shixiong , Xu Zhiqiang , Liu Yong , Jian Zonghui , Zhao Jingying , Zhao Rouhan , Zi Xiannian , Gu Dahai , Liu Lixian , Li Qihua , Wu Dong-Dong , Su Zhengchang , Jia Junjing , Ge Changrong , Wang Kun
Published: January 2024

Background

Although multiple chicken genomes have been assembled and annotated, the number of protein-coding genes in chicken genomes is still uncertain due to the low quality of these genome assemblies and limited resources used in gene annotations.

Results

To fill the gap, we annotated our four recently assembled high-quality genomes of four indigenous chickens with distinct traits using a combination of RNA-seq- and homology-based approach. Our annotated genes in the four chickens recovered 51 of the 274 “missing” genes in birds in general and 36 of the 174 “missing” genes in chickens in particular. Intriguingly, based on deeply sequenced RNA-seq data collected in multiple tissues in each chicken breed, we found a total of 1,420 new protein-coding genes in the four chicken genomes, which were missed in the reference chicken genome annotations. These newly annotated genes (NAGs) tend to have high G/C contents and be located in sub-telomeric regions of almost all assembled chromosomes and some unplaced contigs. The NAGs showed tissue-specific expression and we were able to verify 39 (92.9%) of 42 randomly selected ones in various tissues of the four chicken breeds using RT-qPCR experiments. We found that most of the NAGs also are encoded in previously assembled chicken genomes. The NAGs form functional modules with homology-supported genes that are involved in many important biological pathways. We also identified numerous unique genes in each indigenous chicken genome that might be related to the unique traits of each breed.

Conclusion

The ubiquitous presence of the NAGs in various chicken genomes indicate that they might play critical roles in chicken physiology. Counting these new genes, chicken genomes harbor more genes than originally thought.
Membrane cliffs are giant, recursive platforms that drive calcium and protein kinase signaling for cell growth
Authors: Trerotola Marco , Relli Valeria , Tripaldi Romina , Simeone Pasquale , Guerra Emanuela , Sacchetti Andrea , Ceci Martina , Pantalone Ludovica , Ciufici Paolo , Moschella Antonino , Caiolfa Valeria R. , Zamai Moreno , Alberti Saverio
Published: January 2024

The transmembrane glycoproteins Trop-1/EpCAM and Trop-2 independently trigger Ca2+and kinase signals for cell growth and tumor progression. We discovered that Trop-1 and Trop-2 are recruited at overlapping sites at free cell edges. Z-stack analysis and three-dimensional reconstruction of these sites revealed previously unrecognized, protruding membrane regions ≥20 µm-long, up to 1.5 µm high, then named ‘cliffs’. Cliffs appeared confined to essentially immobile sites of the cell membrane, where they recursively assembled over hundreds of seconds. Cliffs were shown to recruit growth-driving kinases and downstream cytoplasmic effectors. Trop-2 stimulates cell growth through a membrane super-complex that comprises CD9 and PKCα. Our findings indicated that the growth-driving Trop-2 super-complex assembles at cliffs. Cliffs acted as sites of phosphorylation/activation of growth-driving kinases and as origins of Ca2+signaling waves, indicating cliffs as novel signaling platforms for drivers of cell growth. Cliffs were induced by growth factors and disappeared upon growth factor deprivation, suggesting cliffs as pivotal platforms for signaling for cell growth.
Preferential apical infection of intestinal cell monolayers by SARS-CoV-2 is associated with damage to cellular barrier integrity: Implications for the physiopathology of COVID-19
Authors: Garrec Clémence , Arrindell Jeffrey , Andrieu Jonatane , Desnues Benoit , Mege Jean-Louis , Osman Ikram Omar , Devaux Christian A.
Published: January 2024

SARS-CoV-2 can infect different organs, including the intestine. In Caco-2 intestinal cell line, SARS-CoV-2 modulates the ACE2 receptor expression and affects the expression of molecules involved in intercellular junctions. To further explore the possibility that the intestinal epithelium serves as an alternative infection route for SARS-CoV-2, we used a model of polarised intestinal cell monolayers grown on the polycarbonate membrane of Transwell inserts, inoculated with the virus either in the upper or lower chamber of culture. In both polarised Caco-2 cell monolayers and co-culture Caco-2/HT29 cell monolayer, apical SARS-CoV-2 inoculation was found to be much more effective in establishing infection than basolateral inoculation. In addition, apical SARS-CoV-2 infection triggers monolayer degeneration, as shown by histological examination, measurement of trans-epithelial electronic resistance, and cell adhesion molecule expression. During this process, the infectious viruses reach the lower chamber, suggesting either a transcytosis mechanism from the apical side to the basolateral side of cells, a paracellular trafficking of the virus after damage to intercellular junctions in the epithelial barrier, or both. Taken together, these data highlight a preferential tropism of SARS-CoV-2 for the apical side of the human intestinal tract and suggests that infection via the intestinal lumen leads to a systemic infection.
Effectiveness of a network Open House model to recruit trainees to post-baccalaureate STEM programs
Authors: Aoki Scott Takeo , Lewellyn Lindsay , Justice Sarah , Mordan-McCombs Sarah , Tewari Neetu , Cantu Jorge , Seiser Robert , Lakhani Ahmed , Kowalski Jennifer R.
Published: January 2024

Post-baccalaureate (post-bac) programs can have a positive impact on science training and STEM career opportunities for junior trainees. A goal for many of these sponsored programs is to increase research exposure for underrepresented minorities, a group that can include African American, Hispanic, Native American, and first-generation college students, among others. Recruiting underrepresented minorities to post-bac programs can be challenging, for reasons that include a lack of available research opportunities, time to pursue these experiences, and awareness of available programs. To this end, an Open House event was created to inform and excite potential students for future post-bac programs. Students were recruited from partnering Minority Serving Institutions (MSIs) to attend a two-day event at a primarily undergraduate institution (PUI) and a research-intensive R1 institution. The students visited both campuses, were informed about post-bac programs and potential research opportunities, and met with faculty, current graduate students, and a former post-bac scholar. Transportation, lodging, and meals were provided. Visiting students completed voluntary pre- and post-surveys. Results indicated that attendees, the majority of whom were underrepresented minorities in STEM, left the event with an increased understanding about post-bac programs and their benefits to a career in STEM and that their attendance at the event made it more likely they would apply to available post-bac programs. Thus, this work demonstrates that in-person events involving integrative partnerships across multiple universities are effective strategies for increasing awareness of opportunities available to students post-graduation and for recruiting underrepresented groups in STEM to post-bac programs.
Coordinated molecular and ecological adaptations underlie a highly successful parasitoid
Authors: Pang Lan , Fang Gangqi , Liu Zhiguo , Dong Zhi , Chen Jiani , Feng Ting , Zhang Qichao , Sheng Yifeng , Lu Yueqi , Wang Ying , Zhang Yixiang , Li Guiyun , Chen Xuexin , Zhan Shuai , Huang Jianhua
Published: January 2024

The success of an organism depends on the molecular and ecological adaptations that promote its beneficial fitness. Parasitoids are valuable biocontrol agents for successfully managing agricultural pests, and they have evolved diversified strategies to adapt to both the physiological condition of hosts and the competition of other parasitoids. Here, we deconstructed the parasitic strategies in a highly successful parasitoid,Trichopria drosophilae, which parasitizes a broad range ofDrosophilahosts, including the globally invasive speciesD. suzukii. We found thatT. drosophilaehad developed specialized venom proteins that arrest host development to obtain more nutrients via secreting tissue inhibitors of metalloproteinases (TIMPs), as well as a unique type of cell— teratocytes—that digest host tissues for feeding by releasing trypsin proteins. In addition to the molecular adaptations that optimize nutritional uptake, this pupal parasitoid has evolved ecologically adaptive strategies including the conditional tolerance of intraspecific competition to enhance parasitic success in older hosts and the obligate avoidance of interspecific competition with larval parasitoids. Our study not only demystifies how parasitoids weaponize themselves to colonize formidable hosts but also provided empirical evidence of the intricate coordination between the molecular and ecological adaptations that drive evolutionary success.
HUB-DT: A tool for unsupervised behavioural discovery and analysis
Authors: Lindsay Adrian , Seamans Jeremy K
Published: January 2024

There has been an expansion in the diversity of tools used to measure various aspects of brain function in behaving animals. While these tools have great potential to transform our understanding of brain function, they are of little value if the behavior of interest is poorly defined or quantified. Traditional methods of behavioural labelling focus on easily quantified gross measure, such as velocity, gate crossing, nosepokes, etc. While these measures are specific and reproducible, they are crude descriptions of behaviour at best. Manually defined behaviours, while providing increased granularity and descriptive power over specific gross measures, suffer from being inexact and somewhat arbitrary. Consistent labelling between human observers is often difficult, and even if manually defined behaviours are subsequently labelled in an automated fashion (via a supervised learning algorithm) these behaviours need to be defined ahead of time, possibly biasing the range of behaviours of interest for a given task.

Here we present HUB-DT, a behavioural discovery pipeline built on the frameworks of several existing tools and methods in the space of behavioural categorisation, the specifics of which will be highlighted in this report, and designed to address the requirements of behavioral discovery.
Metatranscriptomic analysis reveals synergistic activities of comammox and anammox bacteria in full-scale attached growth nitrogen removal system
Authors: Johnston Juliet , Vilardi Katherine , Cotto Irmarie , Sudarshan Ashwin , Bian Kaiqin , Klaus Stephanie , Bachmann Megan , Parsons Mike , Wilson Christopher , Bott Charles , Pinto Ameet
Published: January 2024

0-

Leveraging comammoxNitrospiraand anammox bacteria for shortcut nitrogen removal can drastically lower the carbon footprint of wastewater treatment facilities by decreasing aeration energy, carbon, alkalinity, and tank volume requirements while also potentially reducing nitrous oxide emissions. However, their co-occurrence as dominant nitrifying bacteria is rarely reported in full-scale wastewater treatment. As a result, there is poor understanding of how operational parameters, in particular dissolved oxygen, impact their activity and synergistic behavior. Here, we report the impact of dissolved oxygen concentration (DO = 2, 4, 6 mg/L) on the microbial community’s transcriptomic expression in a full-scale integrated fixed film activated sludge (IFAS) municipal wastewater treatment facility predominantly performed by comammoxNitrospiraand anammox bacterial populations. 16S rRNA transcript compositions revealed anammox bacteria andNitrospirawere significantly more active in IFAS biofilms compared to suspended sludge biomass. In IFAS biofilms, anammox bacteria significantly increasedhzoexpression at lower dissolved oxygen concentrations and this increase was highly correlated with theamoAexpression levels of comammox bacteria. Interestingly, the genes involved in nitrite oxidation by comammox bacteria were significantly more upregulated relative to the genes involved in ammonia oxidation with decreasing dissolved oxygen concentrations. Ultimately, our findings suggest that comammoxNitrospirasupply anammox bacteria with nitrite via ammonia oxidation and that this synergistic behavior is dependent on dissolved oxygen concentrations.

Synopsis

Comammox bacteria differentially regulate ammonia and nitrite oxidation in response to dissolved oxygen concentration suggesting dissolved oxygen dependence of their synergistic nitrogen removal with anammox bacteria in IFAS biofilms.
CD271 restrains the B1b cell antibody response in a T cell dependent manner
Authors: Lebel Marie-Ève , Bonkoungou Carole A. , Thibault Jade , Rauch Joyce , Alugupalli Kishore R. , Melichar Heather J.
Published: January 2024

Co-signaling molecules modulate T cell function and are essential to control the duration and amplitude of immune responses. These molecules belong to the immunoglobulin and tumor necrosis factor receptor (TNFR) superfamilies and have been extensively studied; however, the immunomodulatory role of several family members remains unknown. We show that CD271 (also known as p75 or NGFR), a TNFR superfamily member, is highly expressed on peritoneal B1 B cells, but not on conventional (B2) B cells at steady state. CD271 expression by B cells specifically restrains the response to T cell-independent type 2 antigens (TI-2). B1 cell-expressed CD271 maintains peritoneal CD4+T cell quiescence, and augmented antibody responses to TI-2 antigens in CD271-deficient mice are dependent on CD4+T cells. This increase in antibody production correlates with improved bacterial neutralizationin vitroand survival after bacterial challengein vivo. Further, our results suggest that CD271 can directly inhibit mouse and human T cell activity to the same extent as PD-L1, a known, negative regulator of T cell function. These results establish CD271 as a co-inhibitory molecule that could be targeted to improve the efficacy of vaccines against pathogenic encapsulated bacteria and to broadly modulate the T cell response in therapeutic contexts.

eTOC summary

Lebel et al. identify an unexpected role for CD271, a neurotrophin receptor, in directly inhibiting T cell function. B1 cell-expressed CD271 maintains CD4+T cell quiescence; in the absence of CD271, T cells bolster antibody production to T-independent antigens, enhancing the response to encapsulated bacteria.
Spatial Transcriptomics Sequencing of Mouse Liver at 2µm Resolution Using a Novel Spatial DNA Chip
Authors: Ding Xun , Hoff Kendall , Swaminathan Radha , Koutrouli Mikaela , Pollom Scott , Huang Tianlong , Li Xiaochi , Zhou Guoqiang , Bai Zhicong , Yu Shizhe , Xia Zongping , Jensen Lars Juhl , Crnogorac Filip , Yu Su , McGall Glenn , Edwards Jeremy , Zhou Wei
Published: January 2024

Spatial transcriptomics enables analysis of gene expression that is spatially resolved within a tissue section, making it possible to elucidate the relationship between individual cells within the context of the tissue. This transformative technology enables researchers to better understand gene function within the context of health tissue, developmental processes, and disease. In this study, we present an innovative spatial transcriptomics technology and data using a high-resolution DNA chip with a total capture region size of 6.5 x 6.5 mm containing 2 x 2 µm features for spatial barcoding with no gaps between the features, thereby maximizing the capture area. These chips are manufactured at wafer scale using photolithography and are transferred to hydrogels, making them compatible with existing workflows for fresh frozen or paraffin-embedded samples. Herein, we examined a fresh frozen sample from an adult mouse liver. To analyze the data, we binned 10 x 10 features to represent a 20 µm x 20 µm capture area. We obtained 1.3 billion unique mapped reads, 68.78% sequencing saturation, with a median of 16,967 unique reads per region, indicating the potential for more unique reads with deeper sequencing. This high-resolution mapping of liver cell types and the visualization of gene expression patterns illustrate significant advancements in spatial sequencing technology.
The spatial landscape of glial pathology and T-cell response in Parkinson’s disease substantia nigra
Authors: Jakubiak Kelly , Paryani Fahad , Kannan Adithya , Lee Jaeseung , Madden Nacoya , Li Juncheng , Chen David , Mahajan Aayushi , Xia Shengnan , Flowers Xena , Menon Vilas , Sulzer David , Goldman James , Sims Peter A. , Al-Dalahmah Osama
Published: January 2024

Parkinson’s Disease (PD) is a progressive neurodegenerative disease that leads to debilitating movement disorders and often dementia. Recent evidence, including identification of specific peripheral T-cell receptor sequences, indicates that the adaptive immune response is associated with disease pathogenesis. However, the properties of T-cells in the brain regions where neurons degenerate are not well characterized. We have analyzed the identities and interactions of T-cells in PD in post-mortem brain tissue using single nucleus RNA sequencing, spatial transcriptomics and T-cell receptor sequencing. We found that T-cells in the substantia nigra of PD brain donors exhibit a CD8+ resident memory phenotype, increased clonal expansion, and altered spatial relationships with astrocytes, myeloid cells, and endothelial cells. We also describe regional differences in astrocytic responses to neurodegeneration. Our findings nominate potential molecular and cellular candidates that allow a deeper understanding of the pathophysiology of neurodegeneration in PD. Together, our work represents a major single nucleus and spatial transcriptional resource for the fields of neurodegeneration and PD.
Enhancement of mediodorsal thalamus rescues aberrant belief dynamics in a mouse model with schizophrenia-associated mutation
Authors: Zhou Tingting , Ho Yi-Yun , Lee Ray X. , Fath Amanda B. , He Kathleen , Scott Jonathan , Bajwa Navdeep , Hartley Nolan D. , Wilde Jonathan , Gao Xian , Li Cui , Hong Evan , Nassar Matthew R. , Wimmer Ralf D. , Singh Tarjinder , Halassa Michael M. , Feng Guoping
Published: January 2024

Optimizing behavioral strategy requires belief updating based on new evidence, a process that engages higher cognition. In schizophrenia, aberrant belief dynamics may lead to psychosis, but the mechanisms underlying this process are unknown, in part, due to lack of appropriate animal models and behavior readouts. Here, we address this challenge by taking two synergistic approaches. First, we generate a mouse model bearing patient-derived point mutation in Grin2a (Grin2aY700X+/−), a gene that confers high-risk for schizophrenia and recently identified by large-scale exome sequencing. Second, we develop a computationally trackable foraging task, in which mice form and update belief-driven strategies in a dynamic environment. We found thatGrin2aY700X+/−mice perform less optimally than their wild-type (WT) littermates, showing unstable behavioral states and a slower belief update rate. Using functional ultrasound imaging, we identified the mediodorsal (MD) thalamus as hypofunctional inGrin2aY700X+/−mice, andin vivotask recordings showed that MD neurons encoded dynamic values and behavioral states in WT mice. Optogenetic inhibition of MD neurons in WT mice phenocopiedGrin2aY700X+/−mice, and enhancing MD activity rescued task deficits in Grin2aY700X+/−mice. Together, our study identifies the MD thalamus as a key node for schizophrenia-relevant cognitive dysfunction, and a potential target for future therapeutics.
Phosphorylation inhibits intramolecular interactions, DNA-binding and protein interactions of Claspin through disordered/ structured conformation transition
Authors: You Zhiying , Hsiao Hao-Wen , Yang Chi-Chun , Goto Hidemasa , Masai Hisao
Published: January 2024

Claspin, known to be highly disordered, plays important roles in replication fork progression, initiation and cellular responses to replication stress. However, regulation of its structure and molecular interactions is not completely understood. We show here, through Proximity-Ligation-Assays, the evidence for intramolecular interaction between the N- and C-terminal segments of Claspin, which depends on the Acidic-Patch [AP] segment near its C-terminus. Interaction of Claspin with DNA and replication factors is highly stimulated in ΔAP mutant and by prior dephosphorylation. The wild-type Claspin inhibits the helicase activity of MCM in an AP-dependent manner. ΔAP and dephosphorylated Claspin exhibit resistance to trypsin digestion compared to wild-type, suggesting the presence of structural domains in the formers. We propose that Claspin is converted from disordered (closed) to structured (open) conformation at initiation, which stimulates its DNA binding and interaction with replication factors and counteracts its helicase inhibitory activity to trigger initiation of DNA replication.
An assessment of the value of deep neural networks in genetic risk prediction for surgically relevant outcomes
Authors: Christensen Mathias A , Sigurdsson Arnór , Bonde Alexander , Rasmussen Simon , Ostrowski Sisse R , Nielsen Mads , Sillesen Martin
Published: January 2024

Introduction

Postoperative complications affect up to 15% of surgical patients constituting a major part of the overall disease burden in a modern healthcare system. While several surgical risk calculators have been developed, none have so far been shown to decrease the associated mortality and morbidity. Combining deep neural networks and genomics with the already established clinical predictors may hold promise for improvement.

Methods

The UK Biobank was utilized to build linear and deep learning models for the prediction of surgery relevant outcomes. An initial GWAS for the relevant outcomes was initially conducted to select the Single Nucleotide Polymorphisms for inclusion in the models. Model performance was assessed with Receiver Operator Characteristics of the Area Under the Curve and optimum precision and recall. Feature importance was assessed with SHapley Additive exPlanations.

Results

Models were generated for atrial fibrillation, venous thromboembolism and pneumonia as genetics only, clinical features only and a combined model. For venous thromboembolism, the ROC-AUCs were 59.6% [59.0%-59.7%], 63.4% [63.2%-63.4%] and 66.1% [65.7%-66.1%] for the linear models and 60.0% [57.8%-61.8%], 63.2% [61.2%-65.0%] and 65.4% [63.6%-67.2%] for the deep learning SNP, clinical and combined models, respectively. For atrial fibrillation, the ROC-AUCs were 60.9% [60.6%-61.0%], 78.7% [78.7%-78.7%] and 80.1% [80.0%-80.1%] for the linear models and 59.9% [.6%-61.3%], 78.8% [77.8%-79.8%] and 79.4% [78.8%-80.5%] for the deep learning SNP, clinical and combined models, respectively. For pneumonia, the ROC-AUCs were 57.3% [56.5%-57.4%], 69.2% [69.1%-69.2%] and 70.5% [70.2%-70.6%] for the linear models and 55.5% [54.1%-56.9%], 69.7% [.5%-70.8%] and 69.9% [68.7%-71.0%] for the deep learning SNP, clinical and combined models, respectively.

Conclusion

In this report we presented linear and deep learning predictive models for surgery relevant outcomes. Overall, predictability was similar between linear and deep learning models and inclusion of genetics seemed to improve accuracy.
Multi-ancestry polygenic risk scores for venous thromboembolism
Authors: Jee Yon Ho , Thibord Florian , Dominguez Alicia , Sept Corriene , Boulier Kristin , Venkateswaran Vidhya , Ding Yi , Cherlin Tess , Verma Shefali Setia , Faro Valeria Lo , Bartz Traci M. , Boland Anne , Brody Jennifer A. , Deleuze Jean-Francois , Emmerich Joseph , Germain Marine , Johnson Andrew D. , Kooperberg Charles , Morange Pierre-Emmanuel , Pankratz Nathan , Psaty Bruce M. , Reiner Alexander P. , Smadja David M. , Sitlani Colleen M. , Suchon Pierre , Tang Weihong , Trégouët David-Alexandre , Zöllner Sebastian , Pasaniuc Bogdan , Damrauer Scott M. , Sanna Serena , Snieder Harold ,   Lifelines Cohort Study, Kabrhel Christopher , Smith Nicholas L. , Kraft Peter ,   INVENT Consortium
Published: January 2024

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality, with large disparities in incidence rates between Black and White Americans. Polygenic risk scores (PRSs) limited to variants discovered in genome-wide association studies in European-ancestry samples can identify European-ancestry individuals at high risk of VTE. However, there is limited evidence on whether high-dimensional PRS constructed using more sophisticated methods and more diverse training data can enhance the predictive ability and their utility across diverse populations. We developed PRSs for VTE using summary statistics from the International Network against Venous Thrombosis (INVENT) consortium GWAS meta-analyses of European- (71,771 cases and 1,059,740 controls) and African-ancestry samples (7,482 cases and 129,975 controls). We used LDpred2 and PRSCSx to construct ancestry-specific and multi-ancestry PRSs and evaluated their performance in an independent European- (6,261 cases and 88,238 controls) and African-ancestry sample (1,385 cases and 12,569 controls). Multi-ancestry PRSs with weights tuned in European- and African-ancestry samples, respectively, outperformed ancestry-specific PRSs in European- (PRSCSXEUR: AUC=0.61 (0.60, 0.61), PRSCSX_combinedEUR: AUC=0.61 (0.60, 0.62)) and African-ancestry test samples (PRSCSXAFR: AUC=0.58 (0.57, 0.6), PRSCSX_combinedAFR: AUC=0.59 (0.57, 0.60)). The highest fifth percentile of the best-performing PRS was associated with 1.9-fold and 1.68-fold increased risk for VTE among European- and African-ancestry subjects, respectively, relative to those in the middle stratum. These findings suggest that the multi-ancestry PRS may be used to identify individuals at highest risk for VTE and provide guidance for the most effective treatment strategy across diverse populations.
Attribution of invasive group A streptococcal infections to varicella and respiratory virus circulation, the Netherlands, 2010-2023
Authors: de Gier Brechje , van de Kassteele Jan , van Asten Liselotte , Schoffelen Annelot ,   ISIS-AR study group, Hooiveld Mariette , te Wierik Margreet J.M. , van Sorge Nina M. , de Melker Hester E.
Published: January 2024

Background

After the lifting of most COVID-19 control measures, many infectious diseases re-emerged in 2022. A strong increase in invasive group A streptococcal (iGAS) infections, among both adults and young children, was reported by several countries. Viral infections such as influenza and varicella, known risk factors for iGAS infection, also increased during 2022. We estimated the proportion of GAS skin and soft tissue infections (SSTI) in children aged 0-5 years attributable to varicella, and the proportion of GAS pneumonia/sepsis in children aged 0-5 and adults attributable to respiratory viruses in the Netherlands.

Methods

We performed time-series regression using weekly data on influenza A and B, RSV, hMPV and SARS-CoV-2, varicella and non-invasive GAS infections, and GAS isolates cultured from blood, lower airways, skin, pus and wounds, from January 2010 to March 2023.

Results

Up to 2022, approximately 50%(95%CI 36-64%) of GAS SSTI in children were attributable to varicella. Between January 2022 and March 2023, 34%(95%CI 24-43%) of GAS SSTI cases were attributable to varicella. Of iGAS pneumonia/sepsis between January 2022 and March 2023, 25%(95%CI 18-31%) and 37%(95% CI 23-53%) was attributable to respiratory virus infections in adults and children, respectively, with the largest contributor being influenza A.

Conclusions

Varicella and respiratory virus infections likely contributed to, but only partly explain, the observed iGAS increase among children and adults in 2022-2023 in the Netherlands. Public health measures to control viral infections, such as vaccination against varicella or influenza, might reduce the iGAS disease burden but will not suffice to curb the current high incidence.
Prevalence of Asymptomatic non-Falciparum and Falciparum Malaria in the 2014-15 Rwanda Demographic Health Survey
Authors: Gaither Claudia , Morgan Camille , Kirby Rebecca , Karema Corine , Gashema Pierre , White Samuel J. , Topazian Hillary M. , Geibrecht David , Thwai Kyaw , Wernsman Young Neeva , Boyter Koby , Munyaneza Tharcisse , Mambo Muvunyi Claude , De Dieu Butera Jean , Bailey Jeffrey A. , Mazarati Jean-Baptiste , Juliano Jonathan J.
Published: January 2024

Non-falciparum and asymptomaticPlasmodium falciparummalaria are prevalent across Rwanda, withP. falciparumlinked to poverty, rural areas, and low elevation. Mixed infections are frequent. Molecular surveillance is crucial to guide effective malaria control efforts.

Background

Recent molecular surveillance suggests an unexpectedly high prevalence of non-falciparum malaria in Africa. Malaria control is also challenged by undetected asymptomaticP. falciparummalaria resulting in an undetectable reservoir for potential transmission. Context-specific surveillance of asymptomaticP. falciparumand non-falciparum species is needed to properly inform malaria control programs.

Methods

We performed quantitative real time PCR for four malaria species in 4,595 primarily adult individuals in Rwanda using the 2014-2015 Demographic Health Survey. We assessed correlates of infection by species to explore attributes associated with each species. AsymptomaticP. ovale spp.,P. malariae, and P. falciparummalaria infection had broad spatial distribution across Rwanda.P. vivaxinfection was rare.

Results

Overall infection prevalence was 23.6% (95%CI [21.7%, 26.0%]), withP. falciparumand non-falciparum at 17.6% [15.9%, 19.0%] and 8.3% [7.0%, 10.0%], respectively. Parasitemias tended to be low and mixed species infections were common, especially where malaria transmission and overall prevalence was the highest.P. falciparuminfection was associated with lower wealth, rural residence and low elevation. Fewer factors were associated with non-falciparum malaria.

Conclusions

Asymptomatic non-falciparum malaria andP. falciparummalaria are common and widely distributed across Rwanda in adults. Continued molecular monitoring ofPlasmodium spp.is needed to strengthen malaria control.
The road to achieving viral hepatitis elimination in Suriname: The progress, the challenges and the goals
Authors: Loe-Sack-Sioe Giovanni E. , Neus Anfernee , Woittiez Lycke , Mawie Terrence , Coenjaerts Frank , Donald – Ottevanger Sigrid Mac , Vreden Stephen
Published: January 2024

Background

Viral hepatitis is one of the leading causes of liver failure, cirrhosis, hepatocellular cancer and mortality worldwide and has long had limited treatment options. Estimates suggest that around 30% of the global population has at one point been infected with HBV, while 3.9% are chronically infected. 1.6 – 2.8% of the world population is estimated to be infected with HCV. With the introduction of the HBV birth-dose vaccines, HBV immunoglobulins and the more recent development of the HCV direct-acting antiviral medication, HBV and HCV infections have now become containable diseases. In 2016, all 194 member states of the World Health Organization endorsed the public-health goal to eradicate viral hepatitis by 2030. Yet, as of 2023, only a small group of countries are on course to achieving this goal. Suriname, a small, multi-ethnic country, located in the north of South America, has an intermediate prevalence of HBV and HCV of 3% and 1% respectively. Previously performed studies, however, show strong ethnic clustering in Suriname.

Aim

With this manuscript we dissect the strategy we developed to tackle the hepatitis challenge in Suriname. We explain the importance of establishing more detailed insight into the geographical distribution of high-prevalence areas, as linked to the ethnic differences in the population. We present the screening and contact tracing approaches and end with our current insights on how to proceed toward further prevention and treatment options. Overall, we provide a blueprint towards eliminating viral hepatitis with simple and effective strategies usable in resource-limited countries with an intermediate to high prevalence of viral hepatitis.
Development of a Novel Risk Score for Predicting One-Year Mortality Risk in Patients with Atrial Fibrillation using XGBoost-Assisted Feature Selection
Authors: Wang Bin , Jin Feifei , Cao Han , Li Qing , Zhang Ping
Published: January 2024

Background

There is a lack of tools specifically designed to assess mortality risk in patients with atrial fibrillation (AF). The aim of this study was to utilize machine learning methods for identifying pertinent variables and developing an easily applicable prognostic score to predict 1-year mortality in AF patients.

Methods

This single-center retrospective cohort study based on the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database focused on patients aged 18 years and older with AF. The study thoroughly scrutinized patient data to identify and analyze variables, encompassing demographic variables, comorbidities, scores, vital signs, laboratory test results, and medication usage. The variable importance from XGBoost guided the development of a logistic model, forming the basis for an AF scoring model. Decision curve analysis was used to compare the AF score with other scores. Python and R software were used for data analysis.

Results

A cohort of 59,595 AF patients was obtained from the MIMIC-IV database; these patients were predominantly elderly (median age 77.3 years) and male (55.6%). The XGBoost model effectively predicted 1-year mortality (Area under the curve (AUC): 0.833; 95% confidence intervals: 0.826-0.839), underscoring the significance of the Charlson Comorbidity Index (CCI) and the presence of metastatic solid tumors.

The CRAMB score (Charlson comorbidity index, readmission, age, metastatic solid tumor, and blood urea nitrogen maximum) outperformed the CCI and CHA2DS2-VASc scores, demonstrating superior predictive value for 1-year mortality. In the test set, the area under the ROC curve (AUC) for the CRAMB score was 0.756 (95% confidence intervals: 0.748-0.764), surpassing the CCI score of 0.720 (95% confidence intervals: 0.712-0.728) and the CHA2DS2-VASc score of 0.609 (95% confidence intervals: 0.600-0.618). Decision curve analysis revealed that the CRAMB score had a consistently positive effect and greater net benefit across the entire threshold range than did the default strategies and other scoring systems. The calibration plot for the test set indicated that the CRAMB score was well calibrated.

Conclusions

This study’s primary contribution is the establishment of a benchmark for utilizing machine learning models in construction of a score for mortality prediction in AF. The CRAMB score was developed by leveraging a large-sample population dataset and employing XGBoost models for predictor screening. The simplicity of the CRAMB score makes it user friendly, allowing for coverage of a broader and more heterogeneous AF population.
Sphingolipid metabolism orchestrates the establishment of the adult hair follicle stem cell niche to control skin homeostasis
Authors: Peters Franziska , Brodesser Susanne , Kruse Kai , Drexler Hannes C.A. , Hu Jiali , Lukas Dominika , von Stebut Esther , Krönke Martin , Niessen Carien M. , Wickström Sara A.
Published: January 2024

Bioactive sphingolipids serve as an essential building block of membranes, forming a selective barrier that ensures subcellular compartmentalization and facilitates cell type-specific intercellular communication through regulation of the plasma membrane receptor repertoire. How cell type-specific lipid compositions are achieved and what is their functional significance in tissue morphogenesis and maintenance has remained unclear. Here, we identify a stem-cell specific role for ceramide synthase 4 (CerS4) in orchestrating fate decisions in skin epidermis. Deletion of CerS4 in the epidermis prevents the effective development of the adult hair follicle bulge stem cell (HFSCs) niche due to altered differentiation trajectories of HFSC precursors towards upper hair follicle and inner bulge fates. Mechanistically, HFSC differentiation defects arise from an imbalance of key ceramides and their derivate sphingolipids in HFSCs associated with hyperactivity of canonical Wnt signaling. Impaired HFSC niche establishment leads to disruption of hair follicle architecture and hair follicle barrier function, ultimately triggering a T helper cell 2 - dominated immune infiltration closely resembling human atopic dermatitis. This work uncovers a fundamental role for a cell state-specific sphingolipid profile in epidermal stem cell homeostasis and the role of an intact stem cell niche in maintaining an intact skin barrier.
Single molecule delivery into living cells
Authors: Chau Chalmers C. , Maffeo Christopher M. , Aksimentiev Aleksei , Radford Sheena E. , Hewitt Eric W. , Actis Paolo
Published: January 2024

Controlled manipulation of cultured cells by delivery of exogenous macromolecules is a cornerstone of experimental biology. Here we describe a platform which uses nanopipettes to deliver defined numbers of macromolecules into cultured cell lines and primary cells at single molecule resolution. In the nanoinjection platform the nanopipette is used as both a scanning ion conductance microscope (SICM) scanning probe and as an injection probe. The SICM is used to position the nanopipette above the cell surface, before the nanopipette is inserted into the cell into a defined location and to a predefined depth. We demonstrate that the nanoinjection platform enables the quantitative delivery of DNA, globular proteins and protein fibrils into cells with single molecule resolution and that delivery results in a phenotypic change in the cell that depends on the identity of the molecules introduced. Using experiments and computational modelling, we also show that macromolecular crowding in the cell increases the signal to noise ratio for the detection of translocation events, thus the cell itself enhances the detection of the molecules delivered.
Computationally guided exploration of borosin biosynthetic strategies
Authors: Lee Aileen R. , Carter Riley S. , Imani Aman S. , Dommaraju Shravan R. , Hudson Graham A. , Mitchell Douglas A. , Freeman Michael F.
Published: January 2024

Borosins are ribosomally synthesized and post-translationally modified peptides containing backbone α-N-methylations. Identification of borosin precursor peptides is difficult because (1) there are no conserved sequence elements among borosin precursor peptides and (2) the biosynthetic gene clusters contain numerous domain architectures and peptide fusions. To tackle this problem, we updated the genome mining tool RODEO to automatically evaluate putative borosin BGCs and identify precursor peptides. Enabled by the new borosin module, we analyzed all borosin BGCs found in available sequence data and assigned precursor peptides to previously orphan borosin methyltransferases. Additionally, we bioinformatically predict and experimentally characterize a new fused borosin domain architecture, in which the modified core is N-terminal to the methyltransferase domain. Finally, we demonstrate that a borosin precursor peptide is the native substrate of shewasin A, a previously characterized pepsin-like aspartic peptidase whose native biological function was unknown.
Timing the cerebellum and its connectivity within the social brain
Authors: Ciricugno Andrea , Ferrari Chiara , Battelli Lorella , Cattaneo Zaira
Published: January 2024

The posterior cerebellum is a recently discovered hub of the affective and social brain, with different subsectors contributing to different social functions. However, very little is known aboutwhenthe posterior cerebellum plays a critical role in social processing. Due to its location and anatomy, it has been difficult to use traditional approaches to directly study the chronometry of the cerebellum. To address this gap in cerebellar knowledge, here we investigated for the first time thecausalcontribution of the posterior cerebellum to social processing using a chronometric transcranial magnetic stimulation (TMS) approach. We show that the posterior cerebellum is recruited at an early stage of the emotional processing (starting from 100 ms after stimulus onset), simultaneously with the posterior superior temporal sulcus (pSTS), a key node of the emotional-social brain. Moreover, using a condition-and-perturb TMS approach, we found that the recruitment of the pSTS in emotional processing is dependent on cerebellar activation. Our results are the first to shed light on chronometric aspects of cerebellar function and its causal connectivity with other nodes of the social brain.
Northeast India: Genetic Inconsistency across Ethnicity and Geography
Authors: Bankura Biswabandhu , Basak Bishnupriya , Singh Prajjval Pratap , Vanlalruata Albert , Chatterjee Arindam , Ghosh Sudakshina , Tamang Rakesh , Hazarika Manjil , Chaubey Gyaneshwer , Das Madhusudan
Published: January 2024

The genetic landscape of South Asia is intriguing. In a vast geographical region like India, mostly genes follow geography, whereas in a smaller geographical region e.g., Nepal, the genetic landscape is more akin to languages. Moreover, in neighboring regions like East and Southeast Asia, language is the major denominator of the genes. However, these are not just the two alternatives, in many geographical pockets, ethnicity plays a stronger role than either of these. Being a crossroads of South and Southeast Asia, the Himalayan region is mostly populated by people speaking the Trans-Himalayan language. Archaeological and anthropological studies suggest migration and cultural diffusion in this region with the Tibetan plateau in the North. To understand this complex pattern, we have performed a fine-grained genetic analysis of the major Mizo population and its various clans living in the Himalayan geography. We have investigated 110 individuals belonging to seven different clans of Mizo people for a hundred thousand autosomal markers. We have used various statistical methods and tested the role of ethnicity and geography in shaping the genetic landscape of the Himalayan region. In contrast to the East and Southeast Asian genetic landscape, our results suggested that the fine-scaled genetic structure of Northeast India is much more complex and a mixture of interplay between languages, ethnicity, and geography. Allelic frequency-based analyses indicated that a novel Trans-Himalayan ancestry unite all the populations of this region.
Tcf12 controls dynamic calvarial bone growth and motor learning in mice
Authors: Yamada Takahiko , Anderson-Ramirez Jesse , Gao Lu , Chen Peng , Zhang Mingyi , Guo Tingwei , Feng Jifan , Ho Thach-Vu , Vorobyova Ivetta , Santa Maria Naomi , Jacobs Russell , Chen Jian-Fu , Chai Yang
Published: January 2024

Heterozygous loss-of-function mutations ofTCF12andTWIST1can each cause craniosynostosis and neurodevelopmental delay in humans. Twist1-Tcf12 interaction plays an important role in regulating suture development. Although the molecular and cellular mechanisms underlying craniosynostosis and neurocognitive dysfunctions inTwist1+/-mice have been studied, less information on the role ofTcf12in these defects is available. To investigate the functional mechanism of Tcf12 in regulating skull and brain development, we analyzed the skull shape ofWnt1-Cre;Mesp1-Cre;Tcf12fl/flmice and found that, despite mild coronal synostosis, their skull shape appears to be similar to that of controls. We also found evidence of impaired motor learning ability inTcf12mutant mice. Furthermore, loss of Tcf12 in neural crest lineage leads to upregulatedRunx2expression in the calvarial mesenchyme and posterior expansion of the frontal bone inWnt1-Cre;Tcf12fl/flmice. Mechanistically, we show thatLmx1bis a direct downstream target of Tcf12 for the regulation of osteogenic differentiation in the calvarial mesenchyme during embryonic development. Importantly, overexpression ofLmx1binhibits osteogenic differentiation in the calvarial mesenchyme ofWnt1-Cre;Tcf12fl/flmice, indicating Tcf12’s regulation ofLmx1bexpression is crucial for controlling osteogenesis during calvarial bone development. Our study suggests that Tcf12 expression in the brain is crucial for motor learning. Moreover, this study establishes a new molecular mechanism underlying regulation of calvarial bone formation.

Author Summary

Craniosynostosis is characterized by premature fusion of cranial sutures and associated with abnormal skull growth, delayed brain development, and often impaired brain functions. Loss-of-function mutation ofTCF12can cause coronal synostosis and neurodevelopmental delay in humans. In developing mouse sutures,Tcf12is essential for maintaining the boundary between sutural and osteogenic cells. However, roles ofTcf12in skull formation and brain development have not been fully investigated. In this study, we show that loss ofTcf12leads to brain abnormalities even in the absence of coronal synostosis and that frontal bone expansion results from upregulated osteogenic differentiation in the calvarial mesenchyme in mice. Furthermore, we identifyLmx1bas a downstream target of Tcf12 for the regulation of osteogenic differentiation in the calvarial mesenchyme during frontal bone development. Our findings highlight the role of Tcf12 in the development of calvarial bones and provide new insight into molecular mechanisms for regulation of calvarial bone formation.