bluuebunny/crossref_metadata_2025 huggingface dataset:
Fire in the bog: responses of peatland vegetation in the Australian Alps to fire
Authors: McDougall Keith L. , Whinam Jennie , Coates Fiona , Morgan John W. , Walsh Neville G. , Wright Genevieve T. , Hope Geoff S.
Published: April 2023

Context Peatlands in the Australian Alps are important ecologically and recognised in national environmental legislation. Increasing fire frequency over the past 40 years has put the community at greater risk of degradation. Aims Using published studies of fire effects in peatlands and new data, we investigate general responses of peatlands to fire so that risk can be evaluated and appropriate management adopted. Methods We present four case studies that employ repeated measures of floristic composition or chronosequences to assess fire-related changes. Key results Cover of frequently-occurring species declined after fire but most had returned to pre-fire cover after 10 years. Recovery of the obligate seeder shrub Dracophyllum continentis (B.L.Burtt) S.Venter and the dominant moss Sphagnum cristatum Hampe was much slower, but variable for the latter, apparently depending on fire intensity and post-fire moisture availability; both species favoured less frequently burnt peatlands with high soil moisture. Some herbs (including non-native species) benefitted from fire, briefly becoming abundant soon afterwards. Overall species richness and diversity were unaffected by fire. Conclusions Peatlands in the Australian Alps tend to be resilient to single fires with effects on species composition being short-lived. However, species cover (especially Sphagnum cristatum) requires perhaps 20 years between fires for full recovery. Fire can cause localised community extinction and this is likely to be exacerbated by other pressures such as trampling and drought. Implications Fire will be difficult to manage in peatlands but resilience might be built by removing other pressures such as trampling by feral animals.
Progress on Poverty in Africa: The Importance of Growth and Inequality
Authors: Fosu Augustin Kwasi
Published: April 2023

Employing World Bank data, this paper, first, historically examines Africa's record on poverty incidence, spread and severity, as compared with other regions of the world, at the US$1.90 and US$3.20 per day (2011 PPP) poverty standards. Second, it evaluates country-specific progress on growth, poverty and inequality, and compares the ‘poverty transformation efficiency vector’ (PTEV) among African countries. Third, the study analyses the relative roles of income growth and inequality changes in explaining African countries' poverty records, through a decomposition of poverty changes using ‘optimal’ income and inequality elasticity estimates from the ‘identity’ model. The study finds that following the dismal record on poverty during the 1980s, progress on poverty has been appreciable since Africa's growth resurgence starting in the mid-1990s, and that this progress was driven mainly by income growth, consistent with the global evidence. Nonetheless, inequality often played a complementary role in most of the countries and, in a small number of cases, it was the primary driver of changes in poverty. Thus, the present study sheds light on country-specific differences in the relative roles of growth and inequality in poverty reduction on the continent, based on both qualitative and quantitative evidence. The study should, therefore, provide a useful compass to those who seek to understand country-specific situations within the African context.
Reliability of the Galactomannan Enzyme-Linked Immunoassay in Healthy Preterm Infants: A Prospective Cohort Study
Authors: Thomann Janine , Bryant Manuel B , Gaertner Vincent D , Marchesi Martina , Zbinden Andrea , Zbinden Reinhard , Bassler Dirk , Rüegger Christoph M
Published: April 2023

In healthy preterm infants, the galactomannan enzyme-linked immunoassay shows a high rate of positive results and should not be used for the early diagnosis of invasive aspergillosis, particularly in the very preterm age group.
International Portfolio Choice with Frictions: Evidence from Mutual Funds
Authors: Bacchetta Philippe , Tièche Simon , van Wincoop Eric
Published: April 2023

Using data on international equity portfolio allocations by U.S. mutual funds, we estimate a portfolio expression derived from a standard mean-variance portfolio model extended with portfolio frictions. The optimal portfolio depends on the previous month and the buy-and-hold portfolio shares, and a present discounted value of expected excess returns. We estimate expected return differentials and use them in the portfolio regressions. The estimates imply significant portfolio frictions and a modest rate of risk aversion. While mutual fund portfolios significantly respond to expected returns, portfolio frictions lead to a weaker and a more gradual portfolio response to changes in expected returns.

Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Patient-Specific iPSC-Derived Models Link Aberrant Endoplasmic Reticulum Stress Sensing and Response to Juvenile Osteochondritis Dissecans Etiology
Authors: Salazar-Noratto Giuliana E , Nations Catriana C , Stevens Hazel Y , Xu Maojia , Gaynard Sean , Dooley Claire , de Nijs Nica , McDonagh Katya , Shen Sanbing , Willimon S Clifton , Barry Frank , Guldberg Robert E
Published: April 2023

Juvenile osteochondritis dissecans (JOCD) is a pediatric disease, which begins with an osteonecrotic lesion in the secondary ossification center which, over time, results in the separation of the necrotic fragment from the parent bone. JOCD predisposes to early-onset osteoarthritis. However, the knowledge gap in JOCD pathomechanisms severely limits current therapeutic strategies. To elucidate its etiology, we conducted a study with induced pluripotent stem cells (iPSCs) from JOCD and control patients. iPSCs from skin biopsies were differentiated to iMSCs (iPSC-derived mesenchymal stromal cells) and subjected to chondrogenic and endochondral ossification, and endoplasmic reticulum (ER)-stress induction assays. Our study, using 3 JOCD donors, showed that JOCD cells have lower chondrogenic capability and their endochondral ossification process differs from control cells; yet, JOCD- and control-cells accomplish osteogenesis of similar quality. Our findings show that endoplasmic reticulum stress sensing and response mechanisms in JOCD cells, which partially regulate chondrocyte and osteoblast differentiation, are related to these differences. We suggest that JOCD cells are more sensitive to ER stress than control cells, and in pathological microenvironments, such as microtrauma and micro-ischemia, JOCD pathogenesis pathways may be initiated. This study is the first, to the best of our knowledge, to realize the important role that resident cells and their differentiating counterparts play in JOCD and to put forth a novel etiological hypothesis that seeks to consolidate and explain previously postulated hypotheses. Furthermore, our results establish well-characterized JOCD-specific iPSC-derived in vitro models and identified potential targets which could be used to improve diagnostic tools and therapeutic strategies in JOCD.
Daratumumab-lenalidomide and daratumumab-pomalidomide in relapsed lenalidomide-exposed or refractory multiple myeloma
Authors: Alhaj Moustafa Muhamad , Parrondo Ricardo , Abdulazeez Mays F. , Roy Vivek , Sher Taimur , Alegria Victoria R. , Warsame Rahma M. , Fonseca Rafael , Rasheed Ahsan , Gonsalves Wilson I. , Kourelis Taxiarchis , Kapoor Prashant , Buadi Francis K. , Dingli David , Hayman Suzanne R. , Reeder Craig B. , Chanan-Khan Asher A. , Ailawadhi Sikander
Published: April 2023

Daratumumab is an anti-CD38 mAb, used frequently in combination with lenalidomide and pomalidomide. No studies compared daratumumab plus lenalidomide and dexamethasone (DRd) to daratumumab plus pomalidomide and dexamethasone (DPd) in lenalidomide-exposed multiple myeloma. We identified 504 consecutive multiple myeloma patients who received daratumumab at Mayo Clinic between January 2015 and April 2019. We excluded patients who received daratumumab in the first line, received more than four lines of therapy prior to daratumumab use, did not receive lenalidomide prior to daratumumab, or had an unknown status of lenalidomide exposure, and patients who received daratumumab combinations other than DRd or DPd. We examined the impact of using DRd compared to DPd on progression-free survival (PFS) and overall survival (OS) in patients with relapsed/refractory multiple myeloma. Out of 504 patients, 162 received DRd or DPd and were included; 67 were lenalidomide-exposed and 95 were lenalidomide-refractory. DRd was used in 76 (47%) and DPd in 86 (53%) patients. In lenalidomide-exposed multiple myeloma, there was no difference in median PFS; 34.2 months [95% confidence interval (CI), 22.8–44.6] for DRd compared to 25.2 months (95% CI, 4.9–35.3) for DPd, P = 0.2. In lenalidomide-refractory multiple myeloma, there was no difference in median PFS; 18.6 months (95% CI, 13–32) for DRd compared to 9 months (95% CI, 5.2–14.6) for DPd, P = 0.09. No difference in median OS was observed in DRd compared to DPd. Our study shows combining daratumumab with lenalidomide in patients with prior lenalidomide use is a viable and effective treatment option.
A Study of Cardiac Outcomes After Droperidol Administration in an Inpatient Psychiatric Cohort
Authors: Yang Tim Zong Tian , Lew Chen , Ilangamage Anushi Thathsara , Gillies Robert Donald , Kulkarni Jayashri
Published: April 2023

Purpose/Background

Droperidol is an antipsychotic medication used in psychiatric emergencies to manage acute behavioral disturbance. Droperidol use carries a risk of prolonged QT interval on the electrocardiogram and associated cardiac arrhythmias including torsades de pointes and ventricular fibrillation. This study aimed to evaluate the safety of droperidol in adults admitted to the psychiatric inpatient unit of a large Australian hospital.

Methods/Procedures

In this retrospective cohort study, psychiatric inpatients admitted between October 22, 2018, and March 1, 2021, who received at least 1 dose of intramuscular droperidol were consecutively included. Outcomes of interest were death, cardiac arrhythmias, and QT prolongation. QT prolongation was identified using the QT-interval nomogram.

Findings/Results

This study included 263 patients without exclusion. No deaths or cases of cardiac arrhythmia were recorded within 24 hours of droperidol administration. Electrocardiogram data were available for 41.1% of patients (n = 108) within 7 days of droperidol administration. Two cases of QT prolongation were identified using the QT-interval nomogram, but these patients were also prescribed other medications that may have contributed to QT prolongation.

Implications/Conclusions

This study contributes the first known large retrospective study of safety outcomes including QT prolongation after droperidol administration in a psychiatric inpatient setting. Our findings corroborate mounting evidence supporting the clinical safety of droperidol use in psychiatric settings. Nonetheless, we note that significant barriers remain with regard to timely electrocardiogram monitoring after droperidol use.
Clozapine Use for Bipolar Disorder
Authors: Loo Lek Wei Javier , Chew Qian Hui , Lin Shih-Ku , Yang Su-Yu , Ouyang Wen-Chen , Chen Chih-Ken , Park Seon-Cheol , Jang Ok-Jin , Park Jun Hyuk , Chee Kok-Yoon , Ding Kwong Sen , Chong Jamaline , Zhang Ling , Li Keqing , Zhu Xiaomin , Jatchavala Chonnakarn , Pariwatcharakul Pornjira , Kallivayalil Roy A. , Grover Sandeep , Avasthi Ajit , Ansari Moin , Maramis Margarita M. , Aung Paing Phyo , Sartorius Norman , Xiang Yu-Tao , Tan Chay-Hoon , Chong Mian-Yoon , Park Yong Chon , Kato Takahiro A. , Shinfuku Naotaka , Baldessarini Ross J. , Sim Kang
Published: April 2023

Background

Pharmacoepidemiological studies of clozapine use to treat bipolar disorder (BD), especially in Asia, are rare, although they can provide insights into associated clinical characteristics and support international comparisons of indications and drug dosing.

Methods

We examined the prevalence and clinical correlates of clozapine treatment for BD in 13 Asian countries and regions (China, Hong Kong SAR, India, Indonesia, Japan, Korea, Malaysia, Myanmar, Pakistan, Singapore, Sri Lanka, Taiwan, and Thailand) within an Asian Prescription Patterns Research Consortium. We compared BD patients treated with clozapine or not in initial bivariate comparisons followed by multivariable logistic regression modeling.

Results

Clozapine was given to 2.13% of BD patients overall, at a mean daily dose of 275 (confidence interval, 267–282) chlorpromazine-equivalent mg/day. Patients receiving clozapine were older, more likely males, hospitalized, currently manic, and given greater numbers of mood-stabilizing and antipsychotic drugs in addition to clozapine. Logistic regression revealed that older age, male sex, current mania, and greater number of other antipsychotics remained significantly associated with clozapine treatment. Clozapine use was not associated with depressed mood, remission of illness, suicidal risk, or electroconvulsive treatment within the previous 12 months.

Conclusions

The identified associations of clozapine use with particular clinical features call for vigilance in personalized clinical monitoring so as to optimize clinical outcomes of BD patients and to limit risks of adverse effects of polytherapy.
Unsupervised Machine Learning Unveil Easily Identifiable Subphenotypes of COVID-19 With Differing Disease Trajectories
Authors: Chen Jacky , Hsu Jocelyn , Szewc Alexandra , Balucini Clotilde , Azad Tej D. , Gong Kirby , Kim Han , Stevens Robert D
Published: April 2023

Background

Given the clinical heterogeneity of COVID-19 infection, we hypothesize the existence of subphenotypes based on early inflammatory responses that are associated with mortality and additional complications.

Methods

For this cross-sectional study, we extracted electronic health data from adults hospitalized patients between March 1, 2020 and May 5, 2021, with confirmed primary diagnosis of COVID-19 across five Johns Hopkins Hospitals. We obtained all electronic health records from the first 24h of the patient’s hospitalization. Mortality was the primary endpoint explored while myocardial infarction (MI), pulmonary embolism (PE), deep vein thrombosis (DVT), stroke, delirium, length of stay (LOS), ICU admission and intubation status were secondary outcomes of interest. First, we employed clustering analysis to identify COVID-19 subphenotypes on admission with only biomarker data and assigned each patient to a subphenotype. We then performed Chi-Squared and Mann-Whitney-U tests to examine associations between COVID-19 subphenotype assignment and outcomes. In addition, correlations between subphenotype and pre-existing comorbidities were measured using Chi-Squared analysis.

Results

A total of 7076 patients were included. Analysis revealed three distinct subgroups by level of inflammation: hypoinflammatory, intermediate, and hyperinflammatory subphenotypes. More than 25% of patients in the hyperinflammatory subphenotype died compared to less than 3% hypoinflammatory subphenotype (p<0.05). Additional analysis found statistically significant increases in the rate of MI, DVT, PE, stroke, delirium and ICU admission as well as LOS in the hyperinflammatory subphenotype.

Conclusion

We identify three distinct inflammatory subphenotypes that predict a range of outcomes, including mortality, MI, DVT, PE, stroke, delirium, ICU admission and LOS. The three subphenotypes are easily identifiable and may aid in clinical decision making.
Online health search via multi-dimensional information quality assessment based on deep language models
Authors: Zhang Boya , Naderi Nona , Mishra Rahul , Teodoro Douglas
Published: April 2023

Background

Widespread misinformation in Web resources can lead to serious implications for individuals seeking health advice. Despite that, information retrieval models are often focused only on the query-document relevance dimension to rank results.

Objective

We investigate a multi-dimensional information quality retrieval model based on deep learning to enhance the effectiveness of online healthcare information search results.

Methods

In this study, we simulated online health information search scenarios with a topic set of 32 different health-related inquiries and a corpus containing one billion Web documents from the April 2019 snapshot of Common Crawl. Using state-of-the-art pre-trained language models, we assessed the quality of the retrieved documents according to their usefulness, supportiveness, and credibility dimensions for a given search query on 6,030 human-annotated query-document pairs. We evaluated this approach using transfer learning and more specific domain adaptation techniques.

Results

In the transfer learning setting, the usefulness model provided the largest distinction between help- and harm-compatible documents with a difference of +5.6%, leading to a majority of helpful documents in the top-10 retrieved. The supportiveness model achieved the best harm compatibility (+2.4%), while the combination of usefulness, supportiveness, and credibility models achieved the largest distinction between help- and harm-compatibility on helpful topics (+16.9%). In the domain adaptation setting, the linear combination of different models showed robust performance with help-harm compatibility above +4.4% for all dimensions and going as high as +6.8%.

Conclusions

These results suggest that integrating automatic ranking models created for specific information quality dimensions can increase the effectiveness of health-related information retrieval. Thus, our approach could be used to enhance searches made by individuals seeking online health information.
Halophilic nematodes live in America’s Dead Sea
Authors: Jung Julie , Loschko Tobias , Reich Shelley , Werner Michael S.
Published: April 2023

Extremophiles can reveal the origins of life on Earth and the possibility of life elsewhere. Most identified extremophiles are single-cell microbes, leaving gaps in our knowledge concerning the origins and habitable limits of multicellular organisms. Here, we report the recovery of roundworms (Phylum Nematoda) from the Great Salt Lake (GSL), UT, a hypersaline lake referred to as “America’s Dead Sea”. Nematodes were found primarily in microbialites, benthic organosedimentary structures once abundant on early Earth. 16S sequencing of individual nematodes revealed a diverse bacterial community distinct from its surrounding habitat. Phylogenetic divergence compared to Owens Lake, another terminal lake in the Great Basin, suggests that GSL nematodes represent multiple previously undescribed species. These findings update our understanding of halophile ecosystems and the habitable limit of animals.

One-Sentence Summary

We report the discovery of novel halophilic nematodes in microbialites of the Great Salt Lake, UT.
An Exploratory Multi-Session Study of Learning High-Dimensional Body-Machine Interfacing for Assistive Robot Control
Authors: Lee Jongmin M. , Gebrekristos Temesgen , De Santis Dalia , Nejati-Javaremi Mahdieh , Gopinath Deepak , Parikh Biraj , Mussa-Ivaldi Ferdinando A. , Argall Brenna D.
Published: April 2023

Individuals who suffer from severe paralysis often lose the capacity to perform fundamental body movements and everyday activities. Empowering these individuals with the ability to operate robotic arms, in high-dimensions, helps to maximize both functional utility and human agency. However, high-dimensional robot teleoperation currently lacks accessibility due to the challenge in capturing high-dimensional control signals from the human, especially in the face of motor impairments. Body-machine interfacing is a viable option that offers the necessary high-dimensional motion capture, and it moreover is noninvasive, affordable, and promotes movement and motor recovery. Nevertheless, to what extent body-machine interfacing is able to scale to high-dimensional robot control, and whether it is feasible for humans to learn, remains an open question. In this exploratory multi-session study, we demonstrate the feasibility of human learning to operate a body-machine interface to control a complex, assistive robotic arm in reaching and Activities of Daily Living tasks. Our results suggest the manner of control space mapping, from interface to robot, to play a critical role in the evolution of human learning.
Context-Aware Amino Acid Embedding Advances Analysis of TCR-Epitope Interactions
Authors: Zhang Pengfei , Bang Seojin , Cai Michael , Lee Heewook
Published: April 2023

Accurate prediction of binding interaction between T cell receptors (TCRs) and host cells is fundamental to understanding the regulation of the adaptive immune system as well as to developing data-driven approaches for personalized immunotherapy. While several machine learning models have been developed for this prediction task, the question of how to specifically embed TCR sequences into numeric representations remains largely unexplored compared to protein sequences in general. Here, we investigate whether the embedding models designed for protein sequences, and the most widely used BLOSUM-based embedding techniques are suitable for TCR analysis. Additionally, we present our context-aware amino acid embedding models (catELMo) designed explicitly for TCR analysis and trained on 4M unlabeled TCR sequences with no supervision. We validate the effectiveness ofcatELMoin both supervised and unsupervised scenarios by stacking the simplest models on top of our learned embeddings. For the supervised task, we choose the binding affinity prediction problem of TCR and epitope sequences and demonstrate notably significant performance gains (up by at least 14% AUC) compared to existing embedding models as well as the state-of-the-art methods. Additionally, we also show that our learned embeddings reduce more than 93% annotation cost while achieving comparable results to the state-of-the-art methods. In TCR clustering task (unsupervised),catELMoidentifies TCR clusters that are more homogeneous and complete about their binding epitopes. Altogether, ourcatELMotrained without any explicit supervision interprets TCR sequences better and negates the need for complex deep neural network architectures in downstream tasks.
Surface-guided computing to analyze subcellular morphology and membrane-associated signals in 3D
Authors: Zhou Felix Y. , Weems Andrew , Gihana Gabriel M. , Chen Bingying , Chang Bo-Jui , Driscoll Meghan , Danuser Gaudenz
Published: April 2023

Signal transduction and cell function are governed by the spatiotemporal organization of membrane-associated molecules. Despite significant advances in visualizing molecular distributions by 3D light microscopy, cell biologists still have limited quantitative understanding of the processes implicated in the regulation of molecular signals at the whole cell scale. In particular, complex and transient cell surface morphologies challenge the complete sampling of cell geometry, membrane-associated molecular concentration and activity and the computing of meaningful parameters such as the cofluctuation between morphology and signals. Here, we introduce u-Unwrap3D, a framework to remap arbitrarily complex 3D cell surfaces and membrane-associated signals into equivalent lower dimensional representations. The mappings are bidirectional, allowing the application of image processing operations in the data representation best suited for the task and to subsequently present the results in any of the other representations, including the original 3D cell surface. Leveraging this surface-guided computing paradigm, we track segmented surface motifs in 2D to quantify the recruitment of Septin polymers by blebbing events; we quantify actin enrichment in peripheral ruffles; and we measure the speed of ruffle movement along topographically complex cell surfaces. Thus, u-Unwrap3D provides access to spatiotemporal analyses of cell biological parameters on unconstrained 3D surface geometries and signals.
SARS-CoV-2 selectively induces the expression of unproductive splicing isoforms of interferon, class I MHC and splicing machinery genes
Authors: Lüscher Dias Thomaz , Mamede Costa Andrade da Conceição Izabela , Toledo Nayara Evelin de , Queiroz Lúcio Rezende , Castro Ícaro , Polidoro Alves Barbosa Rafael , Del-Bem Luiz Eduardo , Nakaya Helder , Franco Glória Regina
Published: April 2023

Splicing is a highly conserved, intricate mechanism intimately linked to transcription elongation, serving as a pivotal regulator of gene expression. Alternative splicing may generate specific transcripts incapable of undergoing translation into proteins, designated as unproductive. A plethora of respiratory viruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), strategically manipulate the host’s splicing machinery to circumvent antiviral responses. During the infection, SARS-CoV-2 effectively suppresses interferon (IFN) expression, leading to B cell and CD8+ T cell leukopenia, while simultaneously increasing the presence of macrophages and neutrophils in patients with severe COVID-19. In this study, we integrated publicly available omics datasets to systematically analyze transcripts at the isoform level and delineate the nascent-peptide translatome landscapes of SARS-CoV-2-infected human cells. Our findings reveal a hitherto uncharacterized mechanism whereby SARS-CoV-2 infection induces the predominant expression of unproductive splicing isoforms in key IFN signaling genes, interferon-stimulated genes (ISGs), class I MHC genes, and splicing machinery genes, including IRF7, OAS3, HLA-B, and HNRNPH1. In stark contrast, cytokine and chemokine genes, such as IL6, CXCL8, and TNF, predominantly express productive (protein-coding) splicing isoforms in response to SARS-CoV-2 infection. We postulate that SARS-CoV-2 employs a previously unreported tactic of exploiting the host splicing machinery to bolster viral replication and subvert the immune response by selectively upregulating unproductive splicing isoforms from antigen presentation and antiviral response genes. Our study sheds new light on the molecular interplay between SARS-CoV-2 and the host immune system, offering a foundation for the development of novel therapeutic strategies to combat COVID-19.
An assessment of the human Sortilin1 protein network, its expression and targetability using small molecules
Authors: Kumar Arun HS
Published: April 2023

Background

Sortilin1 (SORT1) is a ubiquitously expressed transporter involved in sorting or clearing proteins and is pathologically linked to tissue fibrosis and calcification. Targeting SORT1 may have potential clinical efficacy in controlling or reversing cardiovascular fibrosis and/or calcification. Hence this study assessed the protein-protein network of human SORT1 and its targetability using small molecule nutra/pharmaceuticals.

Material and methods

Network proteins of SORT1 in homo sapiens was identified using the String database, and the affinity of the protein-protein interaction of this network was analysed using Chimera software. The tissue specific expression profile of SORT1 was evaluated and assessed for enrichment in different cell types including the immune cells. A library of in-house small molecules and currently used therapeutics for cardiovascular diseases were screened using AutoDock vina to assess targetability of human SORT1. Concentration affinity (CA) ratio of the small molecules was estimated to assess the clinical feasibility of targeting SORT1.

Results

IGF2R, NTRK2, GRN and GGA1 were identified as high affinity interaction networks of SORT1. Of these high affinity interactions, IGF2R and GRN can be considered as relevant networks in regulating tissue fibrosis or microcalcification process due to their influence on T-cell activation, inflammation, wound repair, and tissue remodelling process. The tissue cell type enrichment indicated major expression of SORT1 in adipocytes, specialised epithelial cells, monocytes, cardiomyocytes, and thyroid glandular cells. The binding pocket analysis of human SORT1 showed twelve potential drug interaction sites with varying binding score (0.86 to 5.83) and probability of interaction (0.004 to 0.304). Five of the drug interaction sites were observed to be targetable at therapeutically feasible concentration of the small molecules evaluated. Empagliflozin, sitagliptin and lycopene showed superior affinity and CA ratio compared to established inhibitors of SORT1.

Conclusion

IGF2R and GRN are relevant networks of SORT1 regulating tissue fibrosis or microcalcification process. SORT1 can be targeted using currently approved small molecule therapeutics (empagliflozin and sitagliptin) or widely used nutraceutical (Lycopene) which should be evaluated in a randomised clinical trial to assess the efficacy to reduce cardiac/vascular microcalcification process.
Binucleated human hepatocytes arise through loss of membrane anchorage to the midbody during endomitosis
Authors: Darmasaputra Gabriella , Chuva de Sousa Lopes Susana M. , Clevers Hans , Galli Matilde
Published: April 2023

Many plant and animal cells transition from canonical to non-canonical cell cycles during development, resulting in the formation of polyploid cells. Two types of non-canonical cell cycles exist: endoreplication, where cells increase their DNA content without entering M phase, and endomitosis, where cells enter M phase but exit prematurely. Although endoreplication has been extensively studied in plants and insects, much less is known on the regulation of endomitosis, which is the most common mode of polyploidization in mammals. In this study, we use fetal-derived human hepatocyte organoids (Hep-Org), to investigate how human hepatocytes initiate and execute endomitosis. We find that cells in endomitosis M phase have normal mitotic timings, but lose membrane anchorage to the midbody during cytokinesis, resulting in regression of the cytokinetic furrow and formation of binucleate cells. Using immunofluorescence, we find that three cortical anchoring proteins, RacGAP1, anillin, and citron kinase (CIT-K), lose their association with the cell cortex during cytokinetic regression. Moreover, reduction of WNT activity by withdrawal of CHIR99021, a GSK3 inhibitor, from the culturing medium increases the percentage of binucleated cells in Hep-Orgs. This effect is lost in organoids with mutations in the atypical E2F proteins, E2F7 and E2F8, which have been implicated in binucleation of rodent hepatocytes. Together, our results identify how human hepatocytes inhibit cell division in endomitosis, and highlight an evolutionary recurrent mechanism to initiate non-canonical cell cycles in mammals.
Resolving a Guanine-Quadruplex Structure in the SARS-CoV-2 Genome through Circular Dichroism and Multiscale Molecular Modeling
Authors: D’Anna Luisa , Miclot Tom , Bignon Emmanuelle , Perricone Ugo , Barone Giampaolo , Monari Antonio , Terenzi Alessio
Published: April 2023

The genome of SARS-CoV-2 coronavirus is made up of a single-stranded RNA fragment that can assume a specific secondary structure, whose stability can influence the virus ability to reproduce. Recent studies have identified putative guanine quadruplex sequences in SARS-CoV-2 genome fragments that are involved in coding for both structural and non-structural proteins. In this contribution, we focus on a specific G-rich sequence referred as RG-2, which codes for the non-structural protein 10 (Nsp10) and assumes a guanine-quadruplex (G4) arrangement. We provide the secondary structure of the RG-2 G4 at atomistic resolution by molecular modeling and simulation, validated by the superposition of experimental and calculated electronic circular dichroism spectrum. Through both experimental and simulation approaches, we have demonstrated that pyridostatin (PDS), a widely recognized G4 binder, can bind to and stabilize RG-2 G4 more strongly than RG-1, another G4 forming sequence that was previously proposed as a potential target for antiviral drug candidates. Overall, this study highlights RG-2 as a valuable target to inhibit the translation and replication of SARS-CoV-2 paving the way towards original therapeutic approaches against emerging RNA viruses.
Origin and early divergence of tandem duplicated sorbitol transporter genes in Rosaceae: insights from evolutionary analysis of the SOT gene family in Angiosperms
Authors: Yang Fan , Luo Jiawei , Guo Wenmeng , Zhang Yuxin , Liu Yunxiao , Yu Ze , Sun Yaqiang , Li Mingjun , Ma Fengwang , Zhao Tao
Published: April 2023

Sorbitol is a critical photosynthate and storage substance in the Rosaceae family. Sorbitol transporters (SOTs) play a vital role in facilitating sorbitol allocation from source to sink organs and sugar accumulation in sink organs. Despite observing gene duplications in the SOT gene family, the origin and evolutionary process of these duplications are unclear, due to the complicated interplay of whole genome duplications and tandem duplications. Here, we investigated the synteny relationships of all detected Polyol/Monosaccharide Transporter (PLT) genes in 61 angiosperm genomes and SOT genes in major representative Rosaceae genomes. Combining phylogenetic analysis, we elucidated the lineage-specific expansion and syntenic conservation of PLTs and SOTs across different plant lineages. We found that Rosaceae SOTs, as PLT family members, originated from a pair of PLT tandem duplicating genes belonging to Class III-A. Additionally, lineage-specific and synergistic duplications in Amygdaloideae had contributed to the expansion of SOTs in Rosaceae plants. Overall, our findings provide insights into the genomic origins, duplication, and divergence of SOT gene family members, which are fundamental for further functional characterizations of each member.
A transferrin receptor 1-targeted PNA-peptide conjugate inhibits microRNA-21 expression in cardiac and other mouse tissues
Authors: Zhang Genwei , Antilla Sarah , Li Chengxi , Loas Andrei , Nielsen Thomas E. , Pentelute Bradley L.
Published: April 2023

MicroRNAs (miRNAs) are implicated in the onset and progression of a variety of diseases. Modulating the expression of specific miRNAs is a possible option for therapeutic intervention. A promising strategy is the use of antisense oligonucleotides (ASOs) to inhibit miRNAs. Targeting ASOs to specific tissues can potentially lower the dosage and improve clinical outcomes by alleviating systemic toxicity. We leverage here automated peptide nucleic acid (PNA) synthesis technology to manufacture an anti-miRNA oligonucleotide (antagomir) covalently attached to a 12-mer peptide that binds to transferrin receptor 1. Our PNA-peptide conjugate is active in cells and animals, effectively inhibiting the expression of miRNA-21 both in cultured mouse cardiomyocytes and different mouse organs (heart, liver, kidney, lung, and spleen), while remaining well-tolerated in animals up to the highest tested dose of 30 mg/kg. Conjugating the targeting ligand to the PNA antagomir significantly improved inhibition of miRNA-21 in the heart by over 50% relative to the PNA alone. Given the modulation of biodistribution observed with our PNA-peptide conjugate, we anticipate this antagomir platform to serve as a starting point for pre-clinical development studies.

Table of Contents Entry

Synopsis

Conjugating T12, a peptide targeting transferrin receptor 1 (TfR1), to a peptide nucleic acid (PNA) oligonucleotide targeting microRNA-21 increases delivery of the PNA-T12 conjugate to cardiac tissue relative to PNA alone.
An integrated single-cell transcriptome landscape of postnatal mouse hypothalamus
Authors: Junaid Muhammad , Choe Han Kyoung , Kondoh Kunio , Lee Eun Jeong , Lim Su Bin
Published: April 2023

The neural stem cells (NSCs) in the hypothalamus are relatively more narrowly defined than in other neurogenic regions of the postnatal brain. By leveraging single-cell RNA sequencing (scRNA-seq) data, we generated an integrated reference dataset comprising 296,282 cells from postnatal hypothalamic regions and the adjacent region, bed nucleus of the stria terminalis (BNST), and identified 30 hypothalamic neuronal and non-neuronal cell populations. The analyses of their gene expression pattern, and specific differentiation trajectories reveal the presence of NSCs and intermediate progenitor cells (IPCs) that show a continuum of activation and differentiation processes in the hypothalamus after birth. Through comparative analyses of the integrated dataset with our lab-generated Connect-seq data obtained from the whole hypothalamus, we further assessed the technical validity of the dataset presented in this study. Our large-scale unified scRNA-seq dataset with harmonized cell-level metadata can serve as a valuable resource for investigating cell type-specific gene expression and cellular differentiation trajectories in the postnatal mouse hypothalamus.
WITHDRAWN: Dual targeting of mitochondrial Lon peptidase 1 and chymotrypsin-like protease by small molecule BT317, as potential therapeutics in malignant astrocytomas
Authors: Douglas Christopher , Jain Shashi , Lomeli Naomi , Di Kaijun , Nandwana Nitesh Kumar , Mohammed Adil Shareef , Vu Thao , Pham James , Lepe Javier , Kenney Maria Cristina , Das Bhaskar , Bota Daniela A.
Published: April 2023

Withdrawal Statement

The authors have withdrawn their manuscript owing to massive revision and data validation. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
The Genetic Architecture of Multimodal Human Brain Age
Authors: Wen Junhao , Zhao Bingxin , Yang Zhijian , Erus Guray , Skampardoni Ioanna , Mamourian Elizabeth , Cui Yuhan , Hwang Gyujoon , Bao Jingxuan , Boquet-Pujadas Aleix , Zhou Zhen , Veturi Yogasudha , Ritchie Marylyn D. , Shou Haochang , Thompson Paul M. , Shen Li , Toga Arthur W. , Davatzikos Christos
Published: April 2023

The complex biological mechanisms underlying human brain aging remain incompletely understood, involving multiple body organs and chronic diseases. In this study, we used multimodal magnetic resonance imaging and artificial intelligence to examine the genetic architecture of the brain age gap (BAG) derived from gray matter volume (GM-BAG,N=31,557 European ancestry), white matter microstructure (WM-BAG,N=31,674), and functional connectivity (FC-BAG,N=32,017). We identified sixteen genomic loci that reached genome-wide significance (P-value<5×10−8). A gene-drug-disease network highlighted genes linked to GM-BAG for treating neurodegenerative and neuropsychiatric disorders and WM-BAG genes for cancer therapy. GM-BAG showed the highest heritability enrichment for genetic variants in conserved regions, whereas WM-BAG exhibited the highest heritability enrichment in the 5’ untranslated regions; oligodendrocytes and astrocytes, but not neurons, showed significant heritability enrichment in WM and FC-BAG, respectively. Mendelian randomization identified potential causal effects of several exposure variables on brain aging, such as type 2 diabetes on GM-BAG (odds ratio=1.05 [1.01, 1.09], P-value=1.96×10−2) and AD on WM-BAG (odds ratio=1.04 [1.02, 1.05], P-value=7.18×10−5). Overall, our results provide valuable insights into the genetics of human brain aging, with clinical implications for potential lifestyle and therapeutic interventions. All results are publicly available at the MEDICINE knowledge portal:https://labs.loni.usc.edu/medicine.
Spatial and temporal regulation of Wnt signaling pathway members in the development of butterfly eyespots
Authors: Banerjee Tirtha Das , Murugesan Suriya Narayanan , Monteiro Antόnia
Published: April 2023

Wnt signaling is involved in the differentiation of eyespot color patterns on the wings of butterflies, but the identity and spatio-temporal regulation of specific Wnt pathway members remains unclear. Here we explore the localization and function of armadillo/β-catenin dependent (canonical) and armadillo/β- catenin independent (non-canonical) Wnt signaling in eyespot development inBicyclus anynanaby localizing Armadillo (Arm), the expression of all sevenwntligand and fourfrizzledreceptor transcripts present in the genome of this species, and testing the function ofarmandfrizzled4using CRISPR-Cas9. During mid to late larval wing development, Arm protein was present in cells at the center of the future eyespots, the foci, and the wing margin, butwntsexpressed on the wing,wnt1(wingless),wnt6, andwnt10showed expression only some distance away from the foci, along the wing margin. The receptorfrizzled9was expressed in the wing margin and in finger-like projections leading to the foci during early larval wing development, overlapping in expression with Arm. At the same time, the receptorfrizzled4showed a novel expression pattern, anti-localized with Arm, where it is likely transducing non-canonical Wnt signaling. In the early pupal stage,wnt1was newly expressed in the foci, as previously shown, along with Arm. In addition,frizzled4andfrizzled9-mediated Wnt signaling is likely repressing the expression offrizzled2, as these receptors have anti-colocalized expression domains. Arm had a conserved expression in three other nymphalid butterflies, and functional knockouts ofarmandfrizzled4inB. anynanashowed that both genes are essential for the differentiation of eyespots. These results show that distinct Wnt signaling pathways are essential for eyespot development in butterflies and are likely interacting to control their active domains.
Compilation of all known protein changes in the human Alzheimer’s disease brain
Authors: Askenazi Manor , Kavanagh Tomas , Pires Geoffrey , Ueberheide Beatrix , Wisniewski Thomas , Drummond Eleanor
Published: April 2023

Proteomic studies of human Alzheimer’s disease brain tissue have exceptional potential to identify protein changes that drive disease and to identify new drug targets. Here, we detail a combined analysis of 38 published Alzheimer’s disease proteomic studies, generating a comprehensive map of protein changes in human brain tissue across thirteen brain regions, three disease stages (preclinical Alzheimer’s disease, mild cognitive impairment, advanced Alzheimer’s disease), and proteins enriched in amyloid plaques, neurofibrillary tangles, and cerebral amyloid angiopathy. Our dataset is compiled into a user-friendly, searchable database called NeuroPro. Our combined analysis included 18,119 reported protein differences in human Alzheimer’s disease brain tissue, which mapped to 5,311 total altered proteins. Proteomic studies were remarkably consistent. 848 proteins were consistently altered in ≥5 studies, many of which are understudied in the Alzheimer’s field. Comparison of protein changes in early-stage and advanced Alzheimer’s disease revealed significant synapse, vesicle, and lysosomal changes early in disease, but widespread mitochondrial changes only in advanced Alzheimer’s disease. Comparison of vulnerable and resistant brain regions suggested that protein changes in resistant regions in advanced Alzheimer’s disease are similar to those in vulnerable regions in early-stage Alzheimer’s disease, indicating a temporal progression of protein dysfunction during Alzheimer’s disease advancement. We conclude that NeuroPro is a powerful new resource that provides new insights into human Alzheimer’s disease brain protein changes and highlights novel proteins of particular interest that may mechanistically drive Alzheimer’s disease.
Spatiotemporal Mapping of Cherry Blossom Blooming by Semi-Automatic Observation System with Street-Level Photos
Authors: Tsutsumida Narumasa , Funada Shuya
Published: April 2023

The importance of floral phenology as a critical indicator of regional climate change and ecosystem services is widely recognized. The annual blooming of cherry blossoms is a nationally celebrated event in Japan, and historical phenological records have been used to document regional climate change. The cultural ecosystem services provided by this phenomenon are important as they not only signal the arrival of spring but also offer a picturesque spring landscape. Despite its importance, constructing a spatiotemporal record of cherry blossom blooming is challenging due to the limited coverage of traditional stationary observations. To address this issue, citizen-based observation programs and remote sensing applications have been implemented; nevertheless, these strategies are still limited by infrequent and insufficient observations throughout space and time. To compensate, we developed a flower detection model for geographically and temporally dispersed street-level photos that may be used as the core component of a semi-automatic observation system. Specifically, we developed a customized YOLOv4 model for cherry blossom detection from street-level photos obtained through Mapillary, one of the social sensing data repositories. The detection model achieved an overall accuracy, recall, and precision of 86.7%, 70.3%, and 90.1%, respectively. By using observation coordinates and dates attached to Mapillary photos, we mapped the probability of cherry trees blooming in a spatial grid of dimensions 10 m x 10 m on a daily basis. With sufficient observations, start, peak, and end of blooming were estimated through time series analysis. A case study conducted at Saitama University’s main campus in 2022 confirmed the possibility of mapping the presence of cherry blossoms and their blooming timing automatically. Since our approach relies solely on geotagged street-level photos that can be taken by anyone with no prior knowledge of cherry tree species identification, we anticipate that it will be easier to build blooming records over space and time than conventional stationary observations or citizen-based observation programs. This novel approach also has potential applications for detecting other species as well.
Determination of the factors responsible for host tropism of SARS-CoV-2-related bat coronaviruses
Authors: Fujita Shigeru , Kosugi Yusuke , Kimura Izumi , Tokunaga Kenzo , Ito Jumpei , Sato Kei
Published: April 2023

Differences in host ACE2 genes may affect the host range of SARS-CoV-2-related coronaviruses (SC2r-CoVs) and further determine the tropism of host ACE2 for the infection receptor. However, the factor(s) responsible for determining the host tropism of SC2r-CoVs, which may in part be determined by the tropism of host ACE2 usage, remains unclear. Here, we use the pseudoviruses with the spike proteins of two Laotian SC2r-CoVs, BANAL-20-236 and BANAL-20-52, and the cells expressing ACE2 proteins of eight different Rhinolophus bat species, and show that these two spikes have different tropisms for Rhinolophus bat ACE2. Through structural analysis and cell culture experiments, we demonstrate that this tropism is determined by residue 493 of the spike and residues 31 and 35 of ACE2. Our results suggest that SC2r-CoVs exhibit differential ACE2 tropism, which may be driven by adaptation to different Rhinolophus bat ACE2 proteins.