bluuebunny/crossref_metadata_2025 huggingface dataset:
Cancers of Unknown Primary Origin: Real-World Clinical Outcomes and Genomic Analysis at the European Institute of Oncology
Authors: Boscolo Bielo Luca , Belli Carmen , Crimini Edoardo , Repetto Matteo , Ascione Liliana , Pellizzari Gloria , Santoro Celeste , Fuorivia Valeria , Barberis Massimo , Fusco Nicola , Rocco Elena Guerini , Curigliano Giuseppe
Published: March 2024

Background

Cancer of unknown primary origin (CUP) poses a significant challenge due to poor clinical outcomes and limited treatment options. As such, further definition of clinicopathological factors and genomic profile to better adapt treatment strategies is required.

Methods

Medical records were interrogated to retrospectively include CUP with available clinical and genomics data at the European Institute of Oncology. Next-generation sequencing (NGS) included targeted panels. Statistical analyses were conducted with R Software 4.2.2.

Results

A total of 44 patients were included. With a median follow-up of 39.46 months (interquartile range [IQR] 35.98-47.41 months), median PFS (mPFS) to first-line regimen was 3.98 months (95% CI 3.22-5.98), with a clinical benefit rate of 26% (95% CI 14%-49%), and disease control rate (DCR) limited to 48.28%. Most patients (26 of 31, 83.87%) received platinum-doublet chemotherapy, with no statistically significant difference between first-line treatment regimens. Median OS (mOS) was 18.8 months (95% CI 12.3-39.9), with a 12-month OS rate of 66% (95% CI 50%-85%). All patients received comprehensive genomic profiling (CGP). For 11 patients, NGS was unsuccessful due to low sample quantity and/or quality. For the remaining, TP53 (n = 16, 48%) and KRAS (n = 10, 30%) represented the most altered (alt) genes. No microsatellite instability was observed (0 of 28), while 6 of 28 (21.43%) tumors carried high TMB (≥10 mutation per megabase). Eight of 33 tumors (24.2%) displayed at least one actionable alteration with potential clinical benefit according to ESCAT. Only 2 of them received targeted therapy matched to genomic alterations, with a combined mPFS of 2.63 months (95% CI 1.84-not evaluable) as third-line regimens. Six patients received anti-PD1/PD-L1 therapy, showing a meaningful mPFS of 13 months (95% CI 2.04-not evaluable).

Conclusion

CUP exhibits poor prognosis with limited benefits from standard treatment regimens. A significant proportion of CUPs carry actionable alterations, underscoring the importance of genomic profiling to gather additional treatment opportunities. In addition, immunotherapy might represent a valuable treatment option for a subset of CUP. Finally, accurate definition of sequencing methods and platforms is crucial to overcome NGS failures.
Is coffee, tea, and red wine consumption beneficial for individuals with hypertension?
Authors: Zhang Shuchen , Xiang Boyang , Su Xiangyu , Zhou Yujia , Zhao Yiheng , Zhou Xiang
Published: March 2024

Objective

To investigate the associations of tea, coffee, and red wine intakes with health risks among individuals with hypertension.

Methods

This prospective cohort study included participants with hypertension from the UK Biobank cohort. Study exposures included self-reported intakes of coffee, tea, and red wine. The primary outcome was all-cause mortality, and the secondary outcomes were cardiovascular mortality and cardiovascular disease. The associations of beverage intake with outcomes were analyzed using Cox regression models. The hazard ratios and 95% confidence intervals were estimated.

Results

A total of 187 708 participants with hypertension were included. The median follow-up period was 13.8 years. In individuals with hypertension, drinking one to two cups/day of coffee or three to four cups/day of tea was significantly associated with the lowest risk of all-cause mortality compared with less than one cup/day [hazard ratio for coffee, 0.943 (95% confidence interval, 0.908–0.979); hazard ratio for tea, 0.882 (95% confidence interval, 0.841–0.924)]. Red wine intake was inversely associated with all-cause mortality risk. Dose–response analysis revealed that high coffee intake (approximately greater than or equal to six cups/day) was significantly associated with increased risks of cardiovascular mortality and cardiovascular disease, but high tea and red wine intakes were not. Furthermore, replacing plain water with tea, but not coffee, significantly reduced the risks of all-cause mortality and cardiovascular disease. Replacing other alcoholic beverages with red wine also significantly reduced the risks of all three outcomes.

Conclusions

These findings suggest that tea and red wine, but not coffee, can be part of a healthy diet for the hypertensive population.
The adverse consequences of quantitative easing (QE): international capital flows and corporate debt growth in China
Authors: Maiani Stefano , Lamla Michael , Wood Geoffrey , Ehrstein Yvonne
Published: March 2024

The economic institutionalist literature often suggests that sub-optimal institutional arrangements impart unique distortions in China, and excessive corporate debt is a symptom of this condition. However, lax monetary policies after the global financial crisis, and specifically, quantitative easing have led to concerns about debt bubbles under a wide range of institutional regimes. This study draws on data from Chinese listed firms, supplemented by numerous macroeconomic control variables, to isolate the effect of international capital flows from other drivers of firm leverage. We conclude that the rise in, and distribution of, Chinese corporate debt can partly be ascribed to the effects of monetary policy outside of China and that Chinese institutional features amplify these effects. Whilst Chinese firms are affected by developments in the global financial ecosystem, domestic institutional realities and distortions may unevenly add their own particular effects, providing further support for and extending the variegated capitalism literature.
Impact of Saussurea lappa against foodborne parasite Trichinella spiralis experimental infections induced variation in DNA damage, oxidative stress and PCNA expression in rat skeletal muscles
Authors: Alghabban Areej Jameel M , Bakr Lamiaa , Elbatawy Aya A , El Atrash Afaf , Tousson Ehab
Published: March 2024

Trichinellosis is a parasite zoonosis that is spread through ingesting raw or undercooked meat that contains the Trichinella spiralis (T. spiralis) infective larvae. It has three clinical phases: intestinal, migratory, and muscular. Kuth root, also known as Costus (Saussurea lappa) roots, is used in many traditional medical systems all over the world to treat a variety of illnesses, such as dyspepsia, diarrhoea, vomiting, and inflammation. Current study assessed the therapeutic Potential of costus roots extract (CRE) treatment on experimental trichinellosis induce changes in DNA damage, oxidative stress and Proliferating cell nuclear antigen (PCNA) expression in muscle fibers in male rats. A total of 60 male Sprague Dawley rats were divided into 6 groups (Gps) [Gp1, Negative control; Gp2, Costus (CRE); Gp3, Positive control or Infected rats with T. spiralis, Gp4; Pre-treated infection with CRE; Gp5 & Gp6, Post treated infection with CRE for one and two weeks respectively]. Current results revealed that; Trichinella spiralis experimentally infection induced significant elevation in tissue malondialdehyde (MDA), DNA damage, PCNA expression and significant depletion in tissue glutathione (GSH), superoxide dismutase (SOD) and catalase (Cat) activities. Pre or/and post CRE treated infected rats with T. spiralis (Gp4-Gp6) induced improvements and depletion in DNA damage, PCNA expression, MDA and elevation in GSH, SOD, catalase as compared to infected rats with T. spiralis (Gp3) with best results for the pretreatments (Gp4). Trichinella spiralis experimental infection induced DNA damage and oxidative stress in rat skeletal muscles and treatments with costus roots extract modulates these changes.
Phylogenetic insights into the terrestrial snails Helicoidei (Gastropoda: Stylommatophora) with special emphasis on the Camaenidae
Authors: Zhang Guoyi , Naggs Fred , Andrus Peter S , Wade Christopher M
Published: March 2024

The superfamily Helicoidei are a widely distributed and diverse infraorder of land snails and slugs. Here, we constructed a phylogenetic tree based on sequences of the large subunit ribosomal RNA gene to investigate the relationships within the Helicoidei. Based on our phylogenetic tree, the family Camaenidae, as currently recognized, is not monophyletic, with the Polygyridae falling within the group. Likewise, the family Hygromiidae as currently defined is not monophyletic and incorporates the Geomitridae. The family Xanthoncyhidae form a monophyletic group that is sister to the Pleurodontidae. Likewise, the family Helicidae form a monophyletic group; it is sister to the branch incorporating Hygromiidae, Geomitridae, Pleurodontidae, Helicodontidae, and Xanthonychidae. The Solaropsidae are the sister group to a clade comprising other Sagdoidea. Our findings suggest that the Hygromiidae s.l. families should be restored to their previous name, Hygromiidae. A new genus of Bradybaeninae, Jiaoliaous Zhang gen. nov., is described here, with a simple genital system, single dart sac with multi-branched mucous glands, and a penis with a penial sheath.
Automating Academic Document Analysis with ChatGPT: A Mendeley Case
Authors: Abuella Mohamed
Published: March 2024

The management and organization of a large collection of academic documents is an important part of scientific research. This study explores the use of ChatGPT, a large language model from OpenAI, to extract insights from a large collection of academic documents stored in Mendeley. The study found that ChatGPT can be used to generate insightful graphs, concise summaries, and other tasks tailored to user needs. The study also demonstrated that ChatGPT can be used to analyze a large number of publications in PDF format. This suggests that ChatGPT could be a valuable tool for researchers who want to save time and effort by automating the analysis of their data. The GitHub repository for the source code and the output of this study is available at:https://github.com/MohamedAbuella/Analysis_Mendeley.
Phospholipase C β4 promotes RANKL-dependent osteoclastogenesis by interacting with MKK3 and p38 MAPK
Authors: Lee Dong-Kyo , Jin Xian , Choi Poo-Reum , Cui Ying , Che Xiangguo , Lee Sihoon , Hur Keun , Kim Hyun-Ju , Choi Je-Yong
Published: March 2024

Phospholipase C beta (PLCβ) exerts diverse biological processes, including inflammatory responses and neurogenesis; however, its role in bone cell function is largely unknown. Among the PLCβ isoforms (β1–β4), we found that PLCβ4 was most highly upregulated during osteoclastogenesis. In this study, we used global knockout and osteoclast lineage-specific PLCβ4 conditional knockout (LysM-PLCβ4−/−) mice and demonstrated that PLCβ4 is a crucial regulator of receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation. Deletion of PLCβ4, both globally and in the osteoclast lineage, resulted in a significant reduction in osteoclast formation and the downregulation of osteoclast marker genes. Importantly,LysM-PLCβ4−/−male mice exhibited greater bone mass and a lower number of osteoclastsin vivothan their wild-type littermates, without altering osteoblast function. Mechanistically, we found that PLCβ4 forms a complex with p38 mitogen-activated protein kinase (MAPK) and MAPK kinase 3 (MKK3) in response to RANKL, thereby modulating p38 activation. An immunofluorescence assay further confirmed the colocalization of PLCβ4 with p38 after RANKL exposure. Moreover, p38 activation rescued the impaired osteoclast formation and restored the reduced p38 phosphorylation due toPLCβ4deficiency. Thus, our findings reveal that PLCβ4 controls osteoclastogenesis via the RANKL-dependent MKK3-p38 MAPK pathway, and PLCβ4 may be a potential therapeutic candidate for bone diseases such as osteoporosis.
Stand structure as the proximate driver of endemic biodiversity and ecosystem functions in tropical mosaic landscapes
Authors: Rajaonarimalala Rindrasoa , Korol Yevgeniya , Andrianarimisa Aristide , Dröge Saskia , Fulgence Thio Rosin , Grass Ingo , Kreft Holger , Osen Kristina , Rakotomalala Anjaharinony A. N. A. , Rakouth Bakolimalala , Ranarijaona Hery Lisy Tiana , Randriamanantena Romual , Ratsoavina Fanomezana Mihaja , Ravaomanarivo Lala Harivelo Raveloson , Raveloaritiana Estelle , Schwab Dominik , Soazafy Marie Rolande , Tscharntke Teja , Wurz Annemarie , Hölscher Dirk , Martin Dominic Andreas
Published: March 2024

Transformation of forests into agricultural lands threatens biodiversity and ecosystem functions globally. In the biodiversity hotspot Madagascar, key ecosystem functions along with highly endemic flora and fauna are under threat. Comprehensive studies identifying proximate drivers are lacking, with no studies accounting for endemic species richness across multiple taxa. We assess how plot-scale stand structural attributes (basal area, leaf area index, diameter diversity, and tree species richness) and landscape-scale forest cover affect biodiversity (species richness of butterflies, ants, birds, amphibians, reptiles, herbaceous plants, and multidiversity) and ecosystem functions (soil organic carbon, predation rate, acoustic diversity index, and multifunctionality) in the tropical mosaic landscape of northeastern Madagascar. Across a prevalent land-use gradient in the region, we sampled five woody land-use types: old-growth forest, forest fragment, woody fallow, forest-derived and fallow-derived vanilla agroforests. Complexly structured stands with a larger basal area and higher tree species richness promoted greater endemic multidiversity and certain ecosystem functions. Landscape-scale forest cover significantly favored, particularly, endemic bird species richness. Our models explained 70% of the variance in endemic multidiversity, 26% in multidiversity, and 43% in multifunctionality. Significant effects directions of our predictors differed between taxa but were univocally positive for endemic species richness. Our findings highlight that a simplified stand structure, resulting from land-use change, substantially reduces endemic biodiversity and ecosystem functions in this historically forested region. Conservation actions should aim at maintaining complex stand structure in forests and agroforests, while restoration interventions should focus on re-building such structures.
The seminal vesicle is a juvenile hormone-responsive tissue in adult maleDrosophila melanogaster
Authors: Kurogi Yoshitomo , Mizuno Yosuke , Okamoto Naoki , Barton Lacy , Niwa Ryusuke
Published: March 2024

Juvenile hormone (JH) is one of the most essential hormones controlling insect metamorphosis and physiology. While it is well known that JH affects many tissues throughout the insects life cycle, the difference in JH responsiveness and the repertoire of JH-inducible genes among different tissues has not been fully investigated. In this study, we monitored JH responsivenessin vivousing transgenicDrosophila melanogasterflies carrying aJH response element-GFP(JHRE-GFP) construct. Our data highlight the high responsiveness of the epithelial cells within the seminal vesicle, a component of the male reproductive tract, to JH. Specifically, we observe an elevation in the JHRE-GFP signal within the seminal vesicle epithelium upon JH analog administration, while suppression occurs upon knockdown of genes encoding the intracellular JH receptors,Methoprene-tolerantandgerm cell-expressed. Starting from published transcriptomic and proteomics datasets, we next identifiedLactate dehydrogenaseas a JH-response gene expressed in the seminal vesicle epithelium, suggesting insect seminal vesicles undergo metabolic regulation by JH. Together, this study sheds new light on biology of the insect reproductive regulatory system.
Complementary genetic and epigenetic changes facilitate rapid adaptation to multiple global change stressors
Authors: Brennan Reid S. , deMayo James A. , Finiguerra Michael , Baumann Hannes , Dam Hans G. , Pespeni Melissa H.
Published: March 2024

To persist in the geologically unprecedented rates of global change, populations can adapt or acclimate. However, how these mechanisms of resilience interact, particularly the role of epigenetic variation in long-term adaptation, is unknown. To address this gap, we experimentally evolved the foundational marine copepodAcartia tonsafor 25 generations under ocean acidification, warming, their combination, and control conditions then measured epigenomic, genomic, and transcriptomic responses. We observed clear and consistent epigenomic and genomic divergence between treatments, with epigenomic divergence concentrated in genes related to stress response and the regulation of transposable elements. However, epigenetic and genetic changes occurred in different regions of the genome such that regions with significant methylation divergence had 2-2.5 fold lower FSTthan regions without methylation divergence. This negative relationship between epigenetic and genetic divergence could be driven by local inhibition of one another or distinct functional targets of selection. In contrast, epigenetic divergence was positively linked to gene expression divergence, indicating that epigenetic changes may facilitate phenotypic change. Taken together, these results suggest that unique, complementary genetic and epigenetic mechanisms promote resilience to global change.

Significance Statement

Organisms must adapt or acclimate to survive global change, but how these processes interact and the role of epigenetic variation is unknown. To address these gaps, we experimentally evolved the marine copepodAcartia tonsafor 25 generations in global change conditions and measured their genomic, epigenomic, and gene expression responses. We found that both genetic and epigenetic changes contributed to resilience and were inversely related, acting in different regions of the genome. Epigenetic changes were functionally linked to the regulation of stress and transposable elements and correlated with shifts in gene expression. Therefore, the resilience of populations to ongoing global change is driven by the complementary contribution of both genetic and epigenetic mechanisms.
SUC2 sucrose transporter is required for leaf apoplasmic sucrose levels. Consequences for phloem loading strategies
Authors: Vilaine Françoise , Bill Laurence , Hir Rozenn Le , Bellini Catherine , Dinant Sylvie
Published: March 2024

Summary

• The SUC/SUT sucrose transporters belong to a family of active H+/sucrose symporters, with a role of SUC2 in active apoplasmic phloem loading to drive long-distance phloem transport of sucrose in Arabidopsis. However, the cooperation with the symplasmic pathway for phloem loading remains unclear.

• In this study, we explored the consequences of reducing either apoplasmic or symplasmic pathways of phloem loading. We compared a series of lines with modified expression ofSUC2gene, and we analyzed the effects on plant growth, sugar accumulation in source and sink organs, phloem transport, and gene expression.

• Our data revealed that a modified expression ofSUC2impacted apoplasmic sucrose levels in source leaves but did not impact phloem transport, as might be expected, while increasing foliar storage of carbohydrates. This response differed from lines in which symplasmic communications between phloem cells was disrupted by the over-expression of a plasmodesmata-associated protein, NHL26.

• Altogether, our studies indicate an unexpected effect of SUC2 for apoplasmic sucrose levels in source leaves, together with SUC1, and suggest a feedback regulation on foliar storage. This data sheds new light on the interplay between symplasmic and apoplasmic pathways for sugar loading and the consequences on leaf water flows.

Summary statement

The mechanisms that coordinate apoplasmic and symplasmic loading pathways, and their effects on foliar carbon storage, remain largely unexplored. Surprisingly, the sucrose transporter SUC2 plays a significant role in maintaining sucrose levels in the apoplasm, shedding light on how apoplasmic sugar levels and water flows can interact for phloem loading.
First evaluation and detection of ivermectin resistance in gastrointestinal nematodes of sheep and goats in South Darfur, Sudan
Authors: Mohammedsalih Khalid M. , Ibrahim Abdoelnaim I. Y. , Juma Fathel-Rahman , Abdalmalaik Abdalhakaim A. H. , Bashar Ahmed , Coles Gerald , von Samson-Himmelstjerna Georg , Krücken Jürgen
Published: March 2024

In Sudan, resistance to benzimidazoles has been reported recently in cattle and goats from South Darfur. Herein, ivermectin efficacy against gastrointestinal nematodes (GINs) was evaluated in sheep and goats in three study areas in South Darfur. The faecal egg count reduction test (FECRT) was used to evaluate the efficacy of ivermectin in sheep and goats naturally infected with GINs in the region of Bulbul (goats:n=106), Kass (goats:n=40) and Nyala (Domaia (sheep:n=47, goats:n=77) and the University farm (goats:n=52)), using different treatment plans, and the efficacy was evaluated 12 days after treatment. Ivermectin efficacy was also evaluated in goats experimentally infected using localHaemonchus contortusisolates from Kass and Nyala. Nematodes surviving ivermectin treatment in goats in Bulbul and Nyala were harvested and larvae used to infect worm-free male sheep (n=6, ≤6 months old). Infected sheep were dosed subcutaneously with ivermectin every eight days with increasing doses from 0.2 mg/kg to 1.6 mg/kg bodyweight (bw). Reduced ivermectin efficacy was identified in sheep and goats in the four study locations. Using a paired statistic, the efficacy of a therapeutic dose in sheep was 75.6% (90% upper credible limit (UCrL): 77.5%), while twice the recommended dose led to a reduction of 92.6% (90% UCrL: 93.3%). In goats, the FECRs of a therapeutic dose were 72.9 – 95.3% (90% UCrL range: 73.6 – 95.7%) in Bulbul, Nyala Domaia, Nyala University farm and Kass. Twice the dose recommended for goats in Bulbul revealed a 90% UCrL of 87.6%. All post-treatment faecal cultures contained onlyHaemonchusspp. larvae. The experimental infection trials in sheep and goats supported our findings from field trials and calculated upper 90% CrL of below 98.9%. For the first time highly ivermectin resistantH. contortuspopulations have been identified in sheep and goats in Sudan, and resistance was experimentally confirmed.
How does perception of zoo animal welfare influence public attitudes, experiences, and behavioural intentions? A mixed-methods systematic review
Authors: Phillips Nicki , Maréchal Laëtitia , Ventura Beth , Cooper Jonathan
Published: March 2024

The public expects zoos to provide high standards of animal care. Failing to meet public expectations can have detrimental impacts on public experiences and behaviour, which in turn can compromise zoos’ organisational goals relative to conservation and public education. Despite increased research interest in understanding how the public perceives animal welfare in zoo settings, to date the factors that influence such perceptions are still unclear. To address this gap in knowledge, we conducted a mixed methods systematic review using a PRISMA approach to identify the factors that influence public perceptions of zoo animal welfare and the potential ramifications of these perceptions on public attitudes, experiences, and behaviours. A total of 115 peer reviewed journal articles were analysed: 43 provided qualitative data for thematic synthesis and 85 reported quantitative data for content analysis. Three main groupings were identified that impacted public perception of animal welfare in zoos: human, animal, and environmental factors. Within the human factors, ethical justifications, direct interactions, and inappropriate visitor behaviours were important. For the animal factors, animals’ behaviour, apparent health status, and the suitability of certain taxa for captivity were found to be key. Finally, several aspects of the environment -- conditions of the facility, the exhibit, and welfare-related educational material --were influential. Overall, negative perceptions of animal welfare resulted in negative visitor attitudes towards zoos, detrimentally impacted experiences, and lowered likelihood to visit zoos and engagement in conservation efforts. The articles in this review provided valuable insights into the factors affecting public perception of zoo animal welfare; however, future research may benefit from a more structured approach to increase comparability and validity of results across studies. We conclude by proposing seven recommendations to increase the robustness and validity of future research in this area.
Molecular events accompanying aggregation-induced energy quenching in Fucoxanthin-Chlorophyll Proteins
Authors: Alexandre Maxime T. A. , Krüger Tjaart P.J. , Pascal Andrew A. , Veremeienko Vasyl , Llansola-Portoles Manuel , Gundermann Kathi , van Grondelle Rienk , Büchel Claudia , Robert Bruno
Published: March 2024

In high light, the antenna system in oxygenic photosynthetic organisms switches to a photoprotective mode, dissipating excess energy in a process called non-photochemical quenching (NPQ). Diatoms exhibit very efficient NPQ, accompanied by a xanthophyll cycle in which diadinoxanthin is de-epoxidized into diatoxanthin. Diatoms accumulate pigments from this cycle in high light, and exhibit faster and more pronounced NPQ. The mechanisms underlying NPQ in diatoms remain unclear, but it can be mimicked by aggregation of their isolated light-harvesting complexes, FCP (fucoxanthin chlorophyll-a/c protein). We assess this model system by resonance Raman measurements of two peripheral FCPs, trimeric FCPa and nonameric FCPb, isolated from high- and low-light-adapted cells (LL, HL). Quenching is associated with a reorganisation of these proteins, affecting the conformation of their bound carotenoids, and in a manner which is highly dependent on the protein considered. FCPa from LL diatoms exhibits significant changes in diadinoxanthin structure, together with a smaller conformational change of at least one fucoxanthin. For these LL-FCPa, quenching is associated with consecutive events, displaying distinct spectral signatures, and its amplitude correlates with the planarity of the diadinoxanthin structure. HL-FCPa aggregation is associated with a change in planarity of a 515-nm-absorbing fucoxanthin, and, to a lesser extent, of diadinoxanthin. Finally, in FCPb, a blue-absorbing fucoxanthin is primarily affected. FCPs thus possess a plastic structure, undergoing several conformational changes upon aggregation, dependent upon their precise composition and structure. NPQ in diatoms may therefore arise from a combination of structural changes, dependent on the environment the cells are adapted to.
Attention-based approach to predict drug-target interactions across seven target superfamilies
Authors: Schulman Aron , Rousu Juho , Aittokallio Tero , Tanoli Ziaurrehman
Published: March 2024

Motivation

Drug-target interactions (DTIs) hold pivotal role in drug repurposing and elucidation of drug mechanisms of action. While single-targeted drugs have demonstrated clinical success, they often exhibit limited efficacy against complex diseases, such as cancers, whose development and treatment is dependent on several biological processes. Therefore, a comprehensive understanding of primary, secondary, and even inactive targets becomes essential in the quest for effective and safe treatments for cancer and other indications. The human proteome offers over a thousand druggable targets. Yet, most FDA-approved drugs bind with only a small fraction of disease targets.

Results

This study introduces an attention-based method to predict drug-target bioactivities for all human proteins across seven superfamilies. Nine different descriptor sets were meticulously examined to identify optimal signature descriptors for predicting novel DTIs. Our testing results demonstrated Spearman correlations exceeding 0.72 (P<0.001) for six out of seven superfamilies. The proposed method outperformed nine state-of-the-art deep learning and graph-based methods, and importantly, maintained relatively high performance for most target superfamilies when tested in independent sources of bioactivity data. We computationally validated 185,676 drug-target pairs from ChEMBL-V33, that were not available in model training, with a reasonable performance of Spearman correlation > 0.57 (P<0.001) for most superfamilies. This justifies the robustness of the proposed method for predicting novel DTIs. Finally, we applied our method to predict missing activities among 3,492 approved molecules in ChEMBL-V33, offering a valuable tool for advancing drug mechanism discovery and repurposing existing drugs for new indications.

Availability and implementation

The codes and training datasets to reproduce and extend the results are available athttps://github.com/AronSchulman/MMAtt-DTA.
Uncovering organizing principles of protein-protein interaction networks
Authors: Ojha Anju K. , Dhar Pawan K.
Published: March 2024

This study explores the intricate world of protein-protein interaction (PPI) networks and the critical role of hub proteins within them. PPIs, mediated by various biomolecular forces, orchestrate diverse cellular processes through transient or stable interactions. The study delves into the unique ability of hubs to connect with numerous partners within the network. This research investigates the network properties and focuses on hub-centric questions. This study explores information-carrying capacity, power laws in protein circuits, connectivity profiles of hub proteins, and network expansion or shrinkage during evolution. The study validates the power law for connectivity, identifies a marginal network compression in evolution, unveils hub connectivity patterns, and encourages the exploration of the correlation between protein structure, connectivity, and function. These findings offer valuable insights into network design principles and the critical role of hub proteins in cellular function and evolution.
Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice
Authors: Syed Farooq , Ballew Olivia , Lee Chih-Chun , Rana Jyoti , Krishnan Preethi , Castela Angela , Weaver Staci A. , Chalasani Namratha Shivani , Thomaidou Sofia F. , Demine Stephane , Chang Garrick , Coomans de Brachène Alexandra , Alvelos Maria Ines , Marselli Lorella , Orr Kara , Felton Jamie L. , Liu Jing , Marchetti Piero , Zaldumbide Arnaud , Scheuner Donalyn , Eizirik Decio L. , Evans-Molina Carmella
Published: March 2024

Tyrosine protein-kinase 2 (TYK2), a member of the Janus kinase family, mediates inflammatory signaling through multiple cytokines, including interferon-α (IFNα), interleukin (IL)-12, and IL-23. Missense mutations in TYK2 are associated with protection against type 1 diabetes (T1D), and inhibition of TYK2 shows promise in the management of other autoimmune conditions. Here, we evaluated the effects of specific TYK2 inhibitors (TYK2is) in pre-clinical models of T1D. First, human β cells, cadaveric donor islets, and iPSC-derived islets were treatedin vitrowith IFNα in combination with a small molecule TYK2i (BMS-986165 or a related molecule BMS-986202). TYK2 inhibition prevented IFNα-induced β cell HLA class I up-regulation, endoplasmic reticulum stress, and chemokine production. In co-culture studies, pre-treatment of β cells with a TYK2i prevented IFNα-induced activation of T cells targeting an epitope of insulin.In vivoadministration of BMS-986202 in two mouse models of T1D (RIP-LCMV-GPmice and NOD mice) reduced systemic and tissue-localized inflammation, prevented β cell death, and delayed T1D onset. Transcriptional phenotyping of pancreatic islets, pancreatic lymph nodes (PLN), and spleen during early disease pathogenesis highlighted a role for TYK2 inhibition in modulating signaling pathways associated with inflammation, translational control, stress signaling, secretory function, immunity, and diabetes. Additionally, TYK2i treatment changed the composition of innate and adaptive immune cell populations in the blood and disease target tissues, resulting in an immune phenotype with a diminished capacity for β cell destruction. Overall, these findings indicate that TYK2i has beneficial effects in both the immune and endocrine compartments in models of T1D, thus supporting a path forward for testing TYK2 inhibitors in human T1D.
The cage effect of electron beam irradiation damage in cryo-electron microscopy
Authors: Li Yi , Kang Dong-Dong , Dai Jia-Yu , Wang Lin-Wang
Published: March 2024

Electron beam irradiation can cause damage to biological and organic samples, as determined via transmission electron microscopy (TEM). Cryo-electron microscopy (cryo-EM) significantly reduces such damage by quickly freezing the environmental water around organic molecules. However, there are multiple hypotheses about the mechanism of cryo-protection in cryo-EM. A lower temperature can cause less molecular dissociation in the first stage, or frozen water can have a “cage” effect by preventing the dissociated fragments from flying away. In this work, we used real-time time-dependent density functional theory (rt-TDDFT-MD) molecular dynamic simulations to study the related dynamics. We used our newly developed natural orbital branching (NOB) algorithm to describe the molecular dissociation process after the molecule is ionized. We found that despite the difference in surrounding water molecules at different temperatures, the initial dissociation process is similar. On the other hand, the dissociated fragments will fly away at room temperature, while they will remain in the same cage when frozen water is used. Our results provide direct support for the cage effect mechanism.
DrugDomain: the evolutionary context of drugs and small molecules bound to domains
Authors: Medvedev Kirill E. , Schaeffer R. Dustin , Grishin Nick V.
Published: March 2024

Interactions between proteins and small organic compounds play a crucial role in regulating protein functions. These interactions can modulate various aspects of protein behavior, including enzymatic activity, signaling cascades, and structural stability. By binding to specific sites on proteins, small organic compounds can induce conformational changes, alter protein-protein interactions, or directly affect catalytic activity. Therefore, many drugs available on the market today are small molecules (72% of all approved drugs in the last five years). Proteins are composed of one or more domains: evolutionary units that convey function or fitness either singly or in concert with others. Understanding which domain(s) of the target protein binds to a drug can lead to additional opportunities for discovering novel targets. The Evolutionary Classification Of protein Domains (ECOD) classifies domains into an evolutionary hierarchy that focuses on distant homology. Previously, no structure-based protein domain classification existed that included information about both the interaction between small molecules or drugs and the structural domains of a target protein. This data is especially important for multidomain proteins and large complexes. Here, we present the DrugDomain database that reports the interaction between ECOD domains of human target proteins and DrugBank molecules and drugs. The pilot version of DrugDomain describes the interaction of 5,160 DrugBank molecules associated with 2,573 human proteins. It describes domains for all experimentally determined structures of these proteins and incorporates AlphaFold models when such structures are unavailable. The DrugDomain database is available online:http://prodata.swmed.edu/DrugDomain/
Effect of copper mill waste material on benthic invertebrates and zooplankton diversity and abundance in Lake Superior beaches
Authors: Larson James H , Lowe Michael R , Bailey Sean W , Bell Amanda H , Cleveland Danielle M
Published: March 2024

From 1900 to 1932 a copper (Cu) mill operated near Gay, Michigan, along the eastern shore of the Keweenaw Peninsula (Lake Superior, Michigan) and discharged waste material (stamp sands [SS]) to a nearby beach. These SS escaped containment structures and have been redeposited by wave action along the beaches in northern Grand Traverse Bay and onto Buffalo Reef, an important spawning area for native fish. Newly hatched fish move into nearby beach habitats where they grow during their first summer. Juvenile fish initially consume zooplankton before switching to benthic invertebrates once they are large enough. SS contain metals (especially Cu) that are toxic to many invertebrate taxa, and studies have observed few benthic taxa in areas covered by SS. We sampled the invertebrate community from four Lake Whitefish nursery areas: one near Buffalo Reef with high SS, one south of the Traverse River with moderate SS, one in nearby Little Traverse Bay with little SS, and a beach ∼58 km away with no SS (Big Bay). We also resampled the benthos at sites that had been sampled as part of an earlier Grand Traverse Bay study. Buffalo Reef (high SS) had fewer benthic taxa, and less density of several taxa than Little Traverse Bay (little SS), especially benthic copepods. All beaches had comparable zooplankton diversity, but the abundance was ∼2 orders of magnitude lower at Buffalo Reef (high SS) than other beaches. Cu and several other metals were elevated at beaches with more SS. We found support for associations between benthic density and diversity with depth (positive effect) and Cu concentration (negative effect). Cu concentration was a better predictor of declines in benthic invertebrate abundance and diversity than SS. We also observed that the relationship between Cu concentration and SS was non-linear, and highly variable. For example, 149 mg Cu/kg dry weight sediment is a consensus toxicity threshold used in the literature, but the prediction interval around that concentration from our model is 26-851 mg Cu/kg dry weight. A better predictive model of this relationship would be beneficial to develop to understand what level of SS reduction would prevent Cu impacts on invertebrates.
Immune gene expression changes more during a malaria transmission season than between consecutive seasons.
Authors: Tebben Kieran , Yirampo Salif , Coulibaly Drissa , Koné Abdoulaye Kassoum , Laurens Matthew Brent , Stucke Emily M , Dembélé Ahmadou , Tolo Youssouf , Traoré Karim , Niangaly Amadou , Berry Andrea A , Kouriba Bourèma , Plowe Christopher V , Doumbo Ogobara K , Lyke Kirsten E , Takala-Harrison Shannon , Thera Mahamadou Aly , Travassos Mark A , Serre David
Published: March 2024

Plasmodium parasites caused over 600,000 deaths in 2022. In Mali, P. falciparum is responsible for the majority of malaria cases and deaths and is transmitted seasonally. Anti-malarial immunity develops slowly over repeated exposures to P. falciparum but some aspects of this immunity (e.g., antibody titers) wane during the non-transmission, dry season. Here, we sequenced RNA from 33 pediatric blood samples collected during P. falciparum infections at the beginning or end of a transmission season and characterized the host and parasite gene expression profiles of paired, consecutive infections. Our analyses showed that human gene expression changes more over the course of one transmission season than it does between seasons, with signatures consistent with the partial development of adaptive immunity during one transmission season, contrasting with the stability in gene expression during the dry season. By contrast, P. falciparum gene expression did not seem to vary significantly and remained stable both across and between seasons. Overall, our results provide novel insights into the dynamics of anti-malarial immunity development over short timeframes.
High-throughput selection of glucose-binding proteins from massive datasets: Integrating molecular docking and molecular dynamics simulations
Authors: Makare Anurag , Chaudhary Amit , De Debankita , Deshpande Parijat , Panwar Ajay Singh
Published: March 2024

Selecting suitable glucose-binding proteins (GBPs) is vital for biosensor development for medical diagnostics and quality control in the food industry. Biosensors offer advantages such as high specificity, selectivity, fast response time, continuous measurement, and cost-effectiveness. The current work utilized a combination of molecular docking, molecular dynamics (MD) simulations, and free energy calculations to develop a high-throughput bioinformatics pipeline to select GBP candidates from an extensive protein database (37,325 proteins). Using molecular docking, GBPs with good binding affinity to glucose (1,447 candidates) were virtually screened from the Protein Data Bank. MD simulations ascertained the binding dynamics of a few selected candidates. Further, steered MD (Brownian dynamics fluctuation-dissipation-theorem) was used to estimate binding free energies of the ligand-protein complex. Correlations between ligand-binding parameters obtained from longer MD simulations and binding parameters interpreted from significantly faster docking simulations were investigated. The correlation plots suggested that a combination of threshold values of the following three docking parameters: docking binding energy, binding cavity depth, and the number of hydrogen bonds between the ligand and binding site residues can be used to predict candidate GBPs reliably. Thus, a high-throughput and accurate protein selection process based on relatively faster docking simulations was proposed to screen GBPs for glucose biosensing.
GLMsim: a GLM-based single cell RNA-seq simulator incorporating batch and biological effects
Authors: Wang Jianan , Chen Lizhong , Thijssen Rachel , Phipson Belinda , Speed Terence P.
Published: March 2024

With development of the single cell RNA-seq technologies, large numbers of cells can now be routinely sequenced by different platforms. This requires us to choose an efficient integration tool to merge those cells, and computational simulators to help benchmark and assess the performance of these tools. Although existing single cell RNA-seq simulators can simulate library size, biological and batch effects separately, they currently do not capture associations among these three factors. Here we present GLMsim, the first single cell RNA-seq simulator to simultaneously capture the library size, biology and unwanted variation and their associations via a generalized linear model, and to simulate data resembling the original experimental data in these respects. GLMsim is capable of quantitatively benchmarking different single cell integration methods, and assessing their abilities to retain biology and remove library size and batch effects.
Multi-omics of a rice population identifies genes and genomic regions in rice that bestow low glycemic index and high protein content
Authors: Badoni Saurabh , Pasion-Uy Erstelle , Kor Sakshi , Kim SungRyul , Misra Gopal , Tiozon Rhowell , Buenafe Reuben James Q. , Ramos-Castrosanto Ana Rose , Pratap Vipin , Slamet-Loedin Inez , Steimker Julia von , Alseekh Saleh , Fernie Alisdair R. , Kohli Ajay , Khush Gurudev S. , Sreenivasulu Nese
Published: March 2024

To address the growing incidences of increased diabetes and to meet the daily protein requirements, we developed low glycemic index (GI) rice varieties with protein yield exceeding 14%. In the development of recombinant inbred lines using Samba Mahsuri and IR36 amylose extender as parental lines, we identified quantitative trait loci (QTLs) and genes associated with low GI, high amylose content (AC), and high protein content (PC). By integrating genetic techniques with classification models, this comprehensive approach identified candidate genes on chromosome 2 (qGI2.1/qAC2.1 spanning the region from 18.62Mb to 19.95Mb), exerting influence on low GI and high amylose. Notably, the phenotypic variant with high value was associated with the recessive allele of the starch branching enzyme 2b (sbeIIb). The genome-edited sbeIIb line confirmed low GI phenotype in milled rice grains. Further, combinations of alleles from the highly significant SNPs from the targeted associations and epistatically interacting genes showed ultra-low GI phenotypes with high amylose and high protein. Metabolomics analysis of rice with varying AC, PC, and GI revealed that the superior lines of high AC and PC, and low GI were preferentially enriched in glycolytic and amino acid metabolism, whereas the inferior lines of low AC and PC and high GI were enriched with fatty acid metabolism. The high amylose high protein RIL (HAHP_101) was enriched in essential amino acids like lysine. Such lines may be highly relevant for food product development to address diabetes and malnutrition.

Significance Statement

The increasing global incidence of diabetes calls for the development of diabetic friendly healthier rice. In this study, we developed recombinant inbred rice lines with milled rice exhibiting ultra-low to low glycemic index and high protein content from the cross between Samba Mahsuri and IR36 amylose extender. We performed comprehensive genomics and metabolomics complemented with modeling analyses emphasizing the importance ofOsSbeIIbalong with additional candidate genes whose variations allowed us to produce target rice lines with lower glycemic index and high protein content in a high-yielding background. These lines represent an important breeding resource to address food and nutritional security.
Aberrant neuronal hyperactivation causes an age- and diet-dependent decline in associative learning behavior
Authors: Aleogho Binta Maria , Mohri Mizuho , Jang Moon Sun , Tsukada Sachio , Al-Hebri Yana , Tsukada Yuki , Mori Ikue , Noma Kentaro
Published: March 2024

The impairment of memory, cognition, and behavior during aging is generally thought to arise from diminished neuronal activities. The nematodeCaenorhabditis elegansexhibits age-dependent declines in an associative learning behavior called thermotaxis. Genetic ablation of individual neurons revealed that an absence of either AWC sensory or AIA inter-neurons preserved the thermotaxis ability of aged animals. Calcium imaging showed age-dependent spontaneous hyperactivities in both neurons. The age-dependent neuronal hyperactivity and behavioral decline were ameliorated by changing diets. We further demonstrate that the enhanced activities of AWC and AIA were differentially dependent on the forms of neurotransmission mediated by neurotransmitters and neuropeptides. Together, our data provides evidence that aberrantly enhanced, not diminished, neuronal responses can impair behavior during aging.

One-Sentence Summary

Enhanced neuronal activity during aging impairsC. eleganslearning behavior.
Consensus Clustering for Robust Bioinformatics Analysis
Authors: Yousefi Behnam , Schwikowski Benno
Published: March 2024

Clustering plays an important role in a multitude of bioinformatics applications, including protein function prediction, population genetics, and gene expression analysis. The results of most clustering algorithms are sensitive to variations of the input data, the clustering algorithm and its parameters, and individual datasets. Consensus clustering (CC) is an extension to clustering algorithms that aims to construct a robust result from those clustering features that are invariant under the above sources of variation. As part of CC, stability scores can provide an idea of the degree of reliability of the resulting clustering. This review structures the CC approaches in the literature into three principal types, introduces and illustrates the concept of stability scores, and illustrates the use of CC in applications to simulated and real-world gene expression datasets. Open-source R implementations for each of these CC algorithms are available in the GitHub repository:https://github.com/behnam-yousefi/ConsensusClustering