bluuebunny/crossref_metadata_2025 huggingface dataset:
eMIND: Enabling automatic collection of protein variation impacts in Alzheimer’s disease from the literature
Authors: Gupta Samir , Qin Xihan , Wang Qinghua , Cowart Julie , Huang Hongzhan , Wu Cathy H , Vijay-Shanker K , Arighi Cecilia N
Published: September 2023

Alzheimer’s disease and related dementias (AD/ADRDs) are among the most common forms of dementia, and yet no effective treatments have been developed. To gain insight into the disease mechanism, capturing the connection of genetic variations to their impacts, at the disease and molecular levels, is essential. The scientific literature continues to be a main source for reporting experimental information about the impact of variants. Thus, development of automatic methods to identify publications and extract the information from the unstructured text would facilitate collecting and organizing information for reuse. We developed eMIND, a deep learning-based text mining system that supports the automatic extraction of annotations of variants and their impacts in AD/ADRDs. In particular, we use this method to capture the impacts of protein-coding variants affecting a selected set of protein properties, such as protein activity/function, structure and post-translational modifications. We conducted an evaluation on the efficacy of eMIND to extract variant impact relations and obtained a recall of 0.84 and a precision of 0.94. The publications and extracted information are integrated into the UniProtKB computationally mapped bibliography to expand annotations on protein entries. eMIND’s text-mined output are presented using controlled vocabularies and ontologies for variant, disease and impact along with the evidence sentences. A sample of annotated abstracts can be accessed at URL:https://research.bioinformatics.udel.edu/itextmine/emind.
Rapid and synchronous chemical induction of replicative-like senescence via a small molecule inhibitor
Authors: Palikyras Spiros , Sofiadis Konstantinos , Stavropoulou Athanasia , Danieli-Mackay Adi , Varamogianni-Mamatsi Vassiliki , Hörl David , Nasiscionyte Simona , Zhu Yajie , Josipovic Natasa , Papadakis Antonis , Zirkel Anne , O’Connell Aoife , Loughran Gary , Keane James , Michel Audrey , Wagner Wolfgang , Beyer Andreas , Harz Hartmann , Leonhardt Heinrich , Lukinavicius Grazvydas , Nikolaou Christoforos , Papantonis Argyris
Published: September 2023

Cellular senescence is now acknowledged as a key contributor to organismal ageing and late-life disease. Although popular, the study of senescencein vitrocan be complicated by the prolonged and asynchronous timing of cells committing to it and its paracrine effects. To address these issues, we repurposed the small molecule inhibitor inflachromene (ICM) to induce senescence to human primary cells. Within six days of treatment with ICM, senescence hallmarks, including the nuclear eviction of HMGB1 and -B2, are uniformly induced across IMR90 cell populations. By generating and comparing various high throughput datasets from ICM-induced and replicative senescence, we uncovered significant similarity of the two states. Notably though, ICM suppresses the proinflammatory secretome associated with senescence, thus alleviating most paracrine effects. In summary, ICM induces a senescence-like phenotype rapidly and synchronously thereby allowing the study of its core regulatory program without any confounding heterogeneity.
Household geckos as a potential vector forSalmonellatransmission in Malawi
Authors: Wilson Catherine N. , Musicha Patrick , Beale Mathew A. , Diness Yohane , Kanjerwa Oscar , Salifu Chifundo , Katuah Zefaniah , Duncan Patricia , Nyangu John , Mungu Andrew , Deleza Muonaouza , Banda Lawrence , Elviss Nicola , Jewell Christopher P. , Pinchbeck Gina , Thomson Nicholas R. , Feasey Nicholas A. , Fèvre Eric M.
Published: September 2023

Salmonellawas isolated from 23/79 (29.1%) gecko stool samples from households in southern Malawi. Whole genome sequencing of 47 isolates revealed 27Salmonellaserovars spanning two subspecies. Our results demonstrate that geckos play an important role in the carriage and potentially, transmission ofSalmonellawithin households.
Machine Learning connects structure, bitterness & mechanism to antimalarial activity
Authors: Sambu S
Published: September 2023

Machine learning allows us to identify patterns we might otherwise have missed in the data. It therefore provides an ample solution to the age-old problem of lossless research. When the pattern is robust and the signal is durable, it is possible to use relatively modest amounts of data to build powerful well-learned models. By constructing a classifier using gradient-boosted machines, it was shown that the model was robust, yielded high quality metrics and demonstrated consistent probability assignments for chemistries that have a suitable chemical backbone qualified for inclusion in antiplasmodic libraries. Critical to model development was the utilization of molecular fingerprinting and extraction of physico-chemical parameters relevant to the mechanism driving antiplasmodic activity. Subsequently, such an approach allows the model to uncover the link between bitterness, molecular structure and therapeutic value. This approach to evaluating antiplasmodic activity in chemistries provides a low-cost tool usable in identifying new classes of molecules for use in reducing malaria morbidity that often affects vulnerable members of the community the most. Additionally, given their relatively broad, low colligation and potent efficacies, these molecules may provide strong safety margins and durability netting high returns for health equity.
Deciphering 3’ UTR mediated gene regulation using interpretable deep representation learning
Authors: Yang Yuning , Li Gen , Pang Kuan , Cao Wuxinhao , Li Xiangtao , Zhang Zhaolei
Published: September 2023

The 3’untranslated regions (3’UTRs) of messenger RNAs contain many important cis-regulatory elements that are under functional and evolutionary constraints. We hypothesize that these constraints are similar to grammars and syntaxes in human languages and can be modeled by advanced natural language models such as Transformers, which has been very effective in modeling protein sequence and structures. Here we describe 3UTRBERT, which implements an attention-based language model, i.e., Bidirectional Encoder Representations from Transformers (BERT). 3UTRBERT was pre-trained on aggregated 3’UTR sequences of human mRNAs in a task-agnostic manner; the pre-trained model was then fine-tuned for specific downstream tasks such as predicting RBP binding sites, m6A RNA modification sites, and predicting RNA sub-cellular localizations. Benchmark results showed that 3UTRBERT generally outperformed other contemporary methods in each of these tasks. We also showed that the self-attention mechanism within 3UTRBERT allows direct visualization of the semantic relationship between sequence elements.
Bayesian phylogenetics on globally emerging SARS-CoV-2 variant BA.2.86 suggest global distribution and rapid evolution
Authors: Rothstein Andrew P. , Qiu Xueting , Robison Keith , Collins Susan , Muir Gabi , Lu Bernadette , Plocik Alex M. , Simen Birgitte B. , Philipson Casandra W.
Published: September 2023

Using bioinformatic pipelines and Bayseian phylogenetic analyses, we characterized a SARS-CoV-2 variant designated by the World Health Organization as a variant under monitoring in August 2023. Here we analyze the genomes of this SARS-CoV-2 variant, BA.2.86, deposited into GISAID within the two weeks of its emergence (2023-08-14 first submission to 2023-08-31), including the first BA.2.86 genome reported from a traveler originating from Japan. We present bioinformatics methods using publicly available tools to help analysts identify the lineage-defining 12 nucleotide insertion (S:Ins16MPLF), which is often masked by most bioinformatics pipelines. We also applied maximum-likelihood and Bayesian phylogenetics to demonstrate the high mutational rate of the tree branch leading to the emergence of BA.2.86, hinting at possible origins, and predict that BA.2.86 emerged around May 2023 and spread globally rapidly. Taken together, these results provide a framework for more rigorous bioinformatics approaches for teams performing genomic surveillance on viral respiratory pathogens.
Topology of molecular deformations induces triphasic catch bonding in selectin-ligand bonds
Authors: Barkan Casey O. , Bruinsma Robijn F.
Published: September 2023

Among the long-standing efforts to elucidate the physical mechanisms of protein–ligand catch bonding, particular attention has been directed at the family of selectin proteins. Selectins exhibit slip, catch-slip, and slip-catch-slip bonding, with minor structural modifications causing major changes in selectins’ response to force. How can a single structural mechanism allow interconversion between these various behaviors? We present a unifying theory of selectin-ligand catch bonding, using a structurally-motivated free energy landscape to show how the topology of force-induced deformations of the molecular system produce the full range of observed behaviors. Our novel approach can be applied broadly to other protein–ligand catch bonds, and our results have implications for such future models. In particular, our model exhibits a severe breakdown of Bell’s theory—a paradigmatic theory that is widely invoked in theories of catch bonding. This raises questions about the suitability of Bell’s theory in modeling other catch bonds.
Derivation, Validation, and Prediction of Loading-Induced Mineral Apposition Rates at Endocortical and Periosteal Bone Surfaces Based on Fluid Velocity and Pore Pressure
Authors: Singh Sanjay , Singh Satwinder Jit , Prasad Jitendra
Published: September 2023

Bones adapt to mechanical forces driven by osteocytes in the lacunae canalicular network (LCN). Osteocytes sense signals such as strain, interstitial fluid flow, and pore pressure. Physiological tissue strain is insufficient to induce bone formation, and fluid flow-based models struggle to predict bone formation at both the periosteal and endocortical surfaces, simultaneously. This prompted the exploration of pore pressure’s role.

The study introduces dissipation energy density as a more significant stimulus, combining various LCN parameters, including the waveforms of both fluid velocity and pore pressure and the number of loading cycles. A pivotal achievement is the mathematical derivation of the Mineral Apposition Rate (MAR), linked proportionally to the square root of the dissipation energy density minus its reference value. This hypothesis is subjected to testing/ validation for both endocortical and periosteal surfaces for an in-vivo study on mouse tibia available in the literature.

Computational implementation of this mathematical model adopts a poroelastic finite element analysis approach, treating bone as a porous fluid-filled entity. Crucially, assumptions underpinning the model, such as the impermeability of the periosteum to fluid and the maintenance of a reference zero pressure at the endosteal surface, are corroborated by relevant experimental studies.

As a bottom line, the resulting model is the first of its kind, as it has been able to predict MAR at both endocortical and periosteal surfaces, significantly advancing our understanding of cortical bone adaptation to exogenous mechanical loading.
Recruitment and Retention in mhealth Interventions for Addiction and Problematic Substance Use: A Systematic Review
Authors: Kidd Bruce , McCormack Jessica C , Newcombe David , Garner Katie , O’Shea Azim , Humphrey Gayl
Published: September 2023

Background

Disordered and problematic addictions are significant public health issues. It has been proposed that mHealth interventions can provide new models and intervention delivery modalities. However, research shows that studies that evaluate mHealth interventions for addiction disorders have low recruitment and high attrition. This study aims to identify published peer-reviewed literature on the recruitment and retention of participants in studies of mHealth interventions for people with addiction or problematic use and to identify successful recruitment and retention strategies.

Methods

Relevant studies were identified through Medline, Embase, PsychINFO, and Cochrane Central Register of Controlled Trials (CENTRAL) after January 1998. Studies were limited to peer-reviewed literature and English language published up to 2023. The revised Cochrane Risk of Bias RoB 2 tool was used to assess the risk of bias.

Results

Of the 2135 articles found, 60 met the inclusion criteria and were included. The majority of studies were for smoking cessation. Only three studies retained 95% of participants at the longest follow-up, with ten studies retaining less than 80% at the longest follow-up, indicating a high risk of retention bias. Those studies with high retention rates used a variety of recruitment modalities; however, they also recruited from populations already partially engaged with health support services rather than those not accessing services.

Conclusions

This review of recruitment and retention outcomes with mHealth interventions highlights the need for multimodal recruitment methods. However, significant gaps in effective engagement and retention strategies limit the positive outcomes expected from mHealth interventions.
Reference frames for encoding of translation and tilt in the caudal cerebellar vermis
Authors: Buron Félix , Martin Christophe Z. , Brooks Jessica X. , Green Andrea M.
Published: September 2023

Many daily behaviors rely critically on estimates of our body’s motion and orientation in space. Vestibular signals are essential for such estimates but to contribute appropriately two key sets of computations are required. First, ambiguous motion information from the otolith organs must be combined with spatially transformed rotational signals (e.g., from the canals) to distinguish head translation from tilt. Second, tilt and translation estimates must be transformed from a head- to a body-centered reference frame to correctly interpret the body’s motion. Studies have shown that cells in the caudal cerebellar vermis (nodulus and ventral uvula, NU) reflect the output of the first set of computations to estimate translation and tilt. However, it remains unknown whether these estimates are encoded exclusively in head-centered coordinates or whether they reflect a further transformation towards body-centered coordinates. Here we addressed this question by examining how the 3D spatial tuning of otolith and canal signals on translation- and tilt-selective NU neurons varies with changes in head-re-body and body-re-gravity orientation. We show that NU cell tuning properties are consistent with head-centered coding of otolith signals during translation. Furthermore, while canals signals in the NU have been transformed into world-referenced estimates of reorientation relative to gravity (i.e., tilt), as needed to resolve the tilt-translation ambiguity, the resulting tilt estimates are encoded in head-centered coordinates. Our results thus suggest that body-centered motion and orientation estimates required for postural control, navigation and reaching are computed elsewhere either by further transforming NU outputs or via computations in other parallel pathways.
The McMaster Racialized Resident Mentorship Program Evaluation Protocol: Evaluating a racialized resident to racialized staff physician mentorship network on resident sense of belonging and medical training outcomes
Authors: Menezes Anjali , Arora Neha , Sobchak Curtis , Mercado Marck , McDonald Madeline , Monteiro Sandra , Semalulu Teresa , Agarwal Gina , Archie Suzanne ,   the DARe Group Collaborative
Published: September 2023

The McMaster Racialized Resident Mentorship Program Evaluation will formally evaluate the effectiveness of a racialized resident mentorship network at increasing racialized residents’ sense of belonging to the medical training environment and reducing the racial attainment gap in medical careers. The program is composed of three phases. Phase 1 is an acceptability study of the collection of race0based data from all matriculating residents at McMaster University. Phases 2 and 3 will focus on family medicine residents. Phase 2 is a formal program evaluation of a mentorship network connecting matriculating racialized residents with racialized physician mentors, intended to run for 24 months and using repeat focus groups to explore the impacts of the program on residents’ sense of belonging. Phase 3 is a cross sectional study of graduating family medicine residents, examining associations between residents’ identities and attainment within residency training.

The program evaluation will involve formal mentor training, a mentor Community of Practice, and mentor and resident focus groups examining experiences within the program and sense of belonging to the Department of Family Medicine and their training sites. The program process inputs will include: the number of faculty who attend mentor training, and the number of racialized faculty mentors and racialized residents who register for the program; attendance at the Community of Practice; and attendance at focus groups of mentors and residents. An exit survey will assess the number of residents who participated in the program, the duration of participation, expected graduation time, number of mentor meetings. Short term outcomes will be measured at the phase 1 survey and at program enrollment and include: resident awareness of racialized mentors, and sense of support and sense of belonging. Long-term outcomes for the program will be assessed in phase 3, examining associations between resident social identities (including race) and family medicine residency training outcomes.

The project results will represent the first investigation of racial attainment in postgraduate medical training in Canada, with changes in residents’ sense of belonging and attainment during residency as indicators of Mentorship program effectiveness.
Detection of carbapenem resistance genes inCampylobacter coliandCampylobacter jejuniisolated from chickens, and diarrheic children aged less than five years in Kampala city, Uganda
Authors: Okello Walter , Nanteza Ann , Opiyo Felix , Okello Justin , Ninsiima Lesley Rose , Marin Peter , Onafruo David , Pithua Patrick , Kankya Clovice , Odoch Terence
Published: September 2023

Campylobacterspecies are recognized as one of the significant causative agents of global foodborne illnesses and potential reservoirs for dissemination of antimicrobial resistance due to their zoonotic nature. Unlike other bacteria such asKlebsiella pneumoniae, E. coli, Enterobacter, etc.,Campylobacterhas shown limited or absent resistance to Carbapenems, critically important “last resort” antibiotics. This distinct resistance profile prompted this investigation into the prevalence of Carbapenem resistance genes inCampylobacterspecies, specificallyCampylobacter coli(C. coli) andCampylobacter jejuni(C. jejuni).

Analyses were conducted on 292 archivedC. coliandC. jejuniisolates obtained from chickens and diarrheic children under five years of age in Kampala city, Uganda. The primary objectives included assessment of phenotypic susceptibility of the isolates to Meropenem and Imipenem using the Kirby Bauer disk diffusion method, as well as determination of the occurrence of four selected Carbapenem resistance genes (blaVIM, blaNDM-1, blaIMP, and blaOXA-48) using multiplex polymerase chain reaction (PCR).

Interestingly, despite the observed phenotypic susceptibility to Meropenem and Imipenem in all theCampylobacterisolates, 29.8% harbored at least one of the four selected Carbapenem resistance genes, including blaVIM, blaNDM-1, blaIMP, and blaOXA-48. The prevalence of the resistance genes was 55(28.1%) in chickens and 15(38.5%) in children. Notably, blaVIM was the predominant gene, detected in 57.1% of the isolates, followed by blaNDM-1 (11.4%), blaIMP (8.6%), and blaOXA-48 (5.7%). Coexistence of multiple resistance genes was also observed, with blaVIM and blaIMP present in 10.0% of the isolates, and blaVIM and blaNDM-1 in 5.7%. One isolate displayed simultaneous presence of blaNDM-1, blaVIM, and blaIMP.

This study uncovered a previously unexplored realm inCampylobacterresearch, identifying Carbapenem resistance genes inCampylobacterin Uganda. The identification of these resistance genes, despite the apparent phenotypic susceptibility to Carbapenems, signifies the presence of a substantial reservoir of carbapenem resistance genes inCampylobacter.
Navigating the Neurological Aftermath of COVID-19: An In-Depth Exploration
Authors: Butt Maliha , Nagpal Shavy , Phillips Ellex , Shah Shazia Q. , Dogar Zeryab , Loh Hanyou , Mishra Sakshi , Vijayan Rupalakshmi , Jeyakumar Rishan , Makkar Sarabjot Singh , Jahan Samia , Díaz Gabriela Marie , Franca Hudson , Javed Schaza , Belizaire Marie-Pierre , Somagutta Manoj Reddy
Published: September 2023

Background

The COVID-19 pandemic caused by SARS-CoV-2 has affected millions of people and can result in both immediate and prolonged neurological effects, including severe complications. While numerous studies have explored the occurrence and consequences of neurological issues in COVID-19, they have often involved limited sample sizes.

Purpose

This paper aims to determine the overall occurrence of neurological complications in COVID-19, examine their links with patient demographics, and assess their impact on patient outcomes. Additionally, it seeks to provide an overview of the current understanding of the underlying mechanisms.

Methodology

Two systematic reviews were conducted to investigate acute and chronic neurological complications associated with COVID-19. A comprehensive search of medical databases was performed, and relevant studies were evaluated following PRISMA guidelines. Meta-analysis was carried out using the Mantel-Haenszel method, with subgroup analysis and meta-regression used to assess heterogeneity.

Results

The analysis of acute complications included 20,011 patients with an average age of 58.1 years and a slight male predominance (55.2%). Common neurological symptoms included loss of taste and smell, headaches, acute encephalopathy, and stroke. For the analysis of long-term complications, 2,094 patients were included. Survivors of COVID-19 experienced ongoing neurological issues ranging from sensory impairments to fatigue, headaches, strokes, and even cognitive and psychiatric problems.

Conclusion

By examining various neurological symptoms, this study found a significant association between these manifestations and worse overall outcomes, especially in patients over 60 years old. Identifying high-risk individuals and maintaining a high level of suspicion are crucial for enhancing our understanding of the underlying mechanisms, validating biomarkers, and improving the management of these neurological issues.
Less neutralization evasion of SARS-CoV-2 BA.2.86 than XBB sublineages and CH.1.1
Authors: Hu Yanping , Zou Jing , Kurhade Chaitanya , Deng Xiangxue , Chang Hope C. , Kim Debora K. , Shi Pei-Yong , Ren Ping , Xie Xuping
Published: September 2023

The highly mutated BA.2.86, with over 30 spike protein mutations in comparison to Omicron BA.2 and XBB.1.5 variants, has raised concerns about its potential to evade COVID-19 vaccination or prior SARS-CoV-2 infection-elicited immunity. In this study, we employ a live SARS-CoV-2 neutralization assay to compare the neutralization evasion ability of BA.2.86 with other emerged SARS-CoV-2 subvariants, including BA.2-derived CH.1.1, Delta-Omicron recombinant XBC.1.6, and XBB descendants XBB.1.5, XBB.1.16, XBB.2.3, EG.5.1 and FL.1.5.1. Our results show that BA.2.86 is less neutralization evasive than XBB sublineages. Among all the tested variants, CH.1.1 exhibits the greatest neutralization evasion. In comparison to XBB.1.5, the more recent XBB descendants, particularly EG.5.1 and FL.1.5.1, display increased resistance to neutralization induced by parental COVID-19 mRNA vaccine and a BA.5-Bivalent-booster. In contrast, XBC.1.6 shows a slight reduction but remains comparable sensitivity to neutralization when compared to BA.5. Furthermore, a recent XBB.1.5-breakthrough infection significantly enhances the breadth and potency of cross-neutralization. These findings reinforce the expectation that the upcoming XBB.1.5 mRNA vaccine would likely boost the neutralization of currently circulating variants, while also underscoring the critical importance of ongoing surveillance to monitor the evolution and immune evasion potential of SARS-CoV-2 variants.
Is the distribution of plasmid lengths bimodal?
Authors: Dewan Ian , Uecker Hildegard
Published: September 2023

The length of a plasmid is a key property which is linked to many aspects of plas-mid biology. When distributions of plasmid lengths are shown in the literature, they are usually plotted with length on a logarithmic scale. However, a quantity and its logarithm have distinct distributions which may differ considerably in shape. Mistaking the distribution of log-lengths for the distribution of lengths can therefore lead to distorted conclusions about the distribution; in particular, the distribution of log-lengths may be bimodal when the distribution of lengths is only unimodal. This particular confusion has arisen in the literature where the length distribution is often claimed to be bimodal based on examination of what is in fact the log-length distribution. While the length distribution is indeed bimodal within many bacterial families, it is not across the ensemble of all plasmids. We suggest that authors should be careful to show the plasmid length distribution, or to distinguish the two distributions, to avoid misleading inferences.

Highlights

The distributions of lengths and log-lengths of plasmids are different, and have considerably different shapes.

The typical practice of using a logarithmic scale for plasmid lengths leads to confusion between the two distributions.

In particular, the distribution of log-lengths can be bimodal when the distribution of lengths is not.

The length distribution within bacterial families is often bimodal, but across all plasmids, it is unimodal.

Clearly distinguishing between the distributions will ensure that biological conclusions drawn from them are robust.
Human Pannexin 1 Channel is NOT Phosphorylated by Src Tyrosine Kinase at Tyr199 and Tyr309
Authors: Ruan Zheng , Lee Junuk , Li Yangyang , Du Juan , Lü Wei
Published: September 2023

Protein phosphorylation is one of the major molecular mechanisms regulating protein activity and function throughout the cell. Pannexin 1 (PANX1) is a large-pore channel permeable to ATP and other cellular metabolites. Its tyrosine phosphorylation and subsequent activation have been found to play critical roles in diverse cellular conditions, including neuronal cell death, acute inflammation, and smooth muscle contraction. Specifically, the non-receptor kinase Src has been reported to phosphorylate Tyr198 and Tyr308 of mouse PANX1 (equivalent to Tyr199 and Tyr309 of human PANX1), resulting in channel opening and ATP release. Although the Src-dependent PANX1 activation mechanism has been widely discussed in the literature, independent validation of the tyrosine phosphorylation of PANX1 has been lacking. Here, we show that commercially available antibodies against the two phosphorylation sites mentioned above—which were used to identify endogenous PANX1 phosphorylation at these two sites— are nonspecific and should not be used to interpret results related to PANX1 phosphorylation. We further provide evidence that neither tyrosine residue is a major phosphorylation site for Src kinase in heterologous expression systems. We call on the field to re-examine the existing paradigm of tyrosine phosphorylation-dependent activation of the PANX1 channel.
Association between Haloperidol use and Risk of Rheumatoid Arthritis
Authors: Ambati Vidya L. , Cummings Tammy H. , Yerramothu Praveen , Nguyen Joseph , Sutton S. Scott , Werner Brian C. , Magagnoli Joseph
Published: September 2023

Haloperidol is an anti-psychotic used for the treatment of schizophrenia or Tourette disorder. Here we report, by studying three large administrative health insurance databases, that haloperidol use is associated with a reduced risk of developing rheumatoid arthritis. A meta-analysis revealed a 31% reduced hazard of incident rheumatoid arthritis among individuals with schizophrenia or Tourette disorder treated with haloperidol compared to those treated with other anti-psychotic drugs. These findings suggest a potential benefit of haloperidol in rheumatoid arthritis and provide a rationale for randomized controlled trials to provide causal insights.
Building National Patient Registries in Mexico: Insights from the MexOMICS Consortium
Authors: Reyes-Perez Paula , Hernández-Ledesma Ana Laura , Román-López Talía V. , García-Vilchis Brisa , Ramírez-González Diego , Lázaro-Figueroa Alejandra , Martínez Domingo , Flores-Ocampo Victor , Espinosa-Méndez Ian M. , Rentería Miguel E. , Ruíz-Contreras Alejandra E. , Alcauter Sarael , Medina-Rivera Alejandra
Published: September 2023

OBJECTIVE

To introduce MexOMICS, a Mexican Consortium focused on establishing electronic databases to collect, cross-reference, and share health-related and omics data on the Mexican population.

METHODS

The Mexican Twin Registry (TwinsMX), Mexican Lupus Registry (LupusRGMX) and the Mexican Parkinson’s Research Network (Mex-PD) were designed and implemented using Research Electronic Data Capture web-based application. Registries were compiled through voluntary participation and on-site engagement with medical specialists. In some instances, DNA samples and Magnetic Resonance Imaging images were also acquired.

RESULTS

Since 2019, the MexOMICS Consortium has successfully established three electronic-based registries: TwinsMX (n=2915), LupusRGMX (n=1761) and Mex-PD (n=750). In addition to sociodemographic, psychosocial, and clinical data, MexOMICS has collected samples for genetic determinations across the three registries. Cognitive function assessments, conducted using the Montreal Cognitive Assessment, have been administered to a subsample of 376 Mex-PD participants. Furthermore, a subset of 267 twins underwent measurements of structural, functional, and spectroscopy brain images; comparable evaluations are projected for LupusRGMX and Mex-PD.

CONCLUSIONS

The MexOMICS registries offer a valuable repository of information concerning the potential interplay of genetic and environmental factors in health conditions among the Mexican population.
Plasma proteins identify increased number of carotid plaques and predict occurring atherosclerotic events
Authors: Baragetti A , Grigore L , Olmastroni E , Mattavelli E , Catapano AL
Published: September 2023

Background

The number of carotid plaques independently predicts incident atherosclerotic cardiovascular disease (ACVD).

However, performing vascular imaging in apparently healthy subjects is challenging, owing organizational/economical barriers. Plasma proteomics can offer an alternative approach to identify individuals with carotid plaques, at high risk of eventually developing ACVD.

Methods

In this observational study, we studied by Normalized Protein eXpression (NPX; OlinkTM), the plasma levels of 368 proteins in 664 subjects from the PLIC study, who were screened by ultrasound for the presence of carotid plaques. We clustered, by artificial intelligence, the proteins that more accurately identified subjects, stratifying them according to the number of plaques they presented with. We also study prediction of occurring events over 22 years.

Results

299/664 subjects had at least 1 carotid plaque. Among those, 77 subjects presented with only one plaque, 101 with 2 plaques and 121 with ≥3 plaques (3+). The remaining 365 subjects with no plaques acted as controls. The proteins differently expressed versus controls increased as a function of the number of plaques. 32 proteins were shared among the groups of subjects with plaques, but 87, significantly associated with the presence of 3+ plaques, improved the AUC of the ROC, together with the ACVD risk factors, to discriminate subjects with 3+ plaques versus the AUC of the ROC considering the ACVD risk factors only (AUC= 0.918 (0.887-0.943) vs AUC= 0.760 (0.716-0.801) respectively, p<0.001). The ACVD risk factors barely predicted the 198 occurring events (AUC= 0.559 (0.521-0.598)), but proteomics associated with plaques improved the prediction (AUC= 0.739 (0.704-0.773), p<0.001).

By analyzing the biological processes, we identified that chemotaxis/migration of leukocytes and the signaling of interleukins/cytokines were the top pathways involved.

Conclusions

Plasma proteomics helps to identify apparently healthy subjects with higher number of carotid plaques more accurately and to predict occurring ACVDs in those individuals.
Voice as a Biomarker to Detect Acute Decompensated Heart Failure: Pilot Study for the Analysis of Voice Using Deep Learning Models
Authors: Lee Jieun , Kim Gwantae , Ham Insung , Ko Kyungdeuk , Park Soohyung , Choi You-Jung , Kang Dong Oh , Choi Jah Yeon , Park Eun Jin , Lee Sunki , Roh Seung Young , Lee Dae-In , Na Jin Oh , Choi Cheol Ung , Kim Jin Won , Rha Seung-Woon , Park Chang Gyu , Kim Eung Ju , Ko Hanseok
Published: September 2023

Background

Acute decompensated heart failure (ADHF) is a systemic congestion state requiring timely management. Admission for ADHF is closely related to the readmission and post-discharge mortality in patients, which makes it imperative to detect ADHF in its early stage.

Methods

Patients with ADHF needed admission were eligible for enrollment, and those with respiratory infection, sepsis, lung/vocal cord disease, acute coronary syndrome, or serum creatinine>3mg/dL were excluded. A total of 112 patients were enrolled between July, 2020 and December, 2022. Voice was recorded two times: at admission for ADHF, and at discharge. Patients were asked to phonate five Korean vowels (‘a/e/i/o/u’) for 3 seconds each, and then to repeat the sentence ‘daehan minkook manse’ five times. Low-level audio features were extracted for classification. Then, Mel-Spectrogram was extracted from waveform and used as input features of the deep learning-based classification models. Two kinds of the deep learning-based classification models, convolutional neural networks and Transformer, were adapted for the further analysis.

Results

For 100 patients in the final analysis, we randomized patients into two mutually exclusive groups: a training group (n=88) and a test group (n=12). In the analysis with low-level audio features, harmonics-to-noise ratio and Shimmer showed classification potential. Then, deep learning models were trained to classify whether certain voice belongs to ADHF state or recovered state. We treated it as a binary classification task, and the best performing model achieved a classification accuracy of 85.11% with DenseNet201. The classification accuracy was improved as 92.76% with ViT-16-large after inputting additional classic features of heart failure. With adding the low-level audio features in a training process, classification task accuracy was improved in DenseNet201 for about 2%.

Conclusions

Our results proposed the clinical possibility of voice as a useful and noninvasive biomarker to detect ADHF in its early stage.
In Vivo Structural Connectivity of the Reward System Along the Hippocampal Long-Axis
Authors: Elliott Blake L. , Mohyee Raana , Ballard Ian C. , Olson Ingrid R. , Ellman Lauren M. , Murty Vishnu P.
Published: September 2023

Recent work has identified a critical role for the hippocampus in reward-sensitive behaviors, including motivated memory, reinforcement learning, and decision-making. Animal histology and human functional neuroimaging have shown that brain regions involved in reward processing and motivation are more interconnected with the ventral/anterior hippocampus. However, direct evidence examining gradients of structural connectivity between reward regions and the hippocampus in humans is lacking. The present study used diffusion MRI and probabilistic tractography to quantify the structural connectivity of the hippocampus with key reward processing regions in vivo. Using a large sample of subjects (N=628) from the human connectome dMRI data release, we found that connectivity profiles with the hippocampus varied widely between different regions of the reward circuit. While the dopaminergic midbrain (VTA) showed stronger connectivity with the anterior versus posterior hippocampus, the vmPFC showed stronger connectivity with the posterior hippocampus. The nucleus accumbens (NAc) showed a more homogeneous connectivity profile along the hippocampal long-axis. This is the first study to generate a probabilistic atlas of the hippocampal structural connectivity with reward-related networks, which is essential to investigating how these circuits contribute to normative adaptive behavior and maladaptive behaviors in psychiatric illness. These findings describe nuanced structural connectivity that sets the foundation to better understand how the hippocampus influences reward-guided behavior in humans.
The high infectivity of the SARS-CoV-2 Omicron variant is associated with an exclusive S477N spike receptor-binding domain mutation
Authors: Santos Jadson C. , Tamarozzi Elvira R. , Dametto Mariangela , Bonacin Rodrigo , Donadi Eduardo A. , Passos Geraldo Aleixo
Published: September 2023

The spike glycoprotein receptor-binding domain (RBD) of SARS-CoV-2 facilitates viral binding to the ACE2 receptor and mediates viral infectivity. The Delta and Omicron variants of concern are the most infectious strains, presenting mutated amino acid residues in their spike RBD. The Omicron variant quickly dominated the COVID-19 pandemic, indicating its greater spreadability. Omicron’s spreading might be associated with mutational substitutions at spike RBD residues. We employedin silicomolecular dynamics (MD) simulation of the spike RBD-ACE2 interaction to compare the impact of specific mutations of the Delta and Omicron variants. The MD of the spike-ACE2 interaction showed the following: i) the amino acid profile involved in the spike-ACE2 interaction differs between Delta and Omicron; ii) the Omicron variant establishes several additional interactions, highlighting the spike RBD (S477), which is a flexible mutational residue. Since the S477N mutation is exclusive to Omicron, which may initiate binding with ACE2, the increased infectivity of Omicron might be associated not only with a mutated RBD but also with unmutated (e.g., G476 and L492) residues, initiating binding due to the influence of the N477 mutation. Compared to previous variants, Omicron’s N477 residue represents a novelty within the spike-ACE2 interaction dynamics interface.
APlasmodium falciparumMORC protein complex modulates epigenetic control of gene expression through interaction with heterochromatin
Authors: Singh Maneesh Kumar , Bonnell Victoria A. , Da Silva Israel Tojal , Santiago Verônica Feijoli , Moraes Miriam S. , Adderley Jack , Doerig Christian , Palmisano Giuseppe , Llinás Manuel , Garcia Célia R. S.
Published: September 2023

Dynamic control of gene expression is critical for blood stage development of malaria parasites. Here, we used multi-omic analyses to investigate transcriptional regulation by the chromatin-associated microrchidia protein, MORC, during asexual blood stage development of the human malaria parasitePlasmodium falciparum. We show thatPfMORC (PF3D7_1468100) interacts with a suite of nuclear proteins, including APETALA2 (AP2) transcription factors (PfAP2-G5,PfAP2-O5,PfAP2-I, PF3D7_0420300, PF3D7_0613800, PF3D7_1107800, and PF3D7_1239200), a DNA helicase DS60 (PF3D7_1227100), and other chromatin remodelers (PfCHD1 andPfEELM2). Transcriptomic analysis ofPfMORCHA-glmSknockdown parasites revealed 163 differentially expressed genes belonging to hypervariable multigene families, along with upregulation of genes mostly involved in host cell invasion.In vivogenome-wide chromatin occupancy analysis during both trophozoite and schizont stages of development demonstrates thatPfMORC is recruited to repressed, multigene families, including thevargenes in subtelomeric chromosomal regions. Collectively, we find thatPfMORC is found in chromatin complexes that play a role in the epigenetic control of asexual blood stage transcriptional regulation and chromatin organization.
Design and validation of a PCR protocol to specifically detect the clade ofPhilastersp. associated withDiadema antillarumscuticociliatosis
Authors: Vilanova-Cuevas Brayan Y. , Reyes-Chavez Brandon , Breitbart Mya , Hewson Ian
Published: September 2023

Diadema antillarumscuticociliatosis (DaSc), caused by a scuticociliate closely related toPhilaster apodigitiformis, has affected Caribbean long-spined urchins since at least January 2022. Quantitative PCR (qPCR) is currently the standard method for detection of this ciliate in tissue and coelomic fluid samples, yet this method requires specialized equipment and is more expensive than standard PCR methods. The DaSc scuticociliate occurs against a backdrop of endo- and ecto-symbiotic ciliates which complicate detection using universal or pan-phylum PCR primer sets. To overcome these limitations, we designed and validated a sensitive and specific PCR primer (scutico-634F) and nested two-step PCR protocol to detect this taxon, which excludes other ciliates associated withD. antillarumand has poor affinity for other related ciliates. This primer and protocol for the DaSc-associated Philaster clade (DaScPc) allow for widely-accessible investigation of this pathogen in new regions and within environmental reservoirs.
Temperature and transmission: novel estimates of the effects of temperature on the human malaria parasite,Plasmodium falciparum
Authors: Suh Eunho , Stopard Isaac J. , Lambert Ben , Waite Jessica L. , Dennington Nina L. , Churcher Thomas S. , Thomas Matthew B.
Published: September 2023

Malaria transmission is strongly influenced by traits such as mosquito life expectancy, vector competence, and the Extrinsic Incubation Period (EIP, which is the development time of the parasite inside the mosquito). Even though these traits are known to be shaped by environmental temperature and there is considerable concern that climate change could increase disease risk in certain areas, surprisingly, these temperature dependencies are poorly characterized. Here, we use a mechanistic model fitted to novel experimental data to describe howPlasmodium falciparuminfection of the African malaria vector,Anopheles gambiae,is modulated by temperature, including its influences on parasite establishment, conversion efficiency through parasite developmental stages, EIP and overall competence. We use these data, together with novel estimates of the survival of infected blood-fed mosquitoes, to explore the potential influence of temperature on transmission in four locations in Kenya, considering recent conditions and future climate change. Results provide insights into factors limiting transmission in cooler environments and indicate that increases in malaria transmission efficiency due to climate warming in areas like the Kenyan Highlands, might be less than previously predicted.
Biological and Genetic Determinants of Glycolysis: Phosphofructokinase Isoforms Boost Energy Status of Stored Red Blood Cells and Transfusion Outcomes
Authors: Nemkov Travis , Stephenson Daniel , Earley Eric J. , Keele Gregory R , Hay Ariel , Key Alicia , Haiman Zachary , Erickson Christopher , Dzieciatkowska Monika , Reisz Julie A. , Moore Amy , Stone Mars , Deng Xutao , Kleinman Steven , Spitalnik Steven L , Hod Eldad A , Hudson Krystalyn E , Hansen Kirk C , Palsson Bernhard O. , Churchill Gary A , Roubinian Nareg , Norris Philip J. , Busch Michael P. , Zimring James C , Page Grier P. , D’Alessandro Angelo
Published: September 2023

Mature red blood cells (RBCs) lack mitochondria, and thus exclusively rely on glycolysis to generate adenosine triphosphate (ATP) during aging in vivo or storage in the blood bank. Here we leveraged 13,029 volunteers from the Recipient Epidemiology and Donor Evaluation Study to identify an association between end-of-storage levels of glycolytic metabolites and donor age, sex, and ancestry-specific genetic polymorphisms in regions encoding phosphofructokinase 1, platelet (detected in mature RBCs), hexokinase 1, ADP-ribosyl cyclase 1 and 2 (CD38/BST1). Gene-metabolite associations were validated in fresh and stored RBCs from 525 Diversity Outbred mice, and via multi-omics characterization of 1,929 samples from 643 human RBC units during storage. ATP and hypoxanthine levels – and the genetic traits linked to them – were associated with hemolysis in vitro and in vivo, both in healthy autologous transfusion recipients and in 5,816 critically ill patients receiving heterologous transfusions, suggesting their potential as markers to improve transfusion outcomes.

eTOC and Highlights

Highlights

Blood donor age and sex affect glycolysis in stored RBCs from 13,029 volunteers;

Ancestry, genetic polymorphisms in PFKP, HK1, CD38/BST1 influence RBC glycolysis;

Modeled PFKP effects relate to preventing loss of the total AXP pool in stored RBCs;

ATP and hypoxanthine are biomarkers of hemolysis in vitro and in vivo.
PfMORC protein regulates chromatin accessibility and transcriptional repression in the human malaria parasite,Plasmodium falciparum
Authors: Chahine Z , Gupta M , Lenz T , Hollin T , Abel S , Banks CAS , Saraf A , Prudhomme J , Bhanvadia S , Florens L , Le Roch KG
Published: September 2023

The environmental challenges the human malaria parasite,Plasmodium falciparum, faces during its progression into its various lifecycle stages warrant the use of effective and highly regulated access to chromatin for transcriptional regulation. Microrchidia (MORC) proteins have been implicated in DNA compaction and gene silencing across plant and animal kingdoms. Accumulating evidence has shed light into the role MORC protein plays as a transcriptional switch in apicomplexan parasites. In this study, using CRISPR/Cas9 genome editing tool along with complementary molecular and genomics approaches, we demonstrate thatPfMORC not only modulates chromatin structure and heterochromatin formation throughout the parasite erythrocytic cycle, but is also essential to the parasite survival. Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) experiments suggest thatPfMORC binds to not only sub-telomeric regions and genes involved in antigenic variation but may also play a role in modulating stage transition. Protein knockdown experiments followed by chromatin conformation capture (Hi-C) studies indicate that downregulation ofPfMORC impairs key histone marks and induces the collapse of the parasite heterochromatin structure leading to its death. All together these findings confirm thatPfMORC plays a crucial role in chromatin structure and gene regulation, validating this factor as a strong candidate for novel antimalarial strategies.