bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel gut microbiota and microbiota-metabolites signatures in gliomas and its predictive/prognosis functions
Authors: Zhou Min , Song Chong , Gu Junwei , Wang Tong , Shi Linyong , Li Chiyang , Zhu Liwen , Li Hong , Qi Songtao , Lu Yuntao
Published: January 2023

Gliomas are the most common malignant tumors in the central nervous system. Host genetic and environmental factors have been implicated as the causes and regulators of gliomas. Evidence shows that alterations of the gut microbiome play an important role in multiple diseases including central nervous system disorders. However, the influence of gut microbiome to the epigenesis of gliomas remains largely unknown. Here we profiled the gut microbiome and metabolome in fecal samples from healthy volunteers and the patients with gliomas through the 16S rRNA gene sequencing and LC-MS analyses. The fecal samples from primary glioma patients (n=51), recurrent glioma patients (n=11), patients who underwent TMZ radio-chemotherapy (n=16) and healthy volunteers (n=37) were collected. 56 discriminatory OTUs and 144 metabolites were observed in gliomas compared to those in healthy volunteers, and some species were correlated with clinical parameters, such as tumor grade, IDH-1 and MGMT status. Moreover, the gliomas group showed increased activity in pathways associated with ectoine biosynthesis, fatty acid elongation (saturated), and protocatechuate degradation. At the same time, we revealed 4 fatty-acid metabolites(palmitic acid, oleic acid, DL−beta−Hydroxypalmitic acid, 4−(Methylamino)−4−(3−pyridyl)butyric acid) as possibly interacting with glioma growth. Random forest modeling indicated that a model involving 8 genera and 10 metabolite biomarkers achieved a high accuracy in gliomas prediction (AUC=94.4%). We investigated interassociations between the microbial genera in glioblastoma multiforme (GBM) and progression-free survival (PFS) and overall survival (OS) by Spearman’s correlation analysis. Patients with high proportions of fecalFaecalibacteriumhad significantly better median PFS or OS than those with low proportions (mPFS 495 vs. 281 days, p=0.005; mOS 604 vs. 395 days, p=0.044). Moreover, animal experiments have verified the causal relationship between the structural changes of gut microbiome and glioma growth. Our current study comprehensively characterizes the perturbed interface of gut microbiome and metabolites in glioma patients, which may be used as diagnostic and prognostic biomarkers of gliomas.
Metagenomic profiling of long-read sequencing for clinical diagnosis of ocular inflammation
Authors: Koyanagi Yoshito , Sajiki Ai Fujita , Ushida Hiroaki , Kawano Kenichi , Fujita Kosuke , Okuda Daishi , Kawabe Mitsuki , Yamada Kazuhisa , Suzumura Ayana , Kachi Shu , Kaneko Hiroki , Komatsu Hiroyuki , Usui Yoshihiko , Goto Hiroshi , Nishiguchi Koji M.
Published: January 2023

Objective

To establish a metagenomic profiling method using long-read sequencing for clinical diagnosis of ocular inflammation and detect the etiologic virus of herpetic uveitis.

Design

A retrospective, cross-sectional study.

Participants

The participants were 44 uveitis patients with a suspected infectious etiology and 22 controls with cataract.

Methods

The anterior aqueous humor (10-20 µl) was subjected to DNA purification, followed by whole genome amplification. The Nanopore MinION™ using the Flongle Flow Cell was used to perform rapid long-read sequencing and the phylogenetic composition of the microorganisms in the specimen was evaluated.

Main Outcomes and Measures

The detection of the DNA sequence reads of the etiologic virus of herpetic uveitis in the generated FASTQ files from nanopore sequencing and the evaluation of the limits of detection (LOD) of metagenomic analysis compared to multiplex polymerase chain reaction (mPCR) testing for etiologic virus detection of herpetic uveitis.

Results

The detection rate of nanopore metagenomic analysis was approximately 59.0% as a result of validation against 22 mPCR-positive cases. The LOD was between 103.6and 106copies of virus DNA. The undetectable cases tended to have significantly lower copy numbers by mPCR, suggesting the lower metagenomic analysis sensitivity compared to mPCR. The nine pathogenic microorganisms evaluated by mPCR were also not detected by nanopore in all mPCR-negative cases and controls. The minimum time to obtain analysis results using this method was approximately 190 minutes.

Conclusions and Relevance

Our established sequencing protocol from the anterior aqueous humor detected the DNA fragments of etiologic viruses in patients with herpes virus uveitis. Conversely, nanopore metagenomic results contained considerable noise and were found to be less sensitive compared to the conventional mPCR tests for ocular infections.
Comparative effectiveness of Paxlovid versus sotrovimab and molnupiravir for preventing severe COVID-19 outcomes in non-hospitalised patients: observational cohort study using the OpenSAFELY platform
Authors: Zheng Bang , Tazare John , Nab Linda , Mehrkar Amir , MacKenna Brian , Goldacre Ben , Douglas Ian J , Tomlinson Laurie A
Published: January 2023

Objective

To compare the effectiveness of Paxlovid vs. sotrovimab and molnupiravir in preventing severe COVID-19 outcomes in non-hospitalised high-risk COVID-19 adult patients.

Design

With the approval of NHS England, we conducted a real-world cohort study using the OpenSAFELY-TPP platform.

Setting

Patient-level electronic health record data were obtained from 24 million people registered with a general practice in England that uses TPP software. The primary care data were securely linked with data on COVID-19 infection and therapeutics, hospital admission, and death within the OpenSAFELY-TPP platform, covering a period where both Paxlovid and sotrovimab were first-line treatment options in community settings.

Participants

Non-hospitalised adult COVID-19 patients at high risk of severe outcomes treated with Paxlovid, sotrovimab or molnupiravir between February 11, 2022 and October 1, 2022.

Interventions

Paxlovid, sotrovimab or molnupiravir administered in the community by COVID-19 Medicine Delivery Units.

Main outcome measure

COVID-19 related hospitalisation or COVID-19 related death within 28 days after treatment initiation.

Results

A total of 7683 eligible patients treated with Paxlovid (n=4836) and sotrovimab (n=2847) were included in the main analysis. The mean age was 54.3 (SD=14.9) years; 64% were female, 93% White and 93% had three or more COVID-19 vaccinations. Within 28 days after treatment initiation, 52 (0.68%) COVID-19 related hospitalisations/deaths were observed (33 (0.68%) treated with Paxlovid and 19 (0.67%) with sotrovimab). Cox proportional hazards model stratified by region showed that after adjusting for demographics, high-risk cohort categories, vaccination status, calendar time, body mass index and other comorbidities, treatment with Paxlovid was associated with a similar risk of outcome event as treatment with sotrovimab (HR=1.14, 95% CI: 0.62 to 2.08; P=0.673). Results from propensity score weighted Cox model also showed comparable risks in these two treatment groups (HR=0.88, 95% CI: 0.45 to 1.71; P=0.700). An exploratory analysis comparing Paxlovid users with 802 molnupiravir users (11 (1.37%) COVID-19 related hospitalisations/deaths) showed some evidence in favour of Paxlovid but with variation in the effect estimates between models (HR ranging from 0.26 to 0.61).

Conclusion

In routine care of non-hospitalised high-risk adult patients with COVID-19 in England, no substantial difference in the risk of severe COVID-19 outcomes was observed between those who received Paxlovid and sotrovimab between February and October 2022, when different subvariants of Omicron were dominant.
Overcrowded Housing Reduces COVID-19 Mitigation Measures and Lowers Emotional Health Among San Diego Refugees from September to November of 2020
Authors: Hassani Ashkan , Omaleki Vinton , Erikat Jeanine , Frost Elizabeth , Streuli Samantha , Sahid Ramla , Yusufi Homayra , Fielding-Miller Rebecca
Published: January 2023

Refugee communities are vulnerable to housing insecurity, which drives numerous health disparity outcomes in a historically marginalized population. The COVID-19 pandemic has only worsened the ongoing affordable housing crisis in the United States while continuing to highlight disparities in health outcomes across populations. We conducted interviewer-administered surveys with refugee and asylum seekers in San Diego County at the height of the COVID-19 pandemic to understand the social effects and drivers of COVID-19 in one of the largest refugee communities in the United States. Staff from a community-based refugee advocacy and research organization administered the surveys from September - November 2020. 544 respondents participated in the survey, which captured the diversity of the San Diego refugee community including East African (38%), Middle Eastern (35%), Afghan (17%), and Southeast Asian (11%) participants. Nearly two-thirds of respondents (65%) reported living in overcrowded conditions (>1 individual per room) and 30% in severely crowded conditions (>1.5 individuals per room). Respondents living in affordable housing units or receiving section 8 housing vouchers had a 66% lower probability of living in severely crowded settings (aOR:0.34, 95% CI:0.19– 0.61). Refugees living in overcrowded and severely overcrowded housing had more than twice the odds to have not accessed COVID-19 testing since the pandemic began (OR: 2.28, 95% CI: 1.38 - 3.78) and had nearly 4 times the odds to report lower emotional health (OR: 3.90, 95% CI: 2.62 - 5.82). Longer United States residency was associated with a 7% reduction in the odds of living in crowded housing per additional year (aOR:0.93, 95% CI:0.90–0.97). Overcrowding housing is a structural burden that reduces COVID-19 risk mitigation behaviors. Improved access to affordable housing units or receiving vouchers could reduce overcrowded housing in vulnerable refugee communities.
A novel description of the network dynamics underpinning working memory
Authors: Rossi Chiara , Vidaurre Diego , Costers Lars , Akbarian Fahimeh , Woolrich Mark , Nagels Guy , Van Schependom Jeroen
Published: January 2023

Working memory (WM) plays a central role in cognition, prompting neuroscientists to investigate its functional and structural substrates. The WM dynamic recruits large-scale frequency-specific brain networks that unfold over a few milliseconds – this complexity challenges traditional neuroimaging analyses. In this study, we unravel the WM network dynamics in an unsupervised, data-driven way, applying the time delay embedded-hidden Markov model (TDE-HMM). We acquired MEG data from 38 healthy subjects performing an n-back working memory task. The TDE-HMM model inferred four task-specific states with each unique temporal (activation), spectral (phase-coherence connections), and spatial (power spectral density distribution) profiles. A theta frontoparietal state performs executive functions, an alpha temporo-occipital state maintains the information, and a broad-band and spatially complex state with an M300 temporal profile leads the retrieval process and motor response. The HMM states can be straightforwardly interpreted within the neuropsychological multi-component model of WM, significantly improving the comprehensive description of WM.

Highlights

Working memory recruits different frequency-specific brain networks that wax and wane at a millisecond scale.

Through the time-delay embedded hidden (TDE-HMM) we are able to extract data-driven functional networks with unique spatial, spectral, and temporal profiles.

We demonstrate the existence of four task-specific brain networks that can be interpreted within the well-known Baddeley’s multicomponent model of working memory.

This novel WM description unveils new features that will lead to a more in-depth characterization of cognitive processes in MEG data.
First record of highly invasive Chinese sleeperPerccottus gleniiDybowski, 1877 (Perciformes: Odontobutidae) in the Elbe River Basin, Czechia
Authors: Šmejkal Marek , Dočkal Ondřej , Thomas Kiran , Kalous Lukáš
Published: January 2023

The Chinese sleeper (Perccottus glenii) has invaded European freshwaters and we present evidence of its first documented occurrence in the Elbe River basin in Czechia. The individual fish was caught by a fisherman and posted on social media. After immediately contacting the person in question, we obtained a live fish from him. The Chinese sleeper appears to have been present in interconnected ponds and streams for ten years and may have spread over a larger area. We recommend that eradication measures be implemented to prevent further spread.

Statement of Significance

The Chinese sleeper has invaded many European countries in the last 50 years, and it is expected to invade western Europe because of the favourable conditions for its establishment. This finding indicates that it could spread in the Elbe River Basin, which could have serious impacts on floodplain and wetland ecosystems. To prevent this scenario, eradication measures should be implemented.
Comparative benchmarking of optical genome mapping and chromosomal microarray reveals high technological concordance in CNV identification and structural variant refinement
Authors: Barseghyan Hayk , Pang Andy , Clifford Ben , Serrano Moises , Chaubey Alka , Hastie Alex
Published: January 2023

PURPOSE

The recommended practice for individuals suspected of a genetic etiology for disorders including unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and multiple congenital anomalies (MCA) involves a genetic testing workflow including chromosomal microarray (CMA), Fragile-X testing, karyotype analysis, and/or sequencing based gene panels. Since genomic imbalances are often found to be causative, CMA is recommended as first tier testing for many indications. Optical genome mapping (OGM) is an emerging next generation cytogenomic technique that can detect not only copy number variants (CNVs), triploidy and absence of heterozygosity (AOH) like CMA, but can also define the location of duplications, and detect other structural variants (SVs), including balanced rearrangements and repeat expansions/contractions. This study compares OGM to CMA for clinically reported genomic variants, some of which have additional structural characterization with fluorescencein situhybridization (FISH).

METHODS

OGM was performed on IRB approved, de-identified specimen from 55 individuals with unbalanced genomic abnormalities previously identified by CMA (61 clinically reported abnormalities). SVs identified by OGM were filtered by a control database to remove polymorphic variants and against an established gene list to prioritize clinically relevant findings before comparing with CMA and FISH results.

RESULTS

TOGM results showed 100% concordance with CMA findings for pathogenic variants and 98% concordant for all pathogenic/likely pathogenic/variants of uncertain significance (VUS), while also providing additional insight into the genomic structure of abnormalities that CMA was unable to provide.

CONCLUSION

OGM demonstrates equivalent or superior performance to CMA and adds to an increasing body of evidence on the analytical validity and ability to detect clinically relevant abnormalities identified by CMA. Moreover, OGM identifies translocations, structures of duplications and complex CNVs intractable by CMA, yielding additional clinical utility.
Test Development with Content Validity in Pediatric Hematology
Authors: Armijo Beeling M. , Abusin Ghada A. , Kreiter Clarence D. , Barlow Patrick B. , Lentz Steven R.
Published: January 2023

Content validity is often lacking in tools for the assessment of competency in medical specialty and subspecialty trainees. The primary aim of this study was to develop a protocol for early test assessment in pediatric hematology using iterative rounds of expert evaluation in the context of explicit knowledge goals. We used the pediatric hematology content of the American Board of Pediatrics as a test case for assessment protocol development. We found that the use of expert input and three rounds of test development increased test content validity. The instrument developed here has the potential to improve assessment of competency in pediatric hematology. This approach also may be useful in the development of competency assessment tools for other medical subspecialties.
Minuteman – A versatile cloud computational platform for collaborative research
Authors: Li Xinkai , Charkaborty Joydeep , Jameson Michael , Moore Hobert , Laux-Biehlmann Alexis , Hayat Sikander , Jain Dhawal
Published: January 2023

Secure platforms for bio-computation are critical to foster increasingly complex and data-intensive collaborations involving biomedical data. Here, we present Minuteman – an open-source cloud computing platform that can be securely used across organizations. Minuteman can be used for hosting data sources and running computational pipelines in an organized way. The platform consists of three fundamental features, 1) data operations including collaborative data processing and analytics, 2) customizable user access management for secure dissemination of the data, and 3) interactive exploration of the data through 3rdparty (e.g. shiny, dashboard etc.) applications that can be scaled using docker containers. Strict data access rules and user-specific roles are applied across the whole platform to maintain data security. Minuteman is ideal for scenarios where data security, and privileged access are critical, such as industry-academia collaborations, and multi-institution consortiums. Using single-cell transcriptomics preprocessing, analyses and visualization pipelines across labs, we showcase the utility of the Minuteman platform for biomedical data analyses. Minuteman code is available at (https://github.com/hayatlab/minuteman)
Antagonism among DUX family members evolved from an ancestral toxic single homeodomain protein
Authors: Bosnakovski Darko , Toso Erik A. , Ener Elizabeth T. , Gearhart Micah D. , Yin Lulu , Lüttmann Felipe F. , Magli Alessandro , Shi Ke , Kim Johnny , Aihara Hideki , Kyba Michael
Published: January 2023

Double homeobox (DUX) genes are unique to eutherian mammals and normally expressed transiently during zygotic genome activation. The canonical member, DUX4, is involved in facioscapulohumeral muscular dystrophy (FSHD) and cancer, when misexpressed in other contexts. We evaluate the 3 human DUX genes and the ancestral single homeobox gene sDUX from the non-eutherian mammal, platypus, and find that DUX4 activities are not shared with DUXA or DUXB, which lack transcriptional activation potential, but surprisingly are shared with platypus sDUX. In human myoblasts, platypus sDUX drives cytotoxicity, inhibits myogenesis, and induces DUX4 target genes, particularly those associated with zygotic genome activation (ZGA), by binding DNA as a homodimer in a way that overlaps the DUX4 homeodomain crystal structure. DUXA lacks transcriptional activity but has DNA-binding and chromatin accessibility overlap with DUX4 and sDUX, including on ZGA genes and LTR elements, and can actually be converted into a DUX4-like cytotoxic factor by fusion to a synthetic transactivation domain. DUXA competition antagonizes the activity of DUX4 on its target genes, including in FSHD patient cells. Since DUXA is an early DUX4 target gene, this activity potentiates feedback inhibition, constraining the window of DUX4 activity. The DUX gene family therefore comprises cross-regulating members of opposing function, with implications for their roles in ZGA, FSHD, and cancer.

HIGHLIGHTS

Platypus sDUX is toxic and inhibits myogenic differentiation.

DUXA targets overlap substantially with those of DUX4.

DUXA fused to a synthetic transactivation domain acquires DUX4-like toxicity.

DUXA behaves as a competitive inhibitor of DUX4.
Nano-computed tomography reveals repeated phenotypic divergence in parasites to escape host defense
Authors: Kolencik Stanislav , Stanley Edward L. , Punnath Aswaj , Grant Avery R. , Doña Jorge , Johnson Kevin P. , Allen Julie M.
Published: January 2023

Understanding how selective pressures drive morphological change is a central question in evolutionary biology. Feather lice have repeatedly diversified into convergent ecomorphs, based on how they escape from host defenses in different microhabitats. Here, we used nano-computed tomography scan data of 89 specimens of feather lice, belonging to four ecomorph groups to quantify variation of functional traits, including mandibular muscle volume, limb length, and three-dimensional head shape data in these tiny insects. The results suggest that the shape of the head, the proportional volume of the chewing muscles, and the length of the leg segments in feather lice are all strongly associated with specific host-habitats. Further, species that co-occur on hosts have increased rates of morphological evolution, suggesting competition for host space is one of the drivers of morphology. This supports previous work indicating that the phenotypic diversity of feather lice is the result of repeated convergence resulting from resource partitioning, microhabitat specialization, and selection pressures imposed by host defense.
A publishing infrastructure for AI-assisted academic authoring
Authors: Pividori Milton , Greene Casey S.
Published: January 2023

In this work we investigate how models with advanced natural language processing capabilities can be used to reduce the time-consuming process of writing and revising scholarly manuscripts. To this end, we integrate large language models into the Manubot publishing ecosystem to suggest revisions for scholarly text. We tested our AI-based revision workflow in three case studies of existing manuscripts, including the present one. Our results suggest that these models can capture the concepts in the scholarly text and produce high-quality revisions that improve clarity. Given the amount of time that researchers put into crafting prose, we anticipate that this advance will revolutionize the type of knowledge work performed by academics.
Representation and Retrieval of Brain Connectivity Information derived from TMS Experiments
Authors: Wittenberg George F. , Fang Xiaoqi , Roy Souvik , Lee Bryan , Miškov-Živanov Nataša , Hochheiser Harry , Banihashemi Layla , Vesia Michael , Ramsey Joseph
Published: January 2023

Background

Transcranial magnetic stimulation (TMS) is a painless non-invasive method that allows focal activation or deactivation of a human brain region in order to assess effects on other brain regions. As such, it has a unique role in elucidating brain connectivity during behavior and at rest. Information regarding brain connectivity derived from TMS experiments has been published in hundreds of papers but is not accessible in aggregate.

Objective

Our objective was to identify, extract, and represent TMS-connectivity data in a graph database. This approach uses nodes connected by edges to capture the directed nature of interregional communication in the brain while also being flexible enough to contain other information about the connections, such as the source of information and details about the experiments that produced them.

Methods

Data related to interregional brain connectivity is first extracted from full-text publications, with creation of a table-like structure that list data of multiple types, principally the source and target brain regions, sign (excitatory/inhibitory) and latency. While machine-reading methods were explored, so far human experts have had to extract and verify data. These data are used to populate aneo4jgraph database. A graphical user interface coupled with a query system allows users to search for networks and display information about connections between any two brain regions of interest.

Results

Experiments involving two TMS stimulating coils, in which one is over a putative source region and the other is over another region with a measurable effect in the body (such as the primary motor cortex) are the most straightforward to represent in the database. Even in those experiments, differing conventions for naming regions, and differing experimental parameters such as stimulation intensity and coil position, create issues for representing data from multiple studies in the same database. Other types of experiments, such a neuromodulatory stimulation such as rTMS, can provide information regarding connectivity, but are harder to represent. But we have, thus far, stored information about 100 connections in the database and demonstrated its utility in exploring direct and indirect connections between brain regions. We have also explored adding a causal inference method to those connections, allowing information about latency to shape the connections retrieved given latency limits.

Conclusion

A graph database can flexibly store information about interregional brain connectivity and is particularly useful for exploring the temporal aspects of brain networks.
AtOM, an ontology model for standardizing use of brain atlases in tools, workflows, and data infrastructures
Authors: Kleven Heidi , Gillespie Thomas H. , Zehl Lyuba , Dickscheid Timo , Bjaalie Jan G. , Martone Maryann E. , Leergaard Trygve B.
Published: January 2023

Brain atlases are important reference resources for accurate anatomical description of neuroscience data. Open access, three-dimensional atlases serve as spatial frameworks for integrating experimental data and defining regions-of-interest in analytic workflows. However, naming conventions, parcellation criteria, area definitions, and underlying mapping methodologies differ considerably between atlases and across atlas versions. This lack of standardization impedes use of atlases in analytic tools and registration of data to different atlases. To establish a machine-readable standard for representing brain atlases, we identified four fundamental atlas elements, defined their relations, and created an ontology model. Here we present our Atlas Ontology Model (AtOM) and exemplify its use by applying it to mouse, rat, and human brain atlases. We propose minimum requirements for FAIR atlases and discuss how AtOM may facilitate atlas interoperability and data integration. AtOM provides a standardized framework for communication and use of brain atlases to create, use, and refer to specific atlas elements and versions. We argue that AtOM will accelerate analysis, sharing, and reuse of neuroscience data.
A genomic panel for studying C3-C4 intermediate photosynthesis in the Brassiceae tribe
Authors: Guerreiro Ricardo , Bonthala Venkata Suresh , Schlüter Urte , Triesch Sebastian , Weber Andreas P.M. , Stich Benjamin
Published: January 2023

Research on C4 and C3-C4 photosynthesis has attracted significant attention because the understanding of the genetic underpinnings of this trait will support the introduction of its characteristics into commercially relevant crop species. We used a panel of 19 taxa of 18 Brassiceae species with different photosynthesis characteristics (C3 and C3-C4) with the following objectives: (i) create draft genome assemblies and annotations, (ii) quantify the level of orthology using synteny maps between all pairs of taxa, (iii) describe the phylogenetic relatedness across all the species, and (iv) track the evolution of C3-C4 intermediate photosynthesis in the Brassiceae tribe.

Our results indicate that the draftde novogenome assemblies are of high quality and cover at least 90% of the gene space. Therewith we more than doubled the sampling depth of genomes of the Brassiceae tribe that comprises commercially important as well as biologically interesting species. The gene annotation generated high-quality gene models, and for most genes extensive upstream sequences are available for all taxa, yielding potential to explore variants in regulatory sequences. The genome-based phylogenetic tree of the Brassiceae contained two main clades and indicated that the C3-C4 intermediate photosynthesis has evolved five times independently. Furthermore, our study provides the first genomic support of the hypothesis thatDiplotaxis muralisis a natural hybrid ofD. tenuifoliaandD. viminea. Altogether, thede novogenome assemblies and the annotations reported in this study are a valuable resource for research on the evolution of C3-C4 intermediate photosynthesis.
RNA Polymerase II, the BAF remodeler and transcription factors synergize to evict nucleosomes
Authors: Brahma Sandipan , Henikoff Steven
Published: January 2023

Chromatin accessibility is a hallmark of active transcription and requires ATP-dependent nucleosome remodeling by Brahma-Associated Factor (BAF). However, the mechanistic link between transcription, nucleosome remodeling, and chromatin accessibility is unclear. Here, we used a chemical-genetic approach to dissect the interplay between RNA Polymerase II (RNAPII), BAF, and DNA-sequence-specific transcription factors (TFs) in mouse embryonic stem cells. By time-resolved chromatin profiling with acute transcription block at distinct stages, we show that RNAPII promoter-proximal pausing stabilizes BAF chromatin occupancy and enhances nucleosome eviction by BAF. We find that RNAPII and BAF probe both transcriptionally active and Polycomb-repressed genomic regions and provide evidence that TFs capture transient site exposure due to nucleosome unwrapping by BAF to confer locus specificity for persistent chromatin remodeling. Our study reveals the mechanistic basis of cell-type-specific chromatin accessibility. We propose a new paradigm for how functional synergy between dynamically acting chromatin factors regulates nucleosome organization.
Mapping drug biology to disease genetics to discover drug impacts on the human phenome
Authors: Habib Mamoon , Lalagkas Panagiotis Nikolaos , Melamed Rachel D.
Published: January 2023

Unintended effects of medications on diverse diseases are widespread, resulting in not only harmful drug side effects, but also beneficial drug repurposing. This implies that drugs can unexpectedly influence disease networks. Then, discovering how biological effects of drugs relate to disease biology can both provide insight into the biological basis for latent drug effects, and can help predict new effects. Rich data now comprehensively profile both drug impacts on biological processes, and known drug associations with human phenotypes. At the same time, systematic phenome-wide genetic studies have linked each common phenotype with putative disease driver genes. Here, we develop Draphnet, a supervised linear model that integrates in vitro data on 429 drugs and gene associations of nearly 200 common phenotypes to learn a network connecting these molecular signals to explain drug effects on disease. The approach uses the -omics level similarity among drugs, and among phenotypes, to extrapolate impacts of drug on disease. Our predicted drug-phenotype relationships outperform a baseline predictive model. But more importantly, by projecting each drug to the space of its influence on disease driver genes, we propose the biological mechanism of unexpected effects of drugs on disease phenotypes. We show that drugs sharing downstream predicted biological effects share known biology (i.e., gene targets), supporting the potential of our method to provide insights into the biology of unexpected drug effects on disease. Using Draphnet to map a drug’s known molecular effects to their downstream effect on the disease genome, we put forward disease genes impacted by drug targets, and we suggest new grouping of drugs based on shared effects on the disease genome. Our approach has multiple applications, including predicting drug uses and learning about drug biology, with potential implications for personalized medicine.

Author summary

Medications can impact a number of cellular processes, resulting in both their intended treatment of a health condition, and also unintended harmful or beneficial effects on other diseases. We aim to understand and predict these drug effects by learning the network connecting the biological processes altered by drugs to the genes driving disease. Our model, called Draphnet, can predict drug side effects and indications, but beyond prediction we show that it is also able to learn a drug’s expected effect on the disease genome. Using Draphnet to summarize the biological impact of each drug, we put forward the disease genes impacted by drugs or drug targets. For instance, both anti-inflammatories and some PPARα-agonists share downstream effect on the cholesterol ester transfer protein (CETP), a gene previously experimentally supported as an effector of fenofibrate. Our approach provides a biological basis for drug repurposing, potentially accelerating clinical advances.
Blind Assessment of Monomeric AlphaFold2 Protein Structure Models with Experimental NMR Data
Authors: Li Ethan H. , Spaman Laura , Tejero Roberto , Huang Yuanpeng Janet , Ramelot Theresa A. , Fraga Keith J. , Prestegard James H. , Kennedy Michael A. , Montelione Gaetano T.
Published: January 2023

Recent advances in molecular modeling of protein structures are changing the field of structural biology.AlphaFold-2(AF2), an AI system developed by DeepMind, Inc., utilizes attention-based deep learning to predict models of protein structures with high accuracy relative to structures determined by X-ray crystallography and cryo-electron microscopy (cryoEM). Comparing AF2 models to structures determined using solution NMR data, both high similarities and distinct differences have been observed. Since AF2 was trained on X-ray crystal and cryoEM structures, we assessed how accurately AF2 can model small, monomeric, solution protein NMR structures which (i) were not used in the AF2 training data set, and (ii) did not have homologous structures in the Protein Data Bank at the time of AF2 training. We identified nine open source protein NMR data sets for such “blind” targets, including chemical shift, raw NMR FID data, NOESY peak lists, and (for 1 case)15N-1H residual dipolar coupling data. For these nine small (70 - 108 residues) monomeric proteins, we generated AF2 prediction models and assessed how well these models fit to these experimental NMR data, using several well-established NMR structure validation tools. In most of these cases, the AF2 models fit the NMR data nearly as well, or sometimes better than, the corresponding NMR structure models previously deposited in the Protein Data Bank. These results provide benchmark NMR data for assessing new NMR data analysis and protein structure prediction methods. They also document the potential for using AF2 as a guiding tool in protein NMR data analysis, and more generally for hypothesis generation in structural biology research.

Highlights

AF2 models assessed against NMR data for 9 monomeric proteins not used in training.

AF2 models fit NMR data almost as well as the experimentally-determined structures.

RPF-DP, PSVS, andPDBStatsoftware provide structure quality and RDC assessment.

RPF-DPanalysis using AF2 models suggests multiple conformational states.
Selective bacteriophages reduce the emergence of resistant bacteria in the bacteriophage-antibiotic combination therapy
Authors: Azam Aa Haeruman , Sato Koji , Miyanaga Kazuhiko , Nakamura Tomohiro , Ojima Shinjiro , Kondo Kohei , Tamura Azumi , Yamashita Wakana , Tanji Yasunori , Kiga Kotaro
Published: January 2023

Escherichia coliO157:H7 is a globally important foodborne pathogen that affects food safety. Antibiotic administration against O157:H7 may contribute to the exacerbation of hemolytic uremic syndrome (HUS) and antibiotic-resistant strains increase; therefore, bacteriophage therapy (phage therapy) is considered a useful alternative. In the treatment of resistant bacterial infections, combination therapy with bacteriophages and antibiotics, taking advantage of the benefits of both agents, has been suggested to be effective in inhibiting the emergence of antimicrobial-resistant strains; however, its effectiveness against O157:H7 is not well understood. In this study, we isolated SP015, a phage that infects O157:H7, and compared the combined effect of the bacteriophage and fosfomycin (FOM) with that of the PP01 phage. Genomic analysis revealed that FOM exerts its antibacterial activity through glycerol-3-phosphate transporter (GlpT) and hexose phosphate transporter (UhpT) proteins, and the receptors of PP01 and SP015 phages are the outer membrane protein C (OmpC) and ferrichrome outer membrane transporter protein (FhuA), respectively. Experiments with knockout strains have suggested that FOM also uses OmpC, the receptor for PP01, as a transporter. This may explain why the combination treatment with PP01 resulted in a faster emergence of resistance than the combination treatment with SP015. We propose that phage-antibiotic combination therapy requires careful selection of the phage to be used.
Hydroxyurea inhibits ERAD-L independently of S-phase arrest in budding yeast
Authors: Takano Yuki , Nakatsukasa Kunio
Published: January 2023

Misfolded luminal and membrane proteins in the endoplasmic reticulum (ER) are recognized and retrotranslocated to the cytosol for proteasomal degradation, a process referred to as ER-associated degradation (ERAD). InSaccharomyces cerevisiae, ERAD substrates with luminal lesions are targeted for proteasomal degradation by the Hrd1 ubiquitin ligase complex (ERAD-L pathway). Membrane proteins containing lesions within their membrane-spanning regions are also targeted for degradation by the Hrd1 complex (ERAD-M pathway), while those containing lesions within their cytosolic regions are targeted for degradation mainly by the Doa10 ubiquitin ligase complex (ERAD-C pathway). Here, we demonstrate that hydroxyurea (HU), which is widely used to arrest cells in S-phase and is also used to manage several diseases including sickle cell anemia and chronic myeloproliferative disorders, inhibited ERAD-L, but not ERAD-M or -C. HU-mediated inhibition of ERAD-L occurred independently of S-phase arrest. In HU-treated cells, the integrity of the Hrd1 ubiquitin ligase complex remained intact and substrate recognition was unaffected. Moreover, induction of the unfolded protein response was undetectable in cells in which ERAD-L was inhibited by HU. These results suggest an unexpected action of HU, which modulates protein quality control in the secretory pathway, and also suggest the existence of an additional regulatory step in ERAD.
Three-dimensional imaging and quantification of mouse ovarian follicles via optical coherence tomography
Authors: Amaral Marcello Magri , Sun Aixia , Li Yilin , Ren Chao , Truong Anh Blue , Nigam Saumya , Jiao Zexu , Wang Ping , Zhou Chao
Published: January 2023

Ovarian tissue cryopreservation has been successfully applied worldwide for fertility preservation. Correctly selecting the ovarian tissue with high follicle loading for freezing and reimplantation increases the likelihood of restoring ovarian function, but it is a challenging process. In this work, we explore the use of three-dimensional spectral-domain optical coherence tomography (SD-OCT) to identify different follicular stages, especially primary follicles, compare the identifications with H&E images, and measure the size and age-related follicular density distribution differences in mice ovaries. We use the thickness of the layers of granulosa cells to differentiate primordial and primary follicles from secondary follicles. The measured dimensions and age-related follicular distribution agree well with histological images and physiological aging. Finally, we apply attenuation coefficient map analyses to significantly improve the image contrast and the contrast-to-noise ratio (p < 0.001), facilitating follicle identification and quantification. We conclude that SD-OCT is a promising method to noninvasively evaluate ovarian follicles.
Multi-omics analyses demonstrate a critical role for EHMT1 methyltransferase in transcriptional repression during oogenesis
Authors: Demond Hannah , Hanna Courtney W. , Castillo-Fernandez Juan , Santos Fátima , Papachristou Evangelia K. , Segonds-Pichon Anne , Kishore Kamal , Andrews Simon , D'Santos Clive S. , Kelsey Gavin
Published: January 2023

EHMT1 (also known as GLP) is a multifunctional protein, best known for its role as an H3K9me1 and H3K9me2 methyltransferase through its reportedly obligatory dimerization with EHMT2 (also known as G9A). Here, we investigated the role of EHMT1 in the oocyte in comparison to EHMT2 using oocyte-specific conditional knockout mouse models (Ehmt2cKO,Ehmt1cKO,Ehmt1/2cDKO), with ablation from the early phase of oocyte growth. Loss of EHMT1 inEhmt1cKO andEhmt1/2cDKO oocytes recapitulated meiotic defects observed in theEhmt2cKO; however, there was a significant impairment in oocyte maturation and developmental competence inEhmt1cKO andEhmt1/2cDKO oocytes beyond that observed in theEhmt2cKO. Consequently, loss of EHMT1 in oogenesis results, upon fertilization, in mid-gestation embryonic lethality. To identify H3K9 methylation and other meaningful biological changes in each mutant to explore the molecular functions of EHMT1 and EHMT2, we performed immunofluorescence imaging, multi-omics sequencing, and mass spectrometry (MS)–based proteome analyses in cKO oocytes. Although H3K9me1 was depleted only upon loss of EHMT1, H3K9me2 was decreased, and H3K9me2-enriched domains were eliminated equally upon loss of EHMT1 or EHMT2. Furthermore, there were more significant changes in the transcriptome, DNA methylome, and proteome inEhmt1/2cDKO thanEhmt2cKO oocytes, with transcriptional derepression leading to increased protein abundance and local changes in genic DNA methylation inEhmt1/2cDKO oocytes. Together, our findings suggest that EHMT1 contributes to local transcriptional repression in the oocyte, partially independent of EHMT2, and is critical for oogenesis and oocyte developmental competence.
Dynamical theory of X-ray diffraction by crystals with different surface relief profiles
Authors: Karpov Andrey V. , Kazakov Dmitry V. , Punegov Vasily I.
Published: January 2023

A dynamical theory is developed of X-ray diffraction on a crystal with surface relief for the case of high-resolution triple-crystal X-ray diffractometry. Crystals with trapezoidal, sinusoidal and parabolic bar profile models are investigated in detail. Numerical simulations of the X-ray diffraction problem for concrete experimental conditions are performed. A simple new method to resolve the crystal relief reconstruction problem is proposed.
Factors affecting organisations' supply chain agility and competitive capability
Authors: Aldhaheri Rashed Thani , Ahmad Syed Zamberi
Published: January 2023

Purpose

This study examines the factors affecting organisations' agility and competitive capability in public and private sectors. Drawn from the literature on supply chain agility (SC agility), the factors of supply chain speed, visibility, flexibility, innovation and leadership are tested for further understanding.

Design/methodology/approach

Through purposive sampling, a sample of 261 responses was collected using a structured questionnaire. The participants were identified as supply chain practitioners from different industries of the United Arab Emirates (UAE). Data were analysed using partial least square-structural equation modelling (PLS-SEM).

Findings

Firms can improve the agility of their supply chains by developing strong supply chain leadership and flexibility, increasing the speed and visibility of the supply chain, and through innovation in supply chain operations. Additionally, competitive capabilities can also be enhanced through SC agility.

Originality/value

This study explores organisations' agility and competitive capability in public and private sectors of the UAE. The findings offer numerous practical insights into the UAE's business context and will help firms gain better competitive advantages through agile supply chain operations.
Do CEO characteristics matter for corporate risk taking? Evidence from Russia
Authors: García-Gómez Conrado Diego , Zavertiaeva Marina , López Iturriaga Félix J.
Published: January 2023

Purpose

This paper aims to study the impact of CEOs’ personality and social connections on corporate risk-taking in the Russian market.

Design/methodology/approach

Using a sample of 93 large listed Russian corporations between 2008 and 2016, this study tests a range of personal traits, including the classical personal characteristics like age and tenure, some country-specific traits such as connections and military experience, as well as other human and social capital characteristics.

Findings

This study finds non-linear relationships between corporate risk-taking and CEO age and tenure. This study also finds that firms run by CEOs with military experience take more corporate risk. On the CEOs’ social capital side, this study’s results suggest that both political and educational connections are positively related to corporate risk-taking.

Originality/value

This study also tests some traits that have usually been ignored by the literature, such as marital and family status.
Forms of supplier relationship exploration and distributor performance
Authors: Wang Meng , Zhao Danyang , Gu Flora F.
Published: January 2023

Purpose

This study aims to differentiate two types of relationship exploration – substitute relationship exploration (SRE) and complementary relationship exploration (CRE) – and examine their effects on a distributor’s detection capability in relationship governance with upstream suppliers and innovation capability in services to downstream customers.

Design/methodology/approach

The authors obtained 176 responses from distributors in the semiconductor industry in China. Structural equation modeling and hierarchical moderated regressions are used to test the hypotheses.

Findings

CRE increases both detection and innovation capability, whereas SRE reduces detection capability and increases innovation capability. Market uncertainty weakens the effect of detection capability but strengthens that of innovation capability on distributor performance.

Research limitations/implications

First, to the best of the authors’ knowledge, this study is among the first to differentiate SRE and CRE, thus enriching the relationship marketing literature. Second, drawing on information economics, the authors uncovered the differential effects of SRE and CRE on detection and innovation capabilities. Third, market uncertainty moderates the effects of the two capabilities on distributor performance.

Practical implications

Distributors should be aware that there are different types of relationship exploration and, for that reason, should explore potential suppliers based on their business needs and firm conditions. The results of this study show that both SRE and CRE are beneficial for distributors’ innovation capability, but SRE reduces their detection capability. Practically, firms need to be aware of the trade-offs associated with different types of relationship exploration. Moreover, when market uncertainty is high, distributors should pay more attention to innovation than to detection capability building.

Originality/value

This study conceptualizes and differentiates between two forms of relationship exploration. By linking them with distributors’ capability building and performance, the authors provide theoretical and practical implications.