bluuebunny/crossref_metadata_2025 huggingface dataset:
Gender and COVID-19 Vaccine disparities in Cameroon
Authors: Amani Adidja , Mossus Tatiana , Lekeumo Cheuyem Fabrice Zobel , Bilounga Chanceline , Mikamb Pamela , Atchou Jonas Basseguin , Minyem Ngombi Aude Perine , Nangmo Armanda , Kamga Yannick , Bediang Georges , Kamgno Joseph , Bissek Anne-Cécile Zoung-Kanyi
Published: June 2022

Six months following the national launch of COVID-19 vaccination in Cameroon, only 1.1% of the target population was fully vaccinated with women representing less than one-third of the vaccinated population regardless of their age, profession or comorbidities. Hence, the aim of this study was to understand the low COVID-19 vaccination rate of women in order to enhance vaccine uptake. A cross-sectional study was conducted between July and October 2021 through an online survey. Also, a retrospective analysis of the Cameroon Ministry of Public Health (MINSANTE) database of the pandemic (COVID-19), for the period of March 2020 to October 2021 was equally carried out. Our sample consisted of 249 responders aged between 18 and 50 years enrolled in the 10 regions of Cameroon, with 142 (57%) who were female. We assessed factors related to having been vaccinated against Covid-19 and predictors to Covid-19 vaccination among non-vaccinated people. Concerning Covid-19 vaccination, 39.2% were not vaccinated. Non-vaccination was statistically associated with being female, being a healthcare worker, fear of adverse effects, and not believing in the vaccine. In the qualitative analysis, women identified themselves as being anti-COVID vaccine for several reasons, including doubts about the quality or safety of the vaccine; the perception that anti-COVID-19 vaccines are presented as being an obligation; including the multitude of vaccines on the market, the believe that there are “more local” effective alternatives to the vaccine. The implementation of the gender approach to COVID vaccination is a condition for the effectiveness and sustainability of actions.
Defining suspected child maltreatment using International Classification of Diseases codes: A scoping literature review
Authors: Liu Yuerong , Terrell Lindsay , Joyce Brianna , Black Julia , Kaplan Samantha J. , Gifford Elizabeth J.
Published: June 2022

Background

Administrative medical and claims records are increasingly used to study prevalence of and outcomes for children exposed to child maltreatment. However, suspicion of child maltreatment is often under-documented in medical records using International Classification of Diseases (ICD) codes. Although researchers have developed strategies to more broadly capture the injuries, illnesses, and circumstances that are suggestive of maltreatment, there is no consensus on which codes to use for this purpose.

Objective

To systematically examine the types of research being conducted with ICD codes related to suspected maltreatment, summarize the methods used to identify the codes, and propose future direction.

Methods

We searched five electronic databases for studies that reported ICD codes suggestive of child maltreatment in any medical setting, included participants aged 0-18 years, and published in a peer-reviewed journal in English. Two reviewers independently screened the titles, abstracts, and the full texts. Data were synthesized in a qualitative manner.

Results

Thirty-seven studies met inclusion criteria. Most studies focused on determining the incidence or trends of maltreatment-related injuries or illnesses. Studies varied greatly in the codes used to identify suspected maltreatment. Only four articles reported on the validation of selected codes. ICD codes for transport accidents were the most frequently excluded co-occurring codes. Studies frequently relied on two seminal studies and two national-level guidelines.

Conclusions

Substantial heterogeneity existed in the ICD codes and methods used to identify suspected maltreatment. The age range for codes, excluded co-occurring codes, and validation of codes are areas future research should address. This review may reduce costs for future researchers so that they could choose optimal measures of suspected maltreatment from our summarized list of codes without reinventing the wheel. Our review provides a basis for the development of recommended guidelines in establishing uniform codes for suspected maltreatment that could promote public health surveillance and allow for more efficient and uniform policy or program evaluation.
Comparing the XGBoost machine learning algorithm to polygenic scoring for the prediction of intelligence based on genotype data
Authors: Fahey Laura , Morris Derek W. , Ó Broin Pilib
Published: June 2022

A polygenic score (PGS) is a linear combination of effects from a GWAS that represents and can be used to predict genetic predisposition to a particular phenotype. A key limitation of the PGS method is that it assumes additive and independent SNP effects, when it is known that epistasis (gene interactions) can contribute to complex traits. Machine learning methods can potentially overcome this limitation by virtue of their ability to capture nonlinear interactions in high dimensional data. Intelligence is a complex trait for which PGS prediction currently explains up to 5.2% of the variance, a relatively small proportion of the heritability estimate of 50% obtained from twin studies. Here, we use gradient boosting, a machine learning technique based on an ensemble of weak prediction models, to predict intelligence from genotype data. We found that while gradient boosting did not outperform the PGS method in predicting intelligence based on SNP data, it was capable of achieving similar predictive performance with less than a quarter of the SNPs with the top SNPs identified as being important for predictive performance being biologically meaningful. These results indicate that ML methods may be useful in interpreting the biological meaning underpinning SNP-phenotype associations due to the smaller number of SNPs required in the ML model as opposed to the standard PGS method based on GWAS.
Cancer type-specific prioritization strategy for targetable dependencies developed from the DepMap profile of head and neck cancer
Authors: Cao Austin C. , Sannigrahi Malay K. , Rajagopalan Pavithra , Brody Robert M. , Raghav Lovely , Gimotty Phyllis A. , Basu Devraj
Published: June 2022

Objectives

The DepMap genome-wide loss of function CRISPR screens offer new insight into gene dependencies in HPV(-) head and neck squamous cell carcinoma (HNSCC) cell lines. We aimed to leverage this data to guide preclinical studies by cataloging novel targetable dependencies that are predicted to offer a useful therapeutic window. We also aimed to identify targets potentially representing synthetic lethalities by testing for associations between genetic alterations and gene dependency profile.

Methods

DepMap was queried for gene probability and effect scores in cell lines from 87 tumors, including 63 HPV(-) HNSCCs plus 24 esophageal squamous cell carcinomas (ESCCs), which have comparable etiology, tissue or origin, and genetic profile to HNSCC. A probability score of ≥ 0.5 was used as the threshold for essentiality. Essential genes were selected for analysis by 4 criteria: (1) presence in ≥10% cell lines, (2) lack of common essential designation by DepMap, (3) lack of predicted dependency in normal cell lineages, and (4) designation as druggable by the Drug-Gene Interaction Database.

Results

The 143 genes meeting selection criteria had a median gene effect score of 0.56. Selection criteria captured targets of standard therapeutic agents of HNSCC includingTYMS(5-FU), tubulin genes (taxanes),EGFR(cetuximab), plus additional known oncogenes likePIK3CAandERBB3. Functional classification analysis showed enrichment of tyrosine kinases, serine/threonine kinases, RNA-binding proteins, and mitochondrial carriers. 90% of the 143 dependencies were not known oncogenes in the OncoKB Database. 10% of targets had inhibitors previously used in a non-HNSCC phase II trial, including 8 that have not yet been tested in cancer. The 13 genes with median gene effect scores greater than of PIK3CA and not well-studied in HNSCC were assigned highest priority, includingDHRSX, MBTPS1, TDP2, FARS2, TMX2, RAB35, CFLAR, GPX4, SLC2A1, TP63, PKN2, MAP3K11,andTIPARP. A novel association was found betweenNOTCH1mutation and increasedTAP1dependency.

Conclusions

The DepMap CRISPR screens capture well-studied targets in HNSCC as well as numerous genes without known roles in HNSCC or malignancy in general. Several of these targets have well-developed inhibitors that provide resources to guide preclinical studies. Association of some of the dependencies with known molecular subgroups in HNSCC may enhance use of cell line models to guide personalization of therapy.
Genome-wide SNP genotyping as a simple and practical tool to accelerate the development of inbred lines in outbred tree species: an example in cacao (Theobroma cacao L.)
Authors: Lopes Uilson Vanderlei , Pires Jose Luis , Gramacho Karina Peres , Grattapaglia Dario
Published: June 2022

Cacao is a globally important crop with a long history of domestication and selective breeding. Despite the increased use of elite clones by cacao farmers, worldwide plantations are established mainly using hybrid progeny material derived from heterozygous parents, therefore displaying high tree-to-tree variability. The deliberate development of hybrids from advanced inbred lines produced by successive generations of self-pollination has not yet been fully considered in cacao breeding. This is largely due to the self-incompatibility of the species, the long generation cycles (3-5 years) and the extensive trial areas needed to accomplish the endeavor. We propose a simple and accessible approach to develop inbred lines based on accelerating the buildup of homozygosity based on regular selfing assisted by genome-wide SNP genotyping. In this study we genotyped 90 clones from the Brazilian CEPEC’s germplasm collection and 49 inbred offspring of six S1 or S2 cacao families derived from self-pollinating clones CCN-51, PS-13.19, TSH-1188 and SIAL-169. A set of 3,380 SNPs distributed across the cacao genome were interrogated on the EMBRAPA multi-species 65k Infinium chip. The 90 cacao clones showed considerable variation in genome-wide SNP homozygosity (mean 0.727± 0.182) and 19 of them with homozygosity >90%. By assessing the increase in homozygosity across two generations of self-pollinations, SNP data revealed the wide variability in homozygosity within and between S1 and S2 families. Even in small families (<10 sibs), individuals were identified with up to ∼1.5 standard deviations above the family mean homozygosity. From baseline homozygosities of 0.476 and 0.454, offspring with homozygosities of 0.862 and 0.879 were recovered for clones TSH-1188 and CCN-51 respectively, in only two generations of selfing (81-93% increase). SNP marker assisted monitoring and selection of inbred individuals can be a practical tool to optimize and accelerate the development of inbred lines of outbred species. This approach will allow a faster and more accurate exploitation of hybrid strategies in cacao breeding programs and potentially in other perennial fruit and forest trees.
Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs
Authors: Donner Jonas , Freyer Jamie , Davison Stephen , Anderson Heidi , Blades Matthew , Honkanen Leena , Inman Laura , Brookhart-Knox Casey A. , Louviere Annette , Forman Oliver P , Foran Rebecca Chodroff
Published: June 2022

Hundreds of genetic variants linked to Mendelian disease have been characterized in dogs to date, and commercial screening is being offered for most of them worldwide. There typically remains a paucity of information regarding the broader population frequency of newly discovered variants, as well as uncertainty regarding their functional and clinical impact on additional genomic ancestry backgrounds beyond the discovery breed. Panel screening of disease variants, commercially offered as direct-to-consumer genetic testing, provides an opportunity to establish large-scale cohorts with both genotype and phenotype data available to address open questions related to variant prevalence and relevance. In this study, we screened the largest canine cohort examined in a single study to date (1,054,293 representative dogs from our existing cohort of more than three million dogs; a total of 811,628 mixed breed dogs and 242,665 purebreds from more than 150 countries and territories) for 250 genetic disease-associated variants to understand their prevalence and distribution in the general population. Electronic medical records from veterinary clinics were available for 43.5% of the genotyped dogs, enabling follow up on the clinical impact of variants. We provide detailed frequencies for all tested variants across breeds and find that 57% of dogs carry at least one copy of a studied Mendelian disease-linked variant. We provide evidence of full penetrance for 10 variants, and at minimum plausible evidence for the clinical significance of 22 variants, on a wide variety of breed backgrounds. We further show that a reduction in genome-wide heterozygosity is associated with an increased Mendelian disease load and assess genome-wide heterozygosity levels in over 100 breeds. The accumulated knowledge represents a resource to guide discussions on disease variant presence and genetic test relevance by breed.
Multi-scale modelling of shear stress on the syncytiotrophoblast: Could maternal blood flow impact placental function across gestation?
Authors: Lee Tet Chuan , Moulvi Ali , James Joanna L. , Clark Alys R.
Published: June 2022

The surface of the placenta is lined by a single multinucleated cell, the syncytiotrophoblast, which forms a functional barrier between maternal and fetal blood in pregnancy. The placenta plays a critical role in healthy fetal development and over the course of pregnancy forms a complex branching tree-like structure which bathes in maternal blood and serves a vital exchange function. It has been suggested that the structure of the placenta may evolve, in part, under the influence of the shear stress exerted by maternal blood flow over its surface, with the syncytiotrophoblast having a role in mechanosensing. However, data describing the mechano-sensitive nature of this cell, particularly in early gestation, is lacking. In this study we show that the syncytiotrophoblast expresses six proteins that have been related to shear sensing, and this expression is higher in the first trimester than at term. This suggests shear on the sycytiotrophoblast as an important factor influencing placental morphogenesis early in pregnancy. We then predict shear stress felt by the syncytiotrophoblast in first trimester and term placental tissue using a combination of porous medium modelling and explicit simulations of blood flow in realistic geometries derived from microCT imaging. Our models predict that typical shear stress on first-trimester tissue is higher than at term, supporting the feasibility of this mechanical stimulus as an important driver of healthy placental development.
Tocilizumab versus baricitinib in hospitalized patients with severe COVID-19: an open label, randomized controlled trial
Authors: Karampitsakos Theodoros , Papaioannou Ourania , Tsiri Panagiota , Katsaras Matthaios , Katsimpris Andreas , Kalogeropoulos Andreas P. , Malakounidou Elli , Zarkadi Eirini , Tsirikos Georgios , Georgiopoulou Vasiliki , Sotiropoulou Vasilina , Koulousousa Electra , Chourpiliadi Charikleia , Matsioulas Apostolos , Lagadinou Maria , Sampsonas Fotios , Akinosoglou Karolina , Marangos Markos , Tzouvelekis Argyris
Published: June 2022

Background

Tocilizumab and baricitinib have proven efficacy in COVID-19. There were no randomized-controlled trials comparing these compounds in patients with COVID-19.

Materials/Patients and Methods

In this open label, randomized controlled trial, we assigned 251 patients with COVID-19 and PaO2/FiO2<200 to receive either tocilizumab (n=126) or baricitinib (n=125) plus standard of care. To determine whether baricitinib was non-inferior to tocilizumab, we assessed if the upper boundary of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.50. The primary outcome was mechanical ventilation or death by day 28. Secondary outcomes included time to hospital discharge by day 28 and change in WHO progression scale at day 10.

Results

Baricitinib was non-inferior to tocilizumab for the primary composite outcome of mechanical ventilation or death by day 28 (HR 0.83, 95% CI: 0.56 to 1.21, p=0.001 for non-inferiority). Baricitinib was non-inferior to tocilizumab for the time to hospital discharge within 28 days (discharged alive-tocilizumab: 52.4% vs baricitinib: 58.4%; HR 0.85, (95% CI: 0.61 to 1.18), p<0.001 for non-inferiority). There was no significant difference between baricitinib and tocilizumab arm in the change in WHO scale at day 10 [0.0 (95% CI: 0.0 to 0.0) vs 0.0 (95% CI: 0.0 to 1.0), p=0.83].

Conclusion

Baricitinib was non-inferior to tocilizumab with regards to the composite outcome of mechanical ventilation or death by day 28 and the time to discharge by day 28 in patients with severe COVID-19. Cost-effectiveness should be taken into account to avoid a dramatic upswing in health system budgets.
Wastewater surveillance in smaller college communities may aid future public health initiatives
Authors: Lee Laura , Valmond Lescia , Thomas John , Kim Audrey , Austin Paul , Foster Michael , Matthews John , Kim Paul , Newman Jamie
Published: June 2022

Since its declaration, the COVID-19 pandemic has resulted in over 530 million cases and over 6 million deaths worldwide. Predominant clinical testing methods, though invaluable, may create an inaccurate depiction of COVID-19 prevalence due to inadequate access, testing, or most recently under-reporting because of at-home testing. These concerns have created a need for unbiased, community-level surveillance. Wastewater-based epidemiology has been used for previous public health threats, and more recently has been established as a complementary method of SARS-CoV-2 surveillance. Here we describe the application of wastewater surveillance for SARS-CoV-2 in two university campus communities located in rural Lincoln Parish, Louisiana. This cost-effective approach is especially well suited to rural areas where limited access to testing may worsen the spread of COVID-19 and quickly exhaust the capacity of local healthcare systems. Our work demonstrates that local universities can leverage scientific resources to advance public health equity in rural areas and enhance their community involvement.
HCP5 prevents ubiquitination-mediated UTP3 degradation to inhibit apoptosis by activating c-Myc transcriptional activity
Authors: Nan Yabing , Luo Qingyu , Wu Xiaowei , Chang Wan , Zhao Pengfei , Liu Shi , Liu Zhihua
Published: June 2022

Inducing cancer cell apoptosis through cytotoxic reagents is the main therapeutic strategy for diverse cancer types. However, several antiapoptotic factors impede curative cancer therapy by driving cancer cells to resist cytotoxic agent-induced apoptosis, thus leading to refractoriness and relapse. To define critical antiapoptotic factors that contribute to chemoresistance in esophageal squamous cell carcinoma (ESCC), we generated two pairs of parental and apoptosis-resistant cell models through cisplatin (DDP) induction and then performed whole-transcriptome sequencing. We identified the long noncoding RNA (lncRNA) histocompatibility leukocyte antigen complex P5 (HCP5) as the chief culprit for chemoresistance. Mechanistically, HCP5 interacts with UTP3 small subunit processome component (UTP3) and prevents UTP3 degradation from E3 ligase tripartite motif containing 29 (TRIM29)-mediated ubiquitination. UTP3 then recruits c-Myc to activate vesicle-associated membrane protein 3 (VAMP3) expression. Activated VAMP3 suppresses caspase-dependent apoptosis and eventually leads to chemoresistance. Accordingly, the expression level of the HCP5/UTP3/c-Myc/VAMP3 axis in chemoresistant patients is significantly higher than that in chemosensitive patients. Thus, our study demonstrated that the HCP5/UTP3/c-Myc/VAMP3 axis plays an important role in the inhibition of cancer cell apoptosis and that HCP5 can be a promising chemosensitive target for cancer treatment.
Continuous tracking of task parameters tunes reaching control online
Authors: De Comite Antoine , Crevecoeur Frédéric , Lefèvre Philippe
Published: June 2022

A hallmark of human reaching movements is that they are appropriately tuned to the task goal and to the environmental context. This was demonstrated by the way humans flexibly respond to mechanical and visual perturbations that happen during movement. Furthermore, it was previously showed that the properties of goal-directed control can change within a movement, following abrupt changes in the goal structure. Such online adjustment was characterized by a modulation of feedback gains following switches in target shape. However, it remains unknown whether the underlying mechanism merely switches between prespecified policies, or whether it results from continuous and potentially dynamic adjustments. Here, we address this question by investigating participants’ feedback control strategies in presence of various changes in target width during reaching. More specifically, we studied whether the feedback responses to mechanical perturbations were sensitive to the rate of change in target width, which would be inconsistent with the hypothesis of a single, discrete switch. Based on movement kinematics and surface EMG data, we observed a modulation of feedback response clearly dependent on dynamical changes in target width. Together, our results demonstrate a continuous and online transformation of task-related parameters into suitable control policies.

Significance statement

Humans can adjust their control policy online in response to changes in the goal structure. However, it was unknown whether this adjustment resulted from a switch between two policies, or from dynamic and continuous adjustments. To address this question, we investigated whether online adjustments were tuned to dynamic changes in goal target which varied at different rates. Our results demonstrated that online adjustments were tuned to the rate of change in target width, suggesting that human reaching control policies are derived based on continuous monitoring of task-related parameters supporting online and dynamic adjustments.
Enhancers that regulateTNFgene transcription in human macrophages in response to TLR3 stimulation
Authors: Gao Junfeng , Li Yapeng , Zhao Dianzheng , Guan Xiaoyu , Motsinger Kirby , Scott-Browne James , Chu Hong Wei , Huang Hua
Published: June 2022

Macrophages play a critical role in inflammatory responses during infections. These cells are activated by infections through stimulation of TLRs expressed on their cell surface and produce pro-inflammatory cytokines, including TNF. However, distal enhancers that regulateTNFgene transcription in human macrophages have not been investigated. This study used an unbiased genomic approach to identify six candidate enhancers in human primary alveolar macrophages within a 131 kb region from the transcription start site (TSS) of theTNFgene, covering 13 genes. Of these candidate enhancers, five showed enhancer activity, with three targeting theTNFgene and two targeting neighboring genes. Deletion of the distalTNFE-16 enhancer led to a 73% reduction inTNFgene transcription in response to poly (I:C) stimulation in the THP-1 human leukemia monocytic cell line. Additionally, deletion of the E-7.1/hHS-8 enhancer resulted in a 41% reduction inTNFmRNA, while deletion of the PE enhancer had a lesser effect, resulting in a 52% reduction inTNFgene transcription. Massively parallel reporter assays (MPRA) indicated that the transcription factor AP-1 and EGR1-binding sites at the distalTNFE-16 enhancer were crucial in mediating enhancer activity. This study shows that both distal and proximal enhancers work together to fully transcribe theTNFgene in human macrophages in response to TLR ligand poly (I:C) stimulation.
The Neural Architecture of Theory-based Reinforcement Learning
Authors: Tomov Momchil S. , Tsividis Pedro A. , Pouncy Thomas , Tenenbaum Joshua B. , Gershman Samuel J.
Published: June 2022

Humans learn internal models of the environment that support efficient planning and flexible generalization in complex, real-world domains. Yet it remains unclear how such internal models are represented and learned in the brain. We approach this question within the framework of theory-based reinforcement learning, a strong form of model-based reinforcement learning in which the model is an intuitive theory – a rich, abstract, causal model of the environment built on a natural ontology of physical objects, intentional agents, relations, and goals. We used a theory-based reinforcement learning model to analyze brain data from human participants learning to play different Atari-style video games while undergoing functional MRI. Theories inferred by the theory-based model explained the signal in inferior frontal gyrus and other prefrontal areas better than several alternative models. Brain activity increased in response to theory update events in inferior frontal gyrus, occipital cortex, and fusiform gyrus, with separate learning signals for different theory components. This corresponded with a transient strengthening of theory representations in those regions. Finally, the effective connectivity pattern during theory updating suggests that information flows top-down from theory-coding regions in the prefrontal cortex to theory updating regions in occipital and temporal cortex. These results are consistent with a neural architecture in which top-down theory representations originating in prefrontal regions shape sensory predictions in visual areas, where factorized theory prediction errors are computed and in turn trigger bottom-up updates of the theory. This initial sketch provides a foundation for understanding of the neural representations and computations that support efficient theory-based reinforcement learning in complex, naturalistic environments.
Structures of perforin-2 in solution and on a membrane reveal mechanisms for pore formation
Authors: Yu Xiulian , Ni Tao , Munson George , Zhang Peijun , Gilbert Robert J. C.
Published: June 2022

Perforin-2 (PFN2, MPEG1) is a key pore-forming protein in mammalian innate immunity restricting intracellular bacteria proliferation. It forms a membrane-bound pre-pore complex that converts to a pore-forming structure upon acidification; but its mechanism of conformational transition has been debated. Here we used cryo-electron microscopy, tomography and subtomogram averaging to determine structures of PFN2 in pre-pore and pore conformations in isolation and bound to liposomes. In isolation and upon acidification, the pre-assembled complete pre-pore rings convert to pores in both flat ring and twisted conformations. The twisted pore structure suggests an intermediate or alternative state to the flat conformation, and a capacity to distort the underlying membrane during membrane insertion. On membranes, in situ assembled PFN2 pre-pores display various degrees of completeness; whereas PFN2 pores are mainly incomplete arc structures that follow the same subunit packing arrangements as found in isolation. Both assemblies on membranes use their P2 β-hairpin for binding to the lipid membrane surface. These structural snapshots in different states reveal a molecular mechanism for PFN2 pre-pore to pore transition on a targeted membrane.
Cloacal virome of an ancient host lineage – the tuatara (Sphenodon punctatus) – reveals abundant and diverse diet-related viruses
Authors: Waller Stephanie J. , Lamar Sarah , Perry Benjamin J. , Grimwood Rebecca M. , Holmes Edward C. , Geoghegan Jemma L.
Published: June 2022

1.

Tuatara (Sphenodon punctatus) are one of the most phylogenetically isolated species and provide a unique host system to study virus evolution. While the tuatara genome, sequenced in 2020, revealed many endogenous viral elements, we know little of the exogenous viruses that infect tuatara. We performed a metatranscriptomics study of tuatara cloaca samples from a wild population on Takapourewa (Stephens Island), Aotearoa New Zealand. From these data we identified 49 potentially novel viral species that spanned 20 RNA viral families and/or orders, the vast majority (48) of which were likely dietary related. Notably, using a protein structure homology search, we identified a highly divergent novel virus within the Picornaviridae which may directly infect tuatara. Additionally, two endogenous tuatara adintoviruses were characterised that exhibited long-term viral-host co-divergence. Overall, our results indicate that the tuatara cloacal virome is highly diverse likely due a large number of dietary related viruses.
The faecal metabolome and its determinants in inflammatory bowel disease
Authors: Vila Arnau Vich , Hu Shixian , Andreu-Sánchez Sergio , Collij Valerie , Jansen B. H. , Augustijn Hannah E. , Bolte Laura , Ruigrok Renate A.A.A. , Abu-Ali Galeb , Giallourakis Cosmas , Schneider Jessica , Parkinson John , Garawi Amal Al , Zhernakova Alexandra , Gacesa Ranko , Fu Jingyuan , Weersma Rinse K.
Published: June 2022

Objective

Inflammatory bowel disease (IBD) is a multifactorial immune-mediated inflammatory disease of the intestine, comprising Crohn’s disease and ulcerative colitis. By characterising metabolites in faeces, combined with faecal metagenomics, host genetics and clinical characteristics, we aimed to unravel metabolic alterations in IBD.

Design

We measured 1,684 different faecal metabolites and 8 short-chain and branched-chain fatty acids in stool samples of 424 IBD patients and 255 non-IBD controls. Regression analyses were used to compare concentrations of metabolites between cases and controls and determine the relationship between metabolites and each participant’s lifestyle, clinical characteristics and gut microbiota composition. Moreover, genome-wide association analysis was conducted on faecal metabolite levels.

Results

We identified over 300 molecules that were differentially abundant in the faeces of patients with IBD. The ratio between a sphingolipid and L-urobilin could discriminate between IBD and non-IBD samples (AUC = 0.85). We found changes in the bile acid pool in patients with dysbiotic microbial communities and a strong association between faecal metabolome and gut microbiota. For example, the abundance of Ruminococcus gnavus was positively associated with tryptamine levels. In addition, we found 158 associations between metabolites and dietary patterns, and polymorphisms near NAT2 strongly associated with coffee metabolism.

Conclusion

In this large-scale analysis, we identified alterations in the metabolome of patients with IBD that are independent of commonly overlooked confounders such as diet and surgical history. Considering the influence of the microbiome on faecal metabolites, our results pave the way for future interventions targeting intestinal inflammation.
Supernumerary proteins of the human mitochondrial ribosomal small subunit are integral for assembly and translation
Authors: Hilander Taru , Monteuuis Geoffray , Awadhpersad Ryan , Broda Krystyna L. , Pohjanpelto Max , Pyman Elizabeth , Singh Sachin Kumar , Nyman Tuula A. , Crevel Isabelle , Taylor Robert W. , Saada Ann , Balboa Diego , Battersby Brendan J. , Jackson Christopher B. , Carroll Christopher J.
Published: June 2022

Mitochondrial ribosomes (mitoribosomes) have undergone substantial structural remodelling throughout evolution. Compared to their prokaryotic counterparts, mitoribosomes show a substantial loss of ribosomal RNA, whilst acquiring unique protein subunits located on the periphery of the ribosomal subunit structures. We set out to investigate the functional properties of all 14 unique (mitochondrial-specific or supernumerary) human mitoribosomal proteins in the small subunit. Using genome editing with CRISPR-Cas9, we made knockouts for each subunit in HEK293 cells to study the effect on mitoribosome assembly and function in protein synthesis. Unexpectedly, we show that each supernumerary knockout leads to a unique mitoribosome assembly defect with variable impact on mitochondrial protein synthesis. Our data demonstrates that all supernumerary subunits are essential structural components except mS37. Surprisingly, we found the stability of mS37 was reduced in all our supernumerary knockouts of the small and large ribosomal subunits as well as patient-derived lines with mitoribosome assembly defects. We identified that a redox regulated CX9C motif in mS37 was essential for protein stability, suggesting a potential mechanism to regulate mitochondrial protein synthesis. Together, our findings support a modular assembly of the human mitochondrial small ribosomal subunit mediated by essential supernumerary subunits and identify a redox regulatory role involving mS37 in mitochondrial protein synthesis in health and disease.
The columnar structure of human telomeric chromatin suggests mechanisms for telomere maintenance
Authors: Soman Aghil , Wong Sook Yi , Korolev Nikolay , Surya Wahyu , Lattman Simon , Vogirala Vinod K. , Chen Qinming , Berezhnoy Nikolay V. , van Noort John , Rhodes Daniela , Nordenskiöld Lars
Published: June 2022

Telomeres, the ends of eukaryotic chromosomes, play pivotal roles in ageing and cancer and are targets of DNA damage and response. However, little is known about the structure and organization of telomeric chromatin at the molecular level. We used electron microscopy and single-molecule magnetic tweezers to characterize well-defined telomeric chromatin fibers of kilobasepair length. The cryo-EM structure of the compact telomeric tetranucleosome revealed a novel columnar folding, unusually short nucleosome repeat length of ∼132bp and the role of the histone N-terminal tails in stabilizing this structure. This is the first near-high resolution structure of chromatin with a native DNA sequence. The columnar structure exposes the DNA, making them susceptible to DNA damage. The telomeric tetranucleosome also exists in an alternative well-defined state, with one nucleosome open, accessible to protein factors. This suggests that protein factors, which plays a role in maintaining telomeres, can bind to telomeric chromatin in its compact heterochromatic form. The features of the telomeric chromatin structure reveals important insights of significant relevance for telomere function in vivo that provides information on mechanisms of nucleosome recognition by chromatin factors
Modes of inhibition used by phage anti-CRISPRs to evade type I-C Cascade
Authors: O’Brien Roisin E. , Bravo Jack P.K. , Ramos Delisa , Hibshman Grace N. , Wright Jacquelyn T. , Taylor David W.
Published: June 2022

Cascades are RNA-guided multi-subunit CRISPR-Cas surveillances complexes that target foreign nucleic acids for destruction. Here, we present a 2.9-Å resolution cryo-electron (cryo-EM) structure of the D. vulgaris type I-C Cascade bound to a double-stranded (ds)DNA target. Our data shows how the 5’-TTC-3’ protospacer adjacent motif (PAM) sequence is recognized, and provides a unique mechanism through which the displaced, single-stranded non-target strand (NTS) is stabilized via stacking interactions with protein subunits in order to favor R-loop formation and prevent dsDNA re-annealing. Additionally, we provide structural insights into how diverse anti-CRISPR (Acr) proteins utilize distinct strategies to achieve a shared mechanism of type I-C Cascade inhibition by blocking initial DNA binding. These observations provide a structural basis for directional R-loop formation and reveal how divergent Acr proteins have converged upon common molecular mechanisms to efficiently shut down CRISPR immunity.
Functional evolutionary convergence of long noncoding RNAs involved in embryonic development
Authors: Olazagoitia-Garmendia Ane , Senovilla-Ganzo Rodrigo , Garcia-Moreno Fernando , Castellanos-Rubio Ainara
Published: June 2022

Long noncoding RNAs (lncRNAs) have been identified in almost all vertebrates, but the functional characterization of these RNA molecules is being challenging, mainly due to the lack of linear sequence homology between species. In this work, we aimed to find functional evolutionary convergent lncRNAs involved in development by screening of k-mer content (non linear similarity) and secondary structure-based approaches combined within silico, in vitroandin vivovalidation analysis. From the currently identified Madagascar gecko genes, we found a lncRNA with a similar k-mer content and structurally concordant with the human lncRNAEVX1AS. Analysis of function related characteristics together with locus-specific targeting of human and geckoEVX1AS(i.e. CRISPR Display) in human neuroepithelial cells and chicken mesencephalon confirmed that geckoEvx1as-likelncRNA mimics humanEVX1ASfunction and inducesEVX1expression independently of the target species. Our data show functional conservation of non-homologous lncRNAs and presents a useful approach for the definition and manipulation of lncRNA function within different model organisms.
An anti-steatosis response regulated by oleic acid through lipid droplet-mediated ERAD enhancement
Authors: Castillo-Quan Jorge Iván , Steinbaugh Michael J. , Paulette Fernández-Cárdenas L. , Pohl Nancy K. , Wu Ziyun , Zhu Feimei , Moroz Natalie , Teixeira Veronica , Bland Monet S. , Lehrbach Nicolas J. , Mazzeo Lorenza E. Moronetti , Teufl Magdalena , Blackwell T. Keith
Published: June 2022

Although excessive lipid accumulation is a hallmark of obesity-related pathologies, some lipids are beneficial. Oleic acid (OA), the most abundant monounsaturated fatty acid (FA), promotes health and longevity. Here we show that OA benefits C. elegans by activating the endoplasmic reticulum (ER)-resident transcription factor SKN-1A (Nrf1/NFE2L1) in a lipid homeostasis response. SKN-1A/Nrf1 is cleared from the ER by the ER-associated degradation (ERAD) machinery and stabilized when proteasome activity is low, and canonically maintains proteasome homeostasis. Unexpectedly, OA increases nuclear SKN-1A levels independently of proteasome activity, through lipid droplet (LD)-mediated enhancement of ERAD. In turn, SKN-1A reduces steatosis by reshaping the lipid metabolism transcriptome, and mediates longevity from OA provided through endogenous accumulation, reduced H3K4 trimethylation, or dietary supplementation. Our findings reveal a surprising mechanism of FA signal transduction, and a lipid homeostasis pathway that provides strategies for opposing steatosis and aging, and may mediate benefits of the OA-rich Mediterranean diet.
Analytical approaches for antimalarial antibody responses to confirm historical and recent malaria transmission: an example from the Philippines
Authors: Macalinao Maria Lourdes M. , Fornace Kimberly M. , Reyes Ralph A. , Bareng Alison Paolo N. , Hall Tom , Adams John H. , Huon Christèle , Chitnis Chetan E. , Luchavez Jennifer S. , Tetteh Kevin K. A. , Yui Katsuyuki , Hafalla Julius Clemence R. , Espino Fe Esperanza J. , Drakeley Chris J.
Published: June 2022

Background

Assessing the status of malaria transmission in endemic areas becomes increasingly challenging as countries approach elimination. Serology can provide robust estimates of malaria transmission intensities, and multiplex serological assays allow for simultaneous assessment of markers of recent and historical malaria exposure.

Methods

Here, we evaluated different statistical and machine learning methods for analyzing multiplex malaria-specific antibody response data to classify recent and historical exposure toPlasmodium falciparumandP. vivax. To assess these methods, we utilized samples from a health-facility based survey (n=9132) in the Philippines, where we quantified antibody responses against 8P. falciparumand 6P. vivax-specific antigens from 3 sites with varying transmission intensity.

Findings

Measurements of antibody responses and seroprevalence were consistent with the 3 sites’ known endemicity status. For predictingP. falciparuminfection, a machine learning (ML) approach (Random Forest model) using 4 serological markers (PfGLURP R2, Etramp5.Ag1, GEXP18 and PfMSP119) gave better predictions for cases in Palawan (AUC: 0·9591, CI 0·9497-0·9684) than individual antigen seropositivity. Although the ML approach did not improveP. vivaxinfection predictions, ML classifications confirmed the absence of recent exposure toP. falciparumandP. vivaxin both Occidental Mindoro and Bataan. For predicting historicalP. falciparumandP. vivaxtransmission, seroprevalence and seroconversion rates based on cumulative exposure markers AMA1 and MSP119showed reliable trends in the 3 sites.

Interpretation

Our study emphasizes the utility of serological markers in predicting recent and historical exposure in a sub-national elimination setting, and also highlights the potential use of machine learning models using multiplex antibody responses to improve assessment of the malaria transmission status of countries aiming for elimination. This work also provides baseline antibody data for monitoring risk in malaria-endemic areas in the Philippines.

Funding

Newton Fund, Philippine Council for Health Research and Development, and UK Medical Research Council.
Evolution of host protease interactions among SARS-CoV-2 variants of concern and related coronaviruses
Authors: Kastenhuber Edward R. , Johnson Jared L. , Yaron Tomer M. , Mercadante Marisa , Cantley Lewis C.
Published: June 2022

Previously, we showed that coagulation factors directly cleave SARS-CoV-2 spike and promote viral entry (Kastenhuber et al., 2022). Here, we show that substitutions in the S1/S2 cleavage site observed in SARS-CoV-2 variants of concern (VOCs) exhibit divergent interactions with host proteases, including factor Xa and furin. Nafamostat remains effective to block coagulation factor-mediated cleavage of variant spike sequences. Furthermore, host protease usage has likely been a selection pressure throughout coronavirus evolution, and we observe convergence of distantly related coronaviruses to attain common host protease interactions, including coagulation factors. Interpretation of genomic surveillance of emerging SARS-CoV-2 variants and future zoonotic spillover is supported by functional characterization of recurrent emerging features.
Transcriptional regulation and chromatin architecture maintenance are decoupled functions at the Sox2 locus
Authors: Taylor Tiegh , Sikorska Natalia , Shchuka Virlana M. , Chahar Sanjay , Ji Chenfan , Macpherson Neil N. , Moorthy Sakthi D. , de Kort Marit A.C. , Mullany Shanelle , Khader Nawrah , Gillespie Zoe E. , Langroudi Lida , Tobias Ian C. , Lenstra Tineke L. , Mitchell Jennifer A. , Sexton Tom
Published: June 2022

How distal regulatory elements control gene transcription and chromatin topology is not clearly defined, yet these processes are closely linked in lineage specification during development. Through allele-specific genome editing and chromatin interaction analyses of the Sox2 locus in mouse embryonic stem cells, we found a striking disconnection between transcriptional control and chromatin architecture. We traced nearly all Sox2 transcriptional activation to a small number of key transcription factor binding sites, whose deletions have no effect on promoter–enhancer interaction frequencies or topological domain organization. Local chromatin architecture maintenance, including at the topologically associating domain (TAD) boundary downstream from the Sox2 enhancer, is widely distributed over multiple transcription factor-bound regions and maintained in a CTCF-independent manner. Furthermore, partial disruption of promoter–enhancer interactions by ectopic chromatin loop formation has no effect on Sox2 transcription. These findings indicate that many transcription factors are involved in modulating chromatin architecture independently of CTCF.
Crystal structure and Hirshfeld surface analysis of (E)-2-(4-bromophenyl)-1-[2,2-dibromo-1-(4-nitrophenyl)ethenyl]diazene
Authors: Akkurt Mehmet , Yıldırım Sema Öztürk , Shikhaliyev Namiq Q. , Mammadova Naila A. , Niyazova Ayten A. , Khrustalev Victor N. , Bhattarai Ajaya
Published: June 2022

The molecule of the title compound, C14H8Br3N3O2, consists of three almost planar groups: the central dibromoethenyldiazene fragment and two attached aromatic rings. The mean planes of these rings form dihedral angles with the plane of the central fragment of 26.35 (15) and 72.57 (14)° for bromine- and nitro-substituted rings, respectively. In the crystal, C—H...Br interactions connect molecules, generating zigzag C(8) chains along the [100] direction. These chains are linked by C—Br...π interactions into layers parallel to (001). van der Waals interactions between the layers aid in the cohesion of the crystal packing. The most substantial contributions to crystal packing, according to a Hirshfeld surface analysis, are from Br...H/H...Br (20.9%), C...H/H...C (15.2%), O...H/H...O (12.6%) and H...H (11.7%) contacts.
A relational model of university's identity and architectural design pre- and post-pandemic
Authors: Beheiry Dalia A. , Shafik Zeinab , Aboubakr Dalia
Published: June 2022

Purpose

The present research aims to explore the relationship between the university's new identity and its architectural design, and to investigate the impact of COVID-19 pandemic on this model. It also aims to analyze the declared identity of the new Egyptian universities.

Design/methodology/approach

To formulate the hypothesis of the relational model, the research started with the literature related to physical and nonphysical variables of university's identity (organizational and visual identity) and the impact of the pandemic on its identity. Secondly, an online questionnaire targeting academic leaders was conducted to identify the relative importance of the selected variables of university's identity pre- and post-pandemic. Thirdly, a content analysis of the new Egyptian universities' identity was used to track the correlation between the selected variables based on information accessible on universities' websites. Finally, the results of the content analysis and the questionnaire were compared to test the hypothesis.

Findings

The study reveals the most important physical variable of university's new identity pre- and post-pandemic is technological infrastructure and flexible design, while the least important is university's unique design. The results highlight that the universities need to revisit the declared identity to reflect the new challenges posed by COVID-19.

Originality/value

This study is considered one of the first researches that links the physical and nonphysical variables of university's new identity. The current study contributes to analyzing the impact of COVID-19 on university identity and architecture.