bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects and dynamics of D-alanine in diabetes
Authors: Sakai Shinsuke , Okushima Hiroki , Iwata Yukimasa , Hayashi Terumasa , Takahara Shiro , Horio Masaru , Mita Masashi , Nakane Maiko , Kimura-Ohba Shihoko , Imamura Ryoichi , Kakuta Yoichi , Mizui Masayuki , Isaka Yoshitaka , Kimura Tomonori
Published: December 2024

Background

D-alanine, a rare enantiomer of alanine, mediates renal gluconeogenesis and protects against viral infections by regulating the circadian clock’s transcriptional network. These features of D-alanine are associated with the diabetes, which disrupts circadian rhythm and worsens Covid-19 outcomes. This study examined the effects and dynamics of D-alanine in diabetic conditions.

Methods

Blood and urine levels of D-alanine were measured in diabetic model mice and patients with diabetic kidney disease using a two-dimensional high-performance liquid chromatography system. Gluconeogenic activity of D-alanine was assessed by glucose production assay inex vivo-cultured kidney cells. Glucose tolerance test was performed in mice treated with D-alanine.

Results

The circadian rhythm of D-alanine, present in healthy mice, was disrupted in diabetic model mice. Patients with diabetic kidney disease showed abnormal urinary excretion of D-alanine. In diabetic mice, D-alanine stimulated gluconeogenesis in kidneys. Although D-alanine treatment temporarily raised blood glucose levels, repetitive treatment of D-alanine did not worsen glucose tolerance in the tested conditions.

Conclusions

An abnormal circadian rhythm of D-alanine is a hallmark of diabetes. In diabetic mice, D-alanine affects kidney function without worsening the diabetic conditions. D-Alanine may provide a therapeutic option for diabetes by correcting circadian rhythms and treating viral infections.
Functional Ultrasound Imaging of Auditory Responses in Comatose Patients
Authors: Chen Zihao , Li Na , Xi Caihua , Zhu Jiejun , Wu Gang , Xia Jinzhao , Fei Chunlong , Sun Lei , Xu Hongzhi , Qiu Zhihai
Published: December 2024

Bedside monitoring of brain function in severely brain-injured patients remains a critical clinical challenge. We demonstrate the translational potential of functional ultrasound (fUS) imaging for this purpose. In two comatose patients (Glasgow Coma Scale ≤8) with cranial windows post-decompressive craniectomy, we used a 7.8 MHz transducer optimized for cortical depths of 1.5–4 cm to perform real-time fUS during auditory stimulation. We observed task-related increases in regional cerebral blood flow (rCBF) in relevant brain regions (P < 10^-3, t-test), which correlated with subsequent neurological recovery at nine-month follow-up. These findings establish fUS as a sensitive and portable tool for bedside brain function assessment, offering potential for improved prognostication, treatment guidance, and development of targeted rehabilitative strategies.
Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases
Authors: Stenton Sarah L. , Laricchia Kristen , Lake Nicole J. , Chaluvadi Sushma , Ganesh Vijay , DiTroia Stephanie , Osei-Owusu Ikeoluwa , Pais Lynn , O’Heir Emily , Austin-Tse Christina , O’Leary Melanie , Abu Shanap Mayada , Barrows Chelsea , Berger Seth , Bönnemann Carsten G. , Bujakowska Kinga M. , Campagna Dean R. , Compton Alison G. , Donkervoort Sandra , Fleming Mark D. , Gallacher Lyndon , Gleeson Joseph G. , Haliloglu Goknur , Pierce Eric A. , Place Emily M. , Sankaran Vijay G. , Shimamura Akiko , Stark Zornitza , Yang Tan Tiong , Thorburn David R. , White Susan M. ,   Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium, Vilain Eric , Lek Monkol , Rehm Heidi L. , O’Donnell-Luria Anne
Published: December 2024

Background

Variants in the mitochondrial genome (mtDNA) cause a diverse collection of mitochondrial diseases and have extensive phenotypic overlap with Mendelian diseases encoded on the nuclear genome. The mtDNA is often not specifically evaluated in patients with suspected Mendelian disease, resulting in overlooked diagnostic variants.

Methods

Using dedicated pipelines to address the technical challenges posed by the mtDNA - circular genome, variant heteroplasmy, and nuclear misalignment - single nucleotide variants, small indels, and large mtDNA deletions were called from exome and genome sequencing data, in addition to RNA-sequencing when available. A cohort of 6,660 rare disease families were analyzed (5,625 genetically undiagnosed, 84%) from the Genomics Research to Elucidate the Genetics of Rare diseases (GREGoR) Consortium as well as other rare disease cohorts.

Results

Diagnostic mtDNA variants were identified in 10 previously genetically undiagnosed families (one large deletion, eight reported pathogenic variants, one novel pathogenic variant). In one additional undiagnosed proband, the detection of >900 heteroplasmic variants provided functional evidence of pathogenicity to a novelde novovariant in the nuclear genePOLG(DNA polymerase gamma), responsible for mtDNA replication and repair.

Conclusion

mtDNA variant calling from data generated by exome and genome sequencing for nuclear variant analysis resulted in a genetic diagnosis or detection of a candidate variant for 0.4% of undiagnosed families affected by a broad range of rare diseases.
MEANtools: multi-omics integration towards metabolite anticipation and biosynthetic pathway prediction
Authors: Singh Kumar Saurabh , Suarez Duran Hernando , Del Pup Elena , Zafra-Delgado Olga , Van Wees Saskia C.M. , van der Hooft Justin J.J.i , Medema Marnix H.
Published: December 2024

During evolution, plants have developed the ability to produce a vast array of specialized metabolites, which play crucial roles in helping plants adapt to different environmental niches. However, their biosynthetic pathways remain largely elusive. In the past decades, increasing numbers of plant biosynthetic pathways have been elucidated based on approaches utilizing genomics, transcriptomics, and metabolomics. These efforts, however, are limited by the fact that they typically adopt a target-based approach, requiring prior knowledge. Here, we present MEANtools, a systematic and unsupervised computational integrative omics workflow to predict candidate metabolic pathwaysde novoby leveraging knowledge of general reaction rules and metabolic structures stored in public databases. In our approach, possible connections between metabolites and transcripts that show correlated abundance across samples are identified using reaction rules linked to the transcript-encoded enzyme families. MEANtools thus assesses whether these reactions can connect transcript-correlated mass features within a candidate metabolic pathway. We validate MEANtools using a paired transcriptomic-metabolomic dataset recently generated to reconstruct the falcarindiol biosynthetic pathway in tomato. MEANtools correctly anticipated five out of seven steps of the characterized pathway and also identified other candidate pathways involved in specialized metabolism, which demonstrates its potential for hypothesis generation. Altogether, MEANtools represents a significant advancement to integrate multi-omics data for the elucidation of biochemical pathways in plants and beyond.
Impact of Proximal Tubule-Specific Deletion of Dipeptidyl Peptidase 4 on Blood Pressure, Renal Sodium Handling, and NHE3 Phosphorylation
Authors: Martins Flavia L. , Ribeiro-Silva Joao Carlos , Jesus Erika Fernandes de , Nistala Ravi , Girardi Adriana C. C.
Published: December 2024

Dipeptidyl peptidase 4 (DPP4) is a transmembrane serine exopeptidase abundantly expressed in the kidneys, predominantly in the proximal tubule (PT); however, its non-enzymatic functions in this nephron segment remain poorly understood. While DPP4 physically associates with the Na+/H+exchanger isoform 3 (NHE3) and its inhibitors exert natriuretic effects, the DPP4 role in blood pressure (BP) regulation remains controversial. This study investigated the effects of PT-specificDpp4deletion (Dpp4ΔPT) and globalDpp4deletion (Dpp4−/−) on systolic blood pressure (SBP), natriuresis, and NHE3 regulation under baseline and angiotensin II (Ang II)-stimulated conditions in both male and female mice. Global and PT-specificDpp4deletion increased diuretic and natriuretic responses to acute saline loading, correlating with enhanced phosphorylation of NHE3 at serine 552 (pS552-NHE3). However, baseline SBP remained unchanged. Ang II stimulation increased DPP4 activity in control mice, with a greater effect in males than in females, reflecting sex-dependent regulation of renal DPP4. InDpp4ΔPTmice, residual kidney DPP4 was unresponsive to Ang II, indicating that PT DPP4, rather than DPP4 in other nephron segments, is regulated by Ang II. Ang II administration increased SBP in all groups; however, the pressor response was significantly attenuated in bothDpp4ΔPTandDpp4−/−mice, coinciding with sustained elevated levels of pS552-NHE3. Collectively, these findings demonstrate that PT DPP4 modulates NHE3 activity through mechanisms that prevent the accumulation of pS552-NHE3, exerting an anti-natriuretic effect. In the absence of DPP4, these mechanisms are disrupted, reducing Ang II sensitivity and maintaining high pS552-NHE3 levels, underscoring the role of DPP4 in PT signaling and function.
Interferon-β induction heterogeneity during KSHV infection is determined by interferon-β enhanceosome transcription factors other than IRF3
Authors: Kaku Machika , Gaglia Marta Maria
Published: December 2024

Strict regulation of type I interferons (IFN) is vital for balancing tissue damage and immunity against infections. We previously found that during Kaposi’s sarcoma-associated herpesvirus infection, IFN induction was limited to a small percentage of infected B cells. This heterogeneity was not explained by viral gene expression. Here, we used a fluorescent reporter and fluorescence-activated cell sorting to investigate the source of this heterogeneity. Surprisingly, the canonical IFN induction pathway culminating in the activation of the IRF3 transcription factor was similar between cells that made high vs. low/no IFN-β. In contrast, the activation or expression of two other IFN transcription factors, NF-κB and AP-1, correlated with heterogeneous IFN-β induction. Our results suggest that at the level of individual cells, IRF3 is crucial as a pathogen detection signal, but NF-κB and AP-1 are limiting for IFN-β induction.
Safety and efficacy of bronchus-blocked ultrasound-guided percutaneous transthoracic needle biopsy (BUS-PTNB) for critically ill patients under invasive mechanical ventilation: a prospective, single-arm trial
Authors: Yu He , Liu Yun , Wang Zhen , Sun Peng , Wang Weiya , Xia Wenxi , Qi Wenli , Wu Linfei , Liu Guangdi , Zhou Yaxiong , Yao Rong , Zhao Yuean , Liu Siyu , Lin Xue , He Qian , Liang Zuoyu , Yin Wanhong , Zhou Ran , Mi Yiqun , Luo Jianjiang , Zhou Hui , Long Huaicong , Luo Zhuang , Fan Junping , Powell Charles A. , Liang Zongan , Wang Ye
Published: December 2024

Objectives

Conventional lung biopsy for critically ill patients who under invasive mechanical ventilation (IMV) is limited due to high risks of procedure-related complications. We developed a novel technique named bronchus-blocked ultrasound-guided percutaneous transthoracic needle biopsy (BUS-PTNB) to mitigate the risks of biopsy under IMV, but its safety and efficacy have not been prospectively evaluated.

Methods

In this prospective, single-arm trial (Chictr.org, ChiCTR2100054047), invasively ventilated patients with undiagnosed lung opacities were screened and underwent BUS-PTNB after enrollment. The peri-operative conditions, severity of complications, pathological findings, and tissue-based metagenomic next-generation sequencing (mNGS) results were systemically evaluated.

Results

A total of 22 critically ill patients (18 men, mean age, 64.2 years [SD 11.7], APACHE II score, 27.0 [SD 5.6], PaO2/FiO2ratio, 120.5 [IQR 91.9–169.1]) under IMV were enrolled in the study. Throughout the procedure, there were no significant changes in respiratory rate or PaO2. Biopsy-related complications occurred in 3 patients (13.6%), including pneumothorax (n=1, 4.5%), intrabronchial hemorrhage (n=2, 9.1%), and hemothorax (n=3, 13.6%). Notably, one patient (P10) required a blood transfusion due to hemothorax, which was classified as a severe complication (1/22, 4.5%). Satisfactory biopsy samples were obtained from 21 patients (95.5%) for pathological study and from all 22 patients (100%) for mNGS.

Conclusions

The novelBUS-PTNB is a promising bedside biopsy technique for ICU patients under IMV with acceptable complication risk. This technique may prove instrumental in advancing pathological studies of severe lung diseases.

Key points and Clinical Relevance Statement

Question

We developed bronchus-blocked ultrasound-guided percutaneous transthoracic needle biopsy (BUS-PTNB) for patients under invasive mechanical ventilation, but its safety and efficacy have not been prospectively evaluated.

Findings

Patients’ vital signs showed no significant fluctuations. Biopsy-related complications occurred in 3 patients out of 22. Satisfactory samples were obtained for pathological study and mNGS.

Clinical Relevance

BUS-PTNB is a promising bedside biopsy technique for ICU patients under IMV with acceptable complication risk. This technique may prove instrumental in advancing pathological studies of severe lung diseases.
Predictors of glycemic control, quality of life and diabetes self-management of patients with diabetes mellitus at a tertiary hospital in Ghana
Authors: Gyan Kwadwo Faka , Agyenim-Boateng Enoch , Hutton-Mensah Kojo Awotwi , Opare-Addo Priscilla Abrafi , Gyabaah Solomon , Ofori Emmanuel , Asamoah Osei Yaw , Naabo Mohammed Najeeb , Owiredu Michael Asiedu , Tannor Elliot Koranteng
Published: December 2024

Background

The burden of diabetes mellitus (DM) in Sub-Saharan Africa is high and continues to increase. Effective DM management focuses on key goals such as glycemic control, prevention of acute and chronic complications and improvement of quality of life (QOL). This study therefore assessed predictors of glycemic control, QOL and diabetes self-management (DSM) of patients with DM in a tertiary hospital in Ghana.

Methods

We conducted a cross-sectional study involving face-to-face interviews of patients with DM attending clinic using structured questionnaires and validated study instruments as well as review of medical records. A multivariable logistics regression analysis was used to identify independent factors associated with good glycemic control, poor QOL and poor DSM practices.

Results

The study involved 360 patients with mean age of 62.5 ± 11.6 years and a female preponderance, 271 (75.3%). The mean HbA1c among study participants was 7.8 ± 2.7% of which 44.7% had HbA1C <7%. Patients on only oral DM medications (aOR 2.14; 95% CI 1.19-3.88, p=0.012) were more likely to have good glycemic control. Urban residence (aOR 0.24; 95% CI 0.06-0.87, p=0.030) and good DSM (aOR 0.05; 95% CI 0.02-0.13, p<0.001) were protective of having poor QOL however, recent hospitalization (within the past 3 months) (aOR 4.58; 95 % CI 1.58-13.26, p=0.005) had higher odds of poor quality of life. Patients who were divorced (aOR 6.79; 95% CI 1.20-40.42, p=0.030) had higher odds of poor DSM, while having attended the clinic for more than 3 years (aOR 0.32; 95% CI 0.12-0.81, p=0.016) was protective of poor DSM.

Conclusion

Good social support and sustained DSM interventions result in good DSM and ultimately improves quality of life of patients with DM.
Chikungunya’s return amidst 2024 dengue season: Implications for future outbreaks in Bangladesh
Authors: Hasan Anamul , Zamil Md. Fahad , Trina Afrida Tabassum , Hossain Mohammad Sharif , Afreen Sajia , Ahmed Dilruba , Alam Mohammad Shafiul
Published: December 2024

Chikungunya, an arboviral disease transmitted byAedesmosquitoes, shares clinical similarities with dengue, but is distinguished by prolonged joint pain. Following a major outbreak in Bangladesh in 2017, chikungunya nearly vanished from its territory. The study participants were recruited prospectively following specific inclusion criteria and obtained written informed consent. Out of 1280 febrile individuals screened, 569 met the criteria of fever onset within 2-5 days, accompanied by symptoms such as headache, myalgia, bone and joint pain, rash, nausea, vomiting, or diarrhea. Of these, 474 underwent real-time RT-PCR testing. Among the samples tested, 213 were PCR-positive for at least one arbovirus. Chikungunya cases totaled 55, including 7 coinfections (6 with DENV, and the first documented CHIKV-ZIKV coinfection in Bangladesh). No infections were reported from January to August, with a peak in October and November. Most CHIKV infections (72.7%) had moderate to high viral loads, with common symptoms of joint pain, myalgia, and headaches. The resurgence of Chikungunya in late 2024 underscores the potential for a major outbreak in 2025, necessitating proactive measures to mitigate public health impact and ensure a robust response to this re-emerging threat.
COVID-19 Beliefs, Behaviors, and Perceptions Among Students on a College Campus During the Global Coronavirus Pandemic
Authors: White Avian , Iverson Guy , Wright LaNika , Fallon John T. , Humphrey Charles
Published: December 2024

Objectives

Elucidating how people think and behave during a disease outbreak may provide valuable insight and help direct programs or surveillance to combat the spread of disease. As universities welcomed students back to their campuses following COVID-19 shutdowns, it became important to know students’ beliefs on COVID-19 and how these beliefs guided behaviors?

The objective of this study was to determine how students at East Carolina University felt about COVID-19, which behaviors they exhibited during the pandemic, and whether their feelings and behaviors differed significantly between the Spring and Fall 2021 semesters.

Methods

Surveys (N= 408) were distributed to students who were currently enrolled in Environmental Health Science classes during the Spring and Fall semesters of 2021. Questions were developed using a Likert scale and were analyzed to determine significant differences (p < 0.05) between semesters. Statistical analyses were performed using SPSS (SPSS Institute, Chicago, Ill).

Results

Results showed most students felt “somewhat concerned” about the COVID-19 pandemic during both semesters. Significant differences in student concern regarding COVID-19 between Spring and Fall semesters, were not observedp= 0.598. Student behaviors regarding weekly gatherings significant differed between semesters with a reported increase in gatherings of 5+ during the Fall semester,p< 0.001. Interestingly, we found more students indicated during the Spring semester in comparison to the Fall that they believed the vaccine was not safe and they would not take it (p< 0.001).

Conclusion

Our findings suggest that as the pandemic went on, behavior changes were observed in students between the semesters. This information may be important to officials as cases may fluctuate over time. Knowledge of attitudes and/or behaviors and awareness may help explain these fluctuations, allowing public health professionals to adjust recommendations and focus more intently on populations at risk.
LinAge2: Providing actionable insights and benchmarking with epigenetic clocks
Authors: Fong Sheng , Denisov Kirill A. , Kennedy Brian K. , Gruber Jan
Published: December 2024

Biological aging is marked by a decline in resilience at the cellular and systemic levels, driving an exponential increase in mortality risk. Here, we evaluate several clinical and epigenetic clocks for their ability to predict mortality, demonstrating that clocks trained on survival and functional aging outperform those trained on chronological age. We present an enhanced clinical clock that predicts mortality more accurately and provides actionable insights for guiding personalized interventions. These findings highlight the potential of mortality-predicting clocks to inform clinical decision-making and promote strategies for healthy longevity.
CORTADO: Hill Climbing Optimization for Cell-Type Specific Marker Gene Discovery
Authors: Lodi Musaddiq K , Clark Leiliani , Roy Satyaki , Ghosh Preetam
Published: December 2024

The advent of single-cell RNA sequencing (scRNA-seq) has greatly enhanced our ability to explore cellular heterogeneity with high resolution. Identifying subpopulations of cells and their associated molecular markers is crucial in understanding their distinct roles in tissues. To address the challenges in marker gene selection, we introduce CORTADO, a computational framework based on hill-climbing optimization for the efficient discovery of cell-type-specific markers. CORTADO optimizes three critical properties: differential expression in the clusters of interest, distinctiveness in gene expression profiles to minimize redundancy, and sparseness to ensure a concise and biologically meaningful marker set. Unlike traditional methods that rely on ranking genes by p-values, CORTADO incorporates both differential expression metrics and penalties for overlapping expression profiles, ensuring that each selected marker uniquely represents its cluster while maintaining biological relevance. Its flexibility supports both constrained and unconstrained marker selection, allowing users to specify the number of markers to identify, making it adaptable to diverse analytical needs and scalable to datasets with varying complexities. To validate its performance, we apply CORTADO to several datasets, including the DLPFC 151507 dataset, the Zeisel mouse brain dataset, and a peripheral blood mononuclear cell dataset. Through enrichment analysis and examination of spatial localization-based expression, we demonstrate the robustness of CORTADO in identifying biologically relevant and non-redundant markers in complex datasets. CORTADO provides an efficient and scalable solution for cell-type marker discovery, offering improved sensitivity and specificity compared to existing methods.
Ganoderma formosanumpolysaccharides enhance antitumor immune responses by downregulating the differentiation of myeloid-derived suppressor cells and tumor-associated macrophages
Authors: Yang Jhe-Yu , Chen Kuei-Liang , Lin Yang-Chia , Chiu Hsien-Chan , Hsieh Hsin-Tien , Chen Chun-Jen
Published: December 2024

Ganoderma formosanumis a native species ofGanodermaisolated in Taiwan, and our previous studies showed that a polysaccharide fraction, PS-F2, purified from the submerged culture fluid ofG. formosanumATCC 76538 exhibited immunostimulatory and antitumor property. In the current study, we investigated the immunomodulatory and antitumor effects of PS-F2 from a UV-mutatedG. formosanumvariant NTU-1, which produced higher yields of PS-F2 than the original strain. Oral administration of PS-F2 effectively suppressed the growth of colon 26 (CT-26) carcinoma and splenomegaly in tumor-bearing mice without adversely affecting the animals’ health. We found that PS-F2 treatment resulted in augmented cytotoxic T lymphocyte (CTL) while significantly reducing the accumulation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and regulatory T (Treg) cells in the spleen. In the tumor, PS-F2 treatment markedly enhanced CTL and Th1 responses, whereas it reduced the accumulation of tumor-associated macrophages (TAMs). Collectively, our data demonstrate that oral treatment of PS-F2 fromG. formosanumNTU-1 in CT26 tumor-bearing mice activates antitumor immune responses and reduces the accumulation of immunosuppressive cells in the spleen and the tumor, leading to delayed tumor progression.
MAPK15 PROTECTS AGAINST THE DEVELOPMENT OF METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE
Authors: Inzalaco Giovanni , Gargiulo Sara , Bonente Denise , Gherardini Lisa , Franci Lorenzo , Lorito Nicla , Turco Serena Del , Tatoni Danilo , Tamborrino Tiziana , Bertelli Eugenio , D’Aurizio Romina , Andreassi Maria Grazia , Basta Giuseppina , Gastaldelli Amalia , Morandi Andrea , Barone Virginia , Chiariello Mario
Published: December 2024

Accumulation of lipids in the liver characterizes metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent chronic liver disease worldwide. As liver injury progresses to metabolic dysfunction-associated steatohepatitis (MASH), MASLD can predispose individuals to cirrhosis and hepatocellular carcinoma. Here, we characterized the first knockout mouse model for mitogen-activated protein kinase 15 (MAPK15) and revealed its critical role in controlling lipid homeostasis in the liver. Indeed,Mapk15-/-mice exhibited a MASLD-like phenotype, and hepatocellular models allowed us to demonstrate that dysregulated accumulation of lipids was due to increased expression and membrane localization of the CD36 fatty acid translocase. Consistently,Mapk15-/-mice exhibited elevated hepatic levels of CD36 and feeding them with a western-type diet significantly accelerated their progression to a MASH-like phenotype. Ultimately, transcriptomic analysis of human cohorts revealed increased liver expression ofMAPK15in MASLD patients, compared to unaffected individuals, ultimately supporting a protective role for MAPK15 against this disease. Overall, our data highlight a critical role for MAPK15 in liver physiopathology, by contributing to maintain physiological intracellular levels of lipids in this tissue.
Framework for assessing the risk to a field from fraudulent research
Authors: Ni Chaoqun , Hutchins B. Ian
Published: December 2024

Concerns over research integrity are rising, with increasing attention to potential threats from untrustworthy authors. We established a framework to gauge the potential negative influence of researchers potentially engaged in misconduct. The field of Alzheimer’s Disease (AD) research has been a focal point of these worries. This study aims to assess the risk posed by questionable studies or individuals potentially engaging in fraudulent science in research by examining citation relationships among papers, taking AD research as an illustrative example. Analysis of citation network structure can elucidate the potential propagation of misinformation arising at the author level. Our analysis revealed that there aren’t any single authors or papers whose citation connections jeopardize a major portion of the field’s literature. This indicates a low probability of single entities undermining the majority of works in this area. However, our findings suggest that attention to research integrity of the most influential scientists is warranted. Some scientists can reach a sizable minority of the literature through citations to their work. Emphasizing oversight of the integrity of these authors is crucial, given their influence on the field. Our study introduces an analytical framework adaptable across various fields and disciplines to evaluate potential risks from fraudulence.
MATING FREQUENCY MEDIATES PERSONALITY EXPRESSION IN FACULTATIVELY POLYANDROUS MITES
Authors: Schausberger Peter , Usugi Shogo , Wang Chenhao , Hinomoto Norihide
Published: December 2024

Animal personalities are characterized by within-individual consistency linked to among-individual variability. Personality expression may change during ontogeny and is often dependent on major life history transitions and events such as mating and the onset of reproduction. While the influence of female personalities on sexual selection and mating has long been known, the influence of the females’ mates on female personality expression after mating is poorly understood. Here we hypothesized that in facultatively polyandrous animals multiple mating increases the females’ assets, also called the residual reproductive value (RRV), due to direct and/or indirect benefits. Based on the predictions of the asset protection principle, higher RRV should promote behaviors that reduce the risk of fitness loss and hence mediate behavioral repeatability displayed in groups. We tested our hypothesis in the group-living, plant-inhabiting predatory mitePhytoseiulus persimilis. To this end, predatory mite females were presented with either a single mate or two mates in sequence and their post-mating repeatability in activity and sociability was evaluated in groups that were composed of females of the same and mixed mating types (monandrous and polyandrous). Mating frequency had little effects on activity patterns but pronounced effects on sociability traits. Polyandrous females were on average more sociable as well as more repeatable in sociability than monandrous females. These behavioral shifts reflect greater risk aversion and strategies to mitigate inter-individual conflicts within groups to enhance asset protection. Our study suggests that the mating frequency can critically influence female personality expression after mating in facultatively polyandrous animals and highlights the importance of considering mate-related variables in animal personality research.
Crossover model of Lep-Rec reveals higher heritability of recombination
Authors: Rastas Pasi , Kivioja Teemu
Published: December 2024

Meiotic recombination, a process that reshuffles DNA between parental chromosomes, is almost universal in multicellular organisms. Recombination accelerates the response to selection by breaking the linkage and creating new allelic combinations that can affect the fitness of the progeny. This motivates us to characterise recombination rate variation and to take it into account in evolutionary models and studies.

Linkage mapping utilises recombination to obtain recombination distances for genetic markers. With (whole) genome sequencing data, very dense linkage maps can be produced, locating crossovers precisely in the genome. This enables direct and accurate calculation of recombination distances, correction of possible errors in the genome and maps, and studying the relation between recombination and physical base-pair distances. This is now a relevant problem, as high-quality genomes are emerging for many species, and available dense linkage map data would supplement these genomes.

Here we present a novel software Lep-Rec to compute the local re-combination rate, i.e. the percentage of crossovers per individual per megabase (cM/Mb) along the genome. Moreover, it can also estimate the underlying, only partly observed, tetrad crossover distribution for each chromosome, while modelling crossover and chromatid interference. Together with Lep-MAP3 and Lep-Anchor, Lep-Rec forms a complete toolbox for studying recombination and crossovers: Lep-MAP3 can robustly construct linkage maps for large number of markers and individuals, while Lep-Anchor can anchor, validate and correct genome assemblies using linkage maps, and together these software provide consistent and complete physical and linkage maps for further analysis with Lep-Rec. Lep-Rec is available fromhttp://sourceforge.net/projects/lep-anchor.

Finally, we demonstrate the performance of Lep-Rec using real and simulated data: It outperforms and simplifies currently available tools and its estimated crossover distribution can improve association analysis and heritability estimates of recombination.
Neural differences in conflict monitoring and stimulus expectancy processes in experienced meditators are likely driven by enhanced attention
Authors: Hill Aron T. , Chung Sung Wook , Emonson Melanie , Corcoran Andrew W. , Fitzgibbon Bernadette M. , Fitzgerald Paul B. , Bailey Neil W.
Published: December 2024

Objectives

Mindfulness meditation has been linked to enhanced attention and executive function, likely resulting from practice-related effects on neural activity patterns. In this study, we used an event-related potential (ERP) paradigm to examine brain responses related to conflict monitoring and attention in experienced mindfulness meditators to better understand key factors driving meditation-related effects.

Methods

We measured electroencephalography-derived N2 and P3 ERPs reflecting conflict monitoring and attention processes from 35 meditators and 29 non-meditators across both an easy and a hard Go/Nogo task (50% Nogo and 25% Nogo stimuli, respectively).

Results

Meditators displayed distinct neural activity patterns compared to non-meditators, with enhanced N2 responses in fronto-midline electrodes following hard Nogo trials (pFDR= 0.011,np2= 0.111). The fronto-midline N2 ERP was also larger following Nogo trials than Go trials, in the harder task condition, and was related to correct responses. Meditators also exhibited a more frontally distributed P3 ERP in the easy task compared to the hard task, while non-meditators showed a more frontally distributed P3 ERP in the hard task (pFDR= 0.015,np2= 0.079).

Conclusions

Mindfulness meditation was associated with distinct topographical patterns of neural activity in the attention task, without corresponding increases in global neural activity amplitudes. These meditation-related effects appear to be driven by attention-specific mechanisms, despite the examined neural activity being associated with conflict monitoring and stimulus expectancy. Our findings suggest that the cognitive benefits of meditation may only emerge in tasks that actively engage targeted cognitive processes, such as sustained attention.
A photoswitchable positive allosteric modulator to control the activation of the metabotropic glutamate receptor 5 by light
Authors: Dumazer Anaëlle , Borras-Tuduri Roser , Truong Iona , Cong Xiaojing , Malhaire Fanny , Rovira Xavier , Gomez-Santacana Xavier , Givalois Laurent , Lebon Guillaume , Llebaria Amadeu , Goudet Cyril
Published: December 2024

1.

The metabotropic glutamate receptor 5 (mGlu5) is widely expressed in the brain, where it plays an important role in synaptic plasticity, learning and memory, making it a therapeutic target of interest in various neurological disorders. In this study, we developed a photoswitchable positive allosteric modulator (PAM) of the mGlu5, as a novel tool for this clinically relevant drug target. To that aim, we used an azologisation strategy of the mGlu5PAM agonist VU0424465 leading to the molecule azoglurax. We observed a reversible photoisomerization of azoglurax in solution with optimal wavelengths of 365 nm and 435 nm fortranstocisandcistotransisomerization, respectively. In cell-based assays, azoglurax potentiates the agonist-induced activity of mGlu5with a sub-micromolar potency in the dark. This potency is reduced under UV illumination. Similar to its parent molecule, azoglurax acts as an allosteric agonist of mGlu5, activating the receptor in absence of glutamate, as demonstrated on a glutamate-insensitive mutant receptor. Docking and site-directed mutagenesis experiments also suggest that azoglurax and VU0424465 bind the same pocket. In addition, molecular dynamics oncis-azoglurax-bound mGlu5suggests that it azoglurax cis isomer does not bind stably in the receptor, in contrast to thetrans-isomer, explaining the difference of activity between the two isomers. In conclusion, azoglurax is the first mGlu5photoswitchable PAM agonist reported to date, retaining the properties and the binding mode of its parent in the dark, while the insertion of an azobenzene confers light-regulated activity.Graphical abstract
Scaling up drug combination surface prediction
Authors: Huusari Riikka , Wang Tianduanyi , Szedmak Sandor , Dias Diogo , Aittokallio Tero , Rousu Juho
Published: December 2024

Drug combinations are required to treat advanced cancers and other complex diseases. Compared to monotherapy, combination treatments can enhance efficacy and reduce toxicity by lowering the doses of single drugs – and there especially synergistic combinations are of interest. Since drug combination screening experiments are costly and time consuming, reliable machine learning models are needed for prioritizing potential combinations for further studies. Most of the current machine learning models are based on scalar-valued approaches, which predict individual response values or synergy scores for drug combinations. We take a functional output prediction approach, in which full, continuous dose-response combination surfaces are predicted for each drug combination on the cell lines. We investigate the predictive power of the recently proposed comboKR method, which is based on a powerful input-output kernel regression technique and functional modelling of the response surface. In this work, we develop a scaled-up formulation of the comboKR, that also implements improved modeling choices: 1) we incorporate new modeling choices for the output drug combination response surfaces to the comboKR framework, and 2) propose a projected gradient descent method to solve the challenging pre-image problem that traditionally is solved with simple candidate set approaches. We provide thorough experimental analysis of comboKR 2.0 with three real-word datasets within various challenging experimental settings, including cases where drugs or cell lines have not been encountered in the training data. Our comparison with synergy score prediction methods further highlights the relevance of dose-response prediction approaches, instead of relying on simple scoring methods.
WNT signaling coordinately controls mouse limb bud outgrowth and establishment of the digit-interdigit pattern
Authors: Malkmus Jonas , Morabito Angela , Lopez-Delisle Lucille , Avino Esteban Laura , Mayran Alexandre , Zuniga Aimee , Sharpe James , Zeller Rolf , Sheth Rushikesh
Published: December 2024

Self-organization, such as the emergence of a pattern from a homogenous state, is a fascinating property of biological systems. Early limb bud outgrowth and patterning in mice are controlled by a robust and self-regulatory signaling system, and initiation of the periodic digit-interdigit pattern appears under control of a self-regulatory Turing system. Previous studies established the requirement of WNT and BMP signaling for both early limb bud and digit-interdigit morphogenesis, but the molecular changes underlying the transition from early limb bud signaling to the digit-interdigit patterning system remained unknown. Here, we use small molecule inhibitors to rapidly but transiently block WNT signaling to identify the early transcriptional targets that are altered during disruption and recovery of limb bud and digit development. Together, this study highlights the overarching role of WNT signaling in controlling early limb bud outgrowth and patterning, and establishment of the periodic digit-interdigit pattern. Finally, the transient WNT signaling disruption approach reveals the plasticity and robustness of these self-organizing limb bud and digit patterning systems.

Summary Statement

It was unknown how the signaling system controlling early limb bud development transitions to the periodic digit-interdigit patterning system. We show that WNT signaling controls this transition as an integral part of both signalling systems.
Fine-scale co-ocurrence patterns in grasslands reflect competition for space rather than broad plant strategies
Authors: Génin Alexandre , Devresse Louis , Garnier Eric , Coq Sylvain
Published: December 2024

Estimating the sign and strength of interactions among plants is central to understand the dynamics and functioning of communities, but is challenging to do for species-rich communities. Instead, spatial relationships between plants (clustering or spatial segregation) are sometimes used as a surrogate for the net effect of interactions ocurring between plants (positive or negative, respectively). However, this approach remains poorly tested outside of arid and alpine ecosystems, the ecological settings it originated from.

In experimental rangelands, we explored how management intensification, sheep exclusion and a natural soil depth gradient control the level of plant spatial segregation, or ‘negative co-occurrence’, usually considered as a measurement of competition intensity. We link these spatial patterns to classical broad plant strategies defined by 11 locally measured functional traits, and to the realized vegetation height and cover.

Plant segregation was highest when both grazing and fertilization were applied. Unexpectedly, general plant strategies (competitive, and acquisitive strategies) had little relationship with plant spatial patterns. Instead, spatial constraints increased segregation wherever cover was high and free bare ground was limited, or where plant growth is restricted by grazing to a few centimeters above ground.

These results show that fine-scale spatial patterns appear to capture competition for space, rather than for light or resources, as suggested by broad plant strategies. This may explain discrepancies in conclusions drawn from spatial patterns in grasslands, and clarifies the way towards a mechanistic understanding of spatial patterns.

Synthesis. The fine scale spatial organization of plant communities has been thought to reflect the intensity of competition among plants, but this approach has struggled to provide consistent results in grasslands. We show here that spatial patterns reflect competition for space rather than broad plant strategies captured by plant functional traits, helping us read observed plant spatial patterns to map interactions among plants in the field.
Phylogenomics of the sigmodontine rodents: Cloud forests and Pliocene extinction explain timing and spread of the radiation of South American mice and rats
Authors: Bangs Max R. , Percequillo Alexandre R. , Pacheco Víctor , Steppan Scott J.
Published: December 2024

Studies of radiations after invasion often overlook the potential role of climatic, biotic, and geologic triggers, instead focusing largely on the conduit for invasion. For example, studies of the rodent subfamily Sigmodontinae, a clade of over 500 species that radiated throughout South America during the Great American Biotic Interchange, have historically focused more on invasion than potential triggers or subsequent environmental change. Here, we put the timing and transitions of this radiation in context of changing climatic, biotic, and geologic factors by reconstructing the biogeography of the radiation. To accomplish this, we generated the largest genomic phylogeny of Sigmodontinae that include over 80% of the genera and 40% of the known species, including allincertae sedistaxa and produced a fossil-calibrated chronogram. Results indicate a single invasion of South America at the base of Sigmodontinae (∼ 10.46 million years ago [mya]) with two waves of increased lineage generation and biogeographic transition rates, the first of which occurred after a four-million-year lag following invasion. The timing and location of this initial radiation (6.61 - 5.78 mya) coincided with the spread of montane cloud forest during the Late Miocene Cooling and sigmodontines did not spread throughout the continent until the Mid-Pliocene Faunal Turnover (4.5 – 3.0 mya), a period of high extinction of South American mammals. A comprehensive classification for the subfamily is provided that accounts for the new results.
Increasing the acquisition speed in oblique plane microscopy via Aliasing
Authors: Mcfadden Conor , Manton James , Fiolka Reto
Published: December 2024

Oblique plane microcopy (OPM), a variant of light-sheet fluorescence microscopy (LSFM), enables rapid volumetric imaging without mechanically scanning the sample or an objective. In an OPM, the sample space is mapped to a distortion free image space via remote focusing, and the oblique light-sheet plane is mapped via a tilted tertiary imaging system onto a camera. As a result, the 3D point-spread function and optical transfer function are tilted to the optical axis of the tertiary imaging system. To satisfy Nyquist sampling, small scanning steps are required to encompass the tilted 3D OTF, slowing down acquisition and increasing sample exposure. Here we show that a judicious amount of under-sampling can lead to a form of aliasing in OPM that can be recovered without a loss of spatial resolution or introducing artifacts. The resulting speed gain depends on the optical parameters of the system and can reach 2-4-fold in our demonstrations. We leverage this speed gain for rapid subcellular 3D imaging of mitochondrial dynamics.
Wafer-scale integration of α-quartz thin films towards super high frequency piezoelectric bioNEMS for arbovirus detection
Authors: Rathar R. , Ding S. , Sanchez-Fuentes D. , Jolly C. , André-Arpin C. , Desgarceaux R. , Garcia-Bermejo R. , Gazquez J. , Plana-Ruiz S. , Picas L. , Carretero-Genevrier A.
Published: December 2024

Micro and nanoelectromechanical systems (MEMS/NEMS), especially piezoelectric resonators, offer a promising strategy for the manufacturing of point-of-care devices providing rapid, sensitive, and field-deployable tests with minimal user training for the diagnostic of viral infections. High-frequency (HF) MEMS/NEMS have the potential for ultrasensible mass-loading devices. Yet, their use for biomedical applications requires challenging manufacturing qualities. Here, we develop a large-scale chemical integration of epitaxial α-quartz (100) thin films on silicon wafers up to 4-inches. This methodology allows the microfabrication of wafer-scale piezoelectric α-quartz/silicon bioMEMS using a recognition layer capable of selectively detecting emerging arboviruses over other viral loads. Using contact-free vibrometry, we show a mass sensitivity of the bioMEMS device of 22.4 pg/Hz in liquid conditions and a Chikungunya virus limit of detection of 9 ng/ml. To reach piezoelectric transduction for compact quartz sensor devices, we develop NEMS resonators at super HF, i.e., 17.8 GHz with a quality factor of 280 which represents a QxF product of 4.98·1012. These α-quartz NEMS can reach thicknesses between 100 and 800 nm and lateral dimensions up to 9 mm2. Our work opens the door for cost-efficient single-chip epitaxial piezoelectric α-quartz/Si ultrasensitive NEMS sensors manufactured exclusively by soft-chemistry for biomedical applications and many other fields.
Chronic infection ofCaenorhabditis elegansby Orsay virus induces age-dependent immunity and superinfection exclusion
Authors: Castiglioni Victoria G. , Villena-Giménez Ana , González-Sánchez Antonio , Toft Christina , Gómez Gustavo G. , Elena Santiago F.
Published: December 2024

Orsay virus (OrV) is a natural pathogen ofC. elegans, which mounts an antiviral response upon infection and enables the investigation of the mechanisms governing infection and immunity. Here, we focus on two of these features, namely the effect of life-long infections and superinfection dynamics. By following the course of an infection throughout the lifespan of a synchronous wild-type population, we describe several viral load peaks followed by sharp decreases in viral load, suggesting that the infection is chronic and that animals manage to suppress viral replication successfully throughout most of their lives. Moreover, we show that animals that have been previously exposed to the virus are able to control viral replication upon a subsequent inoculation, indicative of superinfection exclusion. Primary infections produced transcriptomic and small RNA alterations, whose extent was highly dependent on the developmental stage of the worm at the time of infection and the time until sampling. Superinfection, in turn, had little impact on the overall transcriptome, but showed a misregulation of piRNAs, rRNAs, and tsRNAs. Superinfection exclusion was robust throughout larval development and adulthood, providing protection against various OrV isolates. However, the protective effect of the initial infection diminished over time, suggesting different mechanisms of action and ultimately favoring the primary infecting virus. This phenomenon was dependent on a functional RNA interference pathway.