bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between prehospital tranexamic acid and cerebral edema in patients with moderate or severe traumatic brain injury
Authors: McKinley William Ian , Lazaridis Christos , Mansour Ali , Hoefer Lea , Polcari Ann , Benjamin Andrew , Schreiber Martin , Rowell Susan E.
Published: February 2025

BACKGROUND

Traumatic brain injury (TBI) contributes to substantial morbidity and mortality worldwide. Tranexamic acid (TXA) has been shown to reduce mortality in patients with traumatic intracranial hemorrhage (ICH) when given within 2 hours of injury. Although TXA is an antifibrinolytic, most studies have observed no difference in ICH progression; recent studies suggest that TXA may reduce cerebral edema in TBI. Our objective was to determine if prehospital TXA administered within 2 hours of injury is associated with surrogates of cerebral edema in patients with moderate or severe TBI.

METHODS

We performed a retrospective analysis of a multinational prehospital trial of TXA administered within 2 hours of injury in patients with moderate or severe TBI. Patients with prehospital Glasgow Coma Scale score of <13 and systolic blood pressure of >90 mm Hg were randomized to placebo, 2-g TXA bolus, or 1-g TXA bolus followed by 1 g 8-hour TXA infusion. Patients who received an intracranial pressure (ICP) monitor were selected for analysis. Baseline demographic, injury severity, and infusion characteristics were compared between TXA dosing cohorts. Proportion of hours spent with ICP of >20 mm Hg, cerebral perfusion pressure (CPP) of <60 mm Hg, and need for craniectomy were compared between groups.

RESULTS

A total of 108 patients with ICP monitors made up the study population (placebo, n = 31; 1 g + 1 g, n = 38; 2-g bolus, n = 39). No differences were identified in age, sex, Abbreviated Injury Scale head, Glasgow Coma Scale, Injury Severity Score, crystalloid and blood product infused in first 24 hours, Marshall score, ICH, or mortality between the three treatment arms. No differences in proportions of hours in which ICP of >20 mm Hg or CPP of <60 mm Hg were identified between treatment arms; rate of craniectomy was also similar.

CONCLUSION

No association could be identified between TXA treatment and ICP elevation, CPP depression, or need for craniectomy. These results question TXA's potential impact on cerebral edema. Further study is needed to confirm this finding based on the exploratory nature and limited number of subjects in this study.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level IV.
The consequences of parental injury: Impacts on children’s health care utilization and financial barriers to care
Authors: Mahajan Arnav , Kamojjala Ruchika , Ilkhani Saba , Curry Caleb W. , Halkiadakis Penelope , Ladha Prerna , Simpson Megen , Sweeney Sarah A. , Ho Vanessa P.
Published: February 2025

BACKGROUND

Unintentional traumatic injuries pose a significant public health challenge, impacting not only injured individuals but also their families. Existing research has largely focused on the effects of a child's injury on their family, with limited attention to the consequences of parental injury on children's health. This study aims to explore the consequences of unintentional parental injury on children's health outcomes, health care utilization, and socioeconomic barriers to care.

METHODS

We utilized data from the National Health Interview Survey (NHIS) for 2020, 2021, and 2023, creating parent-child dyads where the parent was injured. Injury was defined by a positive response to experiencing an injury and seeking medical consultation after. Children aged 5 years to 17 years and their parents were included. Three outcome domains were examined: health outcomes, health care utilization, and socioeconomic health impacts. Bivariate and logistic regression analyses were conducted to assess the impact of parental injury on these outcomes.

RESULTS

We identified 414 (weighted = 1,338,068) injured parent-child dyads and 10,352 noninjured dyads. Children of injured parents had higher odds of being diagnosed with attention-deficit hyperactivity disorder/attention-deficit disorder (odds ratio [OR], 1.69; 95% confidence interval [CI], 1.31–2.40; p = 0.005), higher Washington Group Composite Disability Scores (OR, 1.77; 95% CI, 1.25–2.47; p = 0.001), and increased injury odds (OR, 2.29; 95% CI, 1.58–3.28; p < 0.001). They also showed higher rates of urgent care visits, with significantly higher emergency department visits (OR, 1.49; 95% CI, 1.02–2.13; p = 0.03). Financial toxicity was significant, with increased odds of delaying (OR, 2.37; 95% CI, 1.14–5.40; p = 0.03) or avoiding care (OR, 3.06; 95% CI, 1.06–7.76; p = 0.02) due to cost.

CONCLUSION

This study highlights the broad-reaching impact of parental injury on children, including worse health outcomes, increased health care utilization, and significant financial barriers. These findings underscore the need for comprehensive trauma care that addresses the holistic needs of families, incorporating strategies to mitigate both health and socioeconomic challenges.

LEVEL OF EVIDENCE

Prognostic/Epidemiological; Level II.
SEEG in 2025: progress and pending challenges in stereotaxy methods, biomarkers and radiofrequency thermocoagulation
Authors: Ryvlin Philippe
Published: February 2025

Purpose of review

Technological innovations and clinical research in SEEG have dramatically increased with its worldwide dissemination. In this review, we summarize the main advances in the field from the last 5 years.

Recent findings

Several large series and meta-analyses have provided consistent data regarding a lower risk of serious complications with SEEG as compared to sub-dural grids, while some studies also suggest a greater diagnostic value. The safety and precision of SEEG partly depends on the type of vascular imaging and method of implantation, with some series suggesting that MR angiography might not provide an optimal delineation of electrode–vessel conflicts and that frameless stereotaxy lacks precision. Noninvasive frame coupled with robot-guided implantation might offer the best precision/invasiveness tradeoff. Small series suggest that SEEG can be safely performed from the age of 16 months, and that adding electrodes during SEEG often prove beneficial. Transhemispheric electrodes targeting the mesial frontal structures, bilaterally, proved safe and informative. Several interictal and ictal biomarkers of the epileptogenic zone have been investigated. Although high-frequency oscillations (HFOs) remain a biomarker of interest, a randomized controlled trial failed to demonstrate its diagnostic value against spikes. Furthermore, other interictal biomarkers proved to better correlate with the epileptogenic zone than HFOs rate, including spike-gamma and spike-ripples. Ictal biomarkers of interest include the so-called chirp and epileptogenic zone fingerprint. Overall, recent data suggest that high-frequency activities are not a mandatory feature of interictal and ictal biomarkers of the epileptogenic zone. Radiofrequency thermocoagulation (RFTC) performed during SEEG investigation have also progressed, with some authors reporting spectacular rates of seizure freedom in patients with localized epileptogenic lesion but also mesial temporal sclerosis. However, a systematic assessment of memory and mental health demonstrated the presence of altered memory and psychiatric complications in a significant proportion of mesial temporal lobe RFTC.

Progress has been made in the technology and methods used to perform SEEG and RFTC, with the view to increase safety and effectiveness. Several interictal and ictal biomarkers appear promising but still face challenges in their validation and implementation in clinical practice. Future research requires harmonization in the concepts of the seizure onset and epileptogenic zones, and prospective pathology-specific studies.
Establishment of an optimized and automated workflow for whole brain probing of neuronal activity.
Authors: CABRERA Sebastien , VACHOUD Nicolas , BREUILLY Marine , DESMERCIERES Stevenson , MACIEL Renato M , MEYER-DILHET Geraldine , ELLOUZE Salma , COURCHET Julien , LUPPI Pierre-Herve , MANDAIRON Nathalie , RAINETEAU Olivier
Published: February 2025

Behaviors are encoded by widespread neural circuits within the brain that change with age and experience. Immunodetection of the immediate early gene c-Fos has been successfully used for decades to reveal neural circuits active during specific tasks or conditions. Our objectives here were to develop and benchmark a workflow that circumvents classical temporal and spatial limitations associated with c-Fos quantification. We combined c-Fos immunohistochemistry with c-Fos driven Cre-dependant tdTomato expression in the TRAP2 mice, to visualize and perform a direct comparison of neural circuits activated at different times or during different tasks. By using open-source software (QuPath and ABBA), we established a workflow that optimize and automate cell detection, cell classification (e.g. c-Fos vs. c-Fos/tdTomato) and whole brain registration. We demonstrate that this workflow, based on fully automatic scripts, allows accurate cell number quantification with minimal interindividual variability. Further, interrogation of brain atlases at different scales (from simplified to detailed) allows gradually zooming on brain regions to explore spatial distribution of activated cells. We illustrate the potential of this approach by comparing patterns of neuronal activation in various contexts (two vigilance states, complex behavioral tasks...), in separate groups of mice or at two time points in the same animals. Finally, we explore software (BrainRender) for intuitive representation of the results. Altogether, this automated workflow accessible to all labs with some expertise in histology, allows an unbiased, fast and accurate analysis of the whole brain activity pattern at the cellular level, in various contexts.
Melanoma cells suppress mast cell growth via a melanin-dependent mechanism
Authors: Rabelo Melo Fabio , Nyman Lea , Menander Ida Österman , Grujic Mirjana , Pejler Gunnar
Published: February 2025

Mast cells (MCs) have a well-established detrimental role in allergic conditions, but they can also impact on diverse malignant conditions, including melanoma. To study the latter, previous studies have mainly evaluated how MCs can influence melanomas/melanoma cells. However, the inverse scenario, i.e., whether melanoma/melanoma cells might impact on MCs has received less attention. Here we investigated this issue and show that melanoma cell-conditioned medium had a strong growth-inhibitory impact on MCs, which was attributed to inhibition of MC proliferation combined with induction of apoptosis. Further, our data indicate that such effects were attributable to melanin present in the melanoma cell-conditioned medium, as similar anti-proliferative effects were seen in response to both free melanin and to melanocores enriched from melanoma-conditioned medium. Melanin did not reduce the expression of MC markers, but was shown to impair MC activation. We also demonstrate that melanin is taken up by MCs, both in cultured MCs andin vivoin melanoma tumors, and it was observed that melanin, after uptake, can be found in the MC nucleus. Further, we show that melanin had marked effects on the nuclear morphology in MCs accompanied by clipping of core histone 3, and it is demonstrated that these events were dependent on translocation of tryptase, a granule-localized protease, into the MC nucleus. Tryptase was also shown to affect the mechanism of melanin-induced cell death. Altogether, the present study outlines a novel mechanism by which melanoma cells can suppress MC function, potentially representing an immunosuppressive mechanism that may influence tumor growth.
The need for speed: ultra-rapid high-resolution outbreak analysis in a front-line hospital microbiology laboratory
Authors: Bloomfield Max , Bakker Sarah , Burton Megan , Dyet Kristin , Eustace Alexandra , Hutton Samantha , Jeram Jamaal , Macartney-Coxson Donia , Winter David J. , White Rhys T.
Published: February 2025

Many hospital laboratories have technical capacity to perform whole-genome sequencing but lack bioinformatic expertise to analyse sequence data. Sending isolates to reference laboratories creates delays that can be highly detrimental to outbreak responses. The Wellington Regional Hospital laboratory, which lacks on-site bioinformaticians, implemented real-time nanopore-based genomic surveillance that has detected several hospital outbreaks at an early stage. This has required off-site analysis, often taking weeks. Solu Genomics, a cloud-based automated bioinformatic platform, requires no bioinformatic or command-line expertise and accepts basecalled sequence files or genome assemblies. This study aimed to use Solu to replicate the analysis of two prior neonatal unit outbreaks detected by on-site genomic surveillance, as if they had occurred now, and compare the output to ‘manual’ bioinformatic analysis. Surveillance isolates that had been sequenced up until the beginning of each outbreak were loaded into Solu to replicate the background genomic data available when each outbreak occurred. The 13 methicillin-resistant Staphylococcus aureus (MRSA) and seven Klebsiella variicola outbreak isolates were then uploaded. Including upload time, each Solu analysis was completed in under 40 minutes. The phylogenetic trees generated showed distinct clustering of outbreak isolates, with overall tree topologies similar to the manual analyses. Median pairwise single-nucleotide variant distances were 12 (range 4-27) and 6 (range 1-11) for the MRSA and K. variicola outbreaks, respectively, versus 6 (range 0-14) and 18 (range 0-54) for the manual analyses. This study demonstrates that Solu Genomics can provide high-resolution, actionable outbreak analysis within minutes, without the need for bioinformatic expertise.

Importance

Outbreaks in healthcare settings present serious risks to patient safety and can disrupt healthcare delivery. Timely and precise detection of these outbreaks is essential for effective infection prevention and control as well as reducing patient harm and service disruptions. This study emphasises the value of an intuitive cloud-based bioinformatics platform, in overcoming a key obstacle to the widespread adoption of whole-genome sequencing in hospital laboratories: bioinformatic analyses. Our research highlights the practicality of real-time genomic monitoring in local laboratories by showing that a non-specialist platform can produce results that complement and align with manual analyses while offering significant time savings. This approach can accelerate the detection and subsequent control of outbreaks caused by organisms like methicillin-resistant Staphylococcus aureus and Klebsiella variicola, ultimately improving patient outcomes and healthcare efficiency.
Genetic parallels in biomineralization of the calcareous spongeSycon ciliatumand stony corals
Authors: Voigt Oliver , Wilde Magdalena V. , Fröhlich Thomas , Fradusco Benedetta , Vargas Sergio , Wörheide Gert
Published: February 2025

The rapid emergence of mineralized structures in diverse animal groups during the late Ediacaran and early Cambrian periods likely resulted from modifications of pre-adapted biomineralization genes inherited from a common ancestor. As the oldest extant phylum with mineralized structures, sponges are key to understanding animal biomineralization. Yet, the biomineralization process in sponges, particularly in forming spicules, is not well-understood. To address this, we conducted transcriptomic, genomic, and proteomic analyses on the calcareous spongeSycon ciliatum, supplemented by in situ hybridization. We identified 829 genes overexpressed in regions of increased calcite spicule formation, including 17 calcarins—proteins analogous to corals’ galaxins localized in the spicule matrix and expressed in sclerocytes. Their expression varied temporally and spatially, specific to certain spicule types, indicating that fine-tuned gene regulation is crucial for biomineralization control. Similar subtle expression changes are also relevant in stony coral biomineralization. Tandem gene arrangements and expression changes suggest that gene duplication and neofunctionalization have significantly shapedSycon ciliatum’s biomineralization, similar to that in corals. These findings suggest a parallel evolution of carbonate biomineralization in the calciticSycon ciliatumand aragonitic corals, exemplifying the evolution of mechanisms crucial for animals to act as ecosystem engineers and form reef structures.
Predicting 30 Days Hospital Readmission for Heart Failure patients using word embeddings
Authors: Shakya Prabin R. , Khaneja Ayush , Wagholikar Kavishwar B.
Published: February 2025

Heart Failure (HF) is a public health concern with a wider impact on quality of life and cost of care. One of the major challenges in HF is the higher rate of unplanned readmissions and sub-optimal performance of models to predict the readmissions. Hence, in this study, we implemented embeddings-based approaches to generate features for improving model performance. Specifically, we compared three embedding approaches including word2vec on terminology codes and CUIs, and BERT on concept descriptions with baseline (one hot-encoding). We found that the embedding approaches significantly improved the performance of the prediction models, and word2vec on the study dataset outperformed pre-trained BERT model.
Persistent Aerointolerant Gut Microbes and Butyrate Depletion in Severe Acute Malnutrition
Authors: Camara Aminata , Konate Salimata , Alou Maryam Tidjani , Armstrong Nicholas , Caputo Aurelia , Togo Amadou Hamidou , Niare Safiatou , Kone Abdoulaye Kassoum , Traore Issa , Levasseur Anthony , Doumbo Ogobara K. , Thera Mahamadou Ali , Million Matthieu
Published: February 2025

Severe acute malnutrition (SAM) constitutes the leading risk for childhood mortality worldwide. Butyrate, a critical metabolite for mucosal immunity produced by anaerobic gut microbes, has been found to be dramatically depleted in children experiencing fatal outcomes related to SAM. However, the association between butyrate depletion and gut microbiota alteration has not yet been fully explored. Here, we performed a large group-matched case-control study in children aged 0-59 months in Mali. We compared faecal short-chain fatty acids (SCFAs) and gut microbiota from children with SAM and healthy controls, using gas chromatography-mass spectrometry and 16S rRNA v3v4 gene amplicon sequencing. A total of 253 children, including 143 with SAM and 110 controls, were included. Our findings revealed a dramatic imbalance in gut microbiota characterised by the predominance of aerotolerant micro-organisms in children with SAM, irrespective of age and sex. Importantly, aerointolerant species were totally absent in eight samples from children with SAM. A pronounced depletion of faecal valeric, butyric, propanoic and, to a lesser extent, acetic acid was observed, correlating with a ten-fold decrease in butyrate-producing microbes among the SAM population. This notable depletion of gut aerointolerant prokaryotes and butyrate levels persisted without being reversed at the time of discharge. Future therapeutic strategies aimed at addressing SAM should focus on restoring the gut anaerobic microbiota and faecal propionate and butyrate.
Investigating the contribution of circulating inflammatory cytokines on the link between obesity and COVID-19
Authors: Khamis Zahra J. , Karteris Emmanouil , Alhajeri Amani , Smith Steven G. , Blakemore Alexandra , Drenos Fotios
Published: February 2025

Background

Coronavirus disease 2019 (COVID-19), is more severe in individuals with obesity. Furthermore, a cytokine storm was observed in many critically ill patients with COVID-19. Since adipose tissue secretes cytokines, we investigated whether cytokines mediate the effect of obesity on COVID-19 severity.

Methods

Using two-sample Mendelian randomization analyses we assessed the causal effect of body mass index (BMI) on COVID-19 severity. We then evaluated the BMI effect on 41 inflammatory cytokines, as well as on JAK-2, lymphocyte percentage and leptin. We also tested the relationship between these immunological factors and COVID-19 severity. The estimates obtained were used in a mediation analysis to understand the immunological factors linking BMI to COVID-19 severity.

Results

Higher BMI increased the risk of COVID-19 severity. BMI was also causally associated with 5 of the 41 inflammatory cytokines, HGF, TRAIL, IL 13, IL6, and IL 7. We identified TNF-α and IL-8 as the only two inflammatory cytokines associated with COVID-19 severity. Leptin-related genetic variation was associated with COVID-19 severity, but JAK-2 and lymphocyte percentage were not. We found no statistical evidence of mediation of immunological factors tested on the relationship between BMI and COVID-19 severity, although our estimate was 52.8%.

Conclusions

We replicated the previously reported association between BMI and COVID-19 severity. We identified the inflammatory cytokines elevated due to higher BMI. Other inflammatory cytokines showed evidence for increasing COVID-19 severity. However, we were unable to find statistical evidence of baseline levels of circulating cytokines, or additional factors involved in a cytokine storm i.e. JAK-2, lymphocyte percentage, and leptin, mediating the link between BMI and severe COVID-19. Although targeting specific cytokines will be of benefit in the general population, further work on cytokine levels during early phases of COVID-19 infection is needed to provide new approaches to decrease the risk of severe COVID-19 with higher BMI.
Effects of food insecurity on infant feeding confidence and practices during the COVID-19 pandemic and its waves
Authors: Hussain Maha , Hyun Jessica , Arduin Elena , Kyle Margaret H. , Abreu Wanda , Scripps Tessa , Nichols Presley H. , Khan Adrita , Glassman Melissa , Stockwell Melissa S. , Walzer Lauren , Dumitriu Dani , Fernández Cristina R.
Published: February 2025

Background

The COVID-19 pandemic has intensified economic hardships, with potential negative impacts on food insecurity and infant feeding beliefs and practices. The relationship between food insecurity and infant feeding beliefs and practices during the pandemic is not yet fully understood. Neither is how these relationships changed over the course of the waves of the pandemic. We examined these relationships in a cohort of infants born during the various waves of the COVID-19 pandemic in New York City (NYC).

Methods

We conducted a cross-sectional analysis of infants enrolled from birth into the COVID-19 Mother-Baby Outcomes (COMBO) study and born March 2020 to May 2024. We measured food insecurity in the prior 30 days with a 2-item survey adapted from Hunger Vital Sign™, infant feeding confidence at hospital discharge, and current infant feeding practices.

Results

40% of women in our sample had been exposed to prenatal SARS-CoV-2 infection and approximately 24% of mothers were food insecure. There was a significant association between food insecurity and prenatal SARS-CoV-2 infection, Spanish as one’s preferred language, and self-identifying as Latina. In unadjusted models of the entire sample, food insecurity was associated with formula feeding (p<0.001), but this relationship was no longer significant after adjusting for covariates (p=0.059). In comparing the first and second waves of the pandemic (March 2020-December 2021 vs. January 2022-May 2024), there was no significant difference in rate of food insecurity. When comparing different waves of the pandemic, food insecurity was associated with increased likelihood of formula feeding, even after adjusting for confounders.

Discussion

Food insecurity was initially associated with feeding methods, but this relationship lost significance after adjusting for confounders. However, when analyzed separately, food insecurity was significantly linked to lower odds of exclusive breastfeeding during different waves of the pandemic, suggesting the influence of external factors like policy changes and social support variations. Other factors, such as maternal BMI, ethnicity, and delivery mode, were also significantly associated with breastfeeding practices, highlighting the need for targeted interventions to support breastfeeding, especially among food-insecure mothers.
A perturbation proteomics-based foundation model for virtual cell construction
Authors: Sun Rui , Qian Liujia , Li Yongge , Cheng Honghan , Xue Zhangzhi , Zhang Xuedong , Tan Lingling , Zhan Yuecheng , Hu Wenbin , Xiao Qi , Liu Zhiwei , Zhang Guangmei , Weinan E , Zhou Peijie , Wen Han , Zhu Yi , Guo Tiannan
Published: February 2025

Building a virtual cell requires comprehensive understanding of protein network dynamics of a cell which necessitates large-scale perturbation proteome data and intelligent computational models learned from the proteome data corpus. Here, we generate a large-scale dataset of over 38 million perturbed protein measurements in breast cancer cell lines and develop a neural ordinary differential equation-based foundation model, namely ProteinTalks. During pretraining, ProteinTalks gains a fundamental understanding of cellular protein network dynamics. Our model encodes protein networks and exhibits consistently improved predictive accuracy across various downstream tasks, highlighting its generalization capabilities and adaptability. In cancer cells, ProteinTalks robustly predicts drug efficacy and synergy, identifies novel drug combinations, and, through its interpretability, uncovers resistance-associated proteins. When applied to more complex system, patient-derived tumor xenografts, ProteinTalks predicts potential responses to drugs. Its integration with clinical patient data enhances the prognosis prediction of breast cancer patients. Collectively, we present a foundational model based on proteome dynamics, offering potential for various downstream applications, including drug discovery, and providing a basis for developing virtual cells.
Neocortical Layer-5 tLTD Relies on Non-Ionotropic Presynaptic NMDA Receptor Signaling
Authors: Thomazeau Aurore , Rannio Sabine , Brock Jennifer A. , Wong Hovy Ho-Wai , Sjöström P. Jesper
Published: February 2025

In the textbook view, NMDA receptors (NMDARs) act as coincidence detectors in Hebbian plasticity by fluxing Ca2+when simultaneously depolarized and glutamate bound. Hebbian coincidence detection requires that NMDARs be located postsynaptically, but enigmatic presynaptic NMDARs (preNMDARs) also exist. It is known that preNMDARs regulate neurotransmitter release, but precisely how remains poorly understood. Emerging evidence suggest that NMDARs can also signal non-ionotropically, without the need for Ca2+flux. At synapses between developing visual cortex layer-5 (L5) pyramidal cells (PCs), preNMDARs rely on Mg2+and Rab3-interacting molecule 1αβ (RIM1αβ) to regulate evoked release during periods of high-frequency firing, but they signal non-ionotropically via c-Jun N-terminal kinase 2 (JNK2) to regulate spontaneous release regardless of frequency. At the same synapses, timing- dependent long-term depression (tLTD) depends on preNMDARs but not on frequency. We therefore tested if tLTD relies on non-ionotropic preNMDAR signaling. We found that tLTD at L5 PC→PC synapses was abolished by pre- but not postsynaptic NMDAR deletion, cementing the view that tLTD requires preNMDARs. In agreement with non-ionotropic NMDAR signaling, tLTD prevailed after channel pore blockade with MK-801, unlike tLTP. Homozygous RIM1αβ deletion did not affect tLTD, but wash-in of the JNK2 blocker SP600125 abolished tLTD. Consistent with a presynaptic need for JNK2, a peptide blocking the interaction between JNK2 and Syntaxin-1a (STX1a) abolished tLTD if loaded pre- but not postsynaptically, regardless of frequency. Finally, low-frequency tLTD was not blocked by the channel pore blocker MK-801, nor by 7-CK, a non-competitive NMDAR antagonist at the co-agonist site. We conclude that neocortical L5 PC→PC tLTD relies on non-ionotropic preNMDAR signaling via JNK2/STX1a. Our study brings closure to long-standing controversy surrounding preNMDARs and highlights how the textbook view of NMDARs as ionotropic coincidence detectors in plasticity needs to be reassessed.
Non-causal association between α-klotho and human lifespan: evidence from multi-omics insights
Authors: Liu Xueyi , Yang Wulin
Published: February 2025

While genetic evidence robustly associates longevity in non-human primates with Klotho protein, such a direct correlation in humans remains elusive. To scrutinize the potential causal link between genetically predicted Klotho levels and human lifespan, we devised a meticulous two-sample Mendelian randomization (MR) analysis, just leveraging single nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS) and protein quantitative trait loci (pQTLs) as instrumental variables, meticulously analyzing the relationship between serum α-klotho and human longevity. By integrating MR estimates across diverse data sources using the fixed-effects inverse-variance weighted (IVW) approach, we consolidated our findings with a fixed-effects meta-analysis, fortified by sensitivity analyses embracing the simple median, weighted median, MR-Egger regression, and MR-pleiotropy residual sum and outlier assessments. Surprisingly, our genome-wide association MR analyses failed to uncover a causal association between Klotho and human lifespan, holding for both experimental and validation cohorts. Furthermore, the analysis grounded in protein quantitative trait loci also yielded no evidence of a causal link, with the sensitivity analyses consistently reinforcing the robustness of our findings. Hence, while animal models suggest a correlation between circulating Klotho and lifespan, this study demonstrates that genetically predicted levels of circulating α klotho do not exhibit a direct causal effect on human longevity.
The VExUS System Has a Limited Clinical Impact in the Evaluation and Management of Hypoosmolar Hyponatremia: A Single-Center Observational Study
Authors: Marques FJ. , Viejo-Boyano I. , González-Calero P. , Ferri A. , Gavilà M. , Mompó M. , Barrios P. , Cholbi-Vives E. , Peris-Fernandez M.
Published: February 2025

Background

Hyponatremia is the most frequent electrolyte disturbance in hospitalized patients, yet assessing volume status remains a diagnostic challenge. The Venous Excess Ultrasound (VExUS) system has been proposed as a noninvasive method to evaluate volume overload and guide management. However, data on its clinical impact in hypoosmolar hyponatremia are limited.

Objective

To investigate whether the VExUS system can support the management of acute hypoosmolar hyponatremia, detect discrepancies with physical examination in assessing volume status, and predict clinical outcomes.

Methods

This single-center observational study included adult inpatients with moderate or severe hypoosmolar hyponatremia (plasma sodium <=130 mEq/L). Patients underwent a standard clinical evaluation (history and physical examination) and a VExUS-based ultrasound assessment of at least two venous regions (inferior vena cava, hepatic veins, portal vein, or renal veins). Internal jugular vein measurements were used when feasible. The treating physicians of the patients were blinded to the ultrasound findings. Serum sodium levels were measured at 24, 48, and 96 hours. Treatments were based on existing clinical guidelines, and any changes in therapy were documented.

Results

Twenty-eight patients were enrolled, and two were excluded due to inadequate ultrasound data or new-onset cirrhosis. VExUS classification differed from clinical examination in 65.4 percent of patients (17 of 26), yet these discrepancies did not lead to significant differences in serum sodium trends or management changes at 24, 48, or 96 hours (p>0.05). Only four patients required therapeutic adjustments within 24 hours, and one displayed discrepant volume classifications. The VExUS system showed limited ability to distinguish euvolemia in patients with SIADH and demonstrated minimal correlation with laboratory parameters such as NT-proBNP and CA-125.

Conclusions

While ultrasound assessment is noninvasive and potentially useful, this study found that discrepancies in VExUS-based volume status classification did not significantly alter clinical outcomes or treatment strategies in hospitalized patients with hypoosmolar hyponatremia. The VExUS method should not replace standard complementary evaluations recommended by hyponatremia guidelines, although it may have a niche role when ruling in or out hypervolemia in selected cases.
Ventral Tegmental Area as the Core Pathophysiological Hub in Bipolar Disorder: Evidence from Resting-State fMRI
Authors: Lee Tien-Wen
Published: February 2025

Objectives

Bipolar disorder (BPD) is a major and complex psychiatric condition, clinically characterized by euthymic, depressive, and manic phases. Through the concept of “dialectic neuroscience,” the ventral tegmental area (VTA) has been proposed as a potential key hub in BPD. This study utilized resting-state functional magnetic resonance imaging (rsfMRI) to investigate functional connectivity (FC) changes seeded by the VTA in BPD.

Methods

MRI data from 98 participants in a publicly available dataset were analyzed (49 stable BPD patients and 49 healthy controls). Using the dopamine receptor D1 distribution template from JuSpace, the representative voxel of the VTA in the midbrain was identified based on the highest correlation with the D1 template. This voxel served as the seed for FC map construction. The FC maps were Fisher-transformed and compared statistically using an independent two-sample t-test.

Results

Significant deviations in BPD were observed in brain regions that were highly consistent with the projections of the VTA, including the ventral and medial prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, and nucleus accumbens.

Conclusions

The FC analysis provided empirical support for the VTA theory in BPD. The role of VTA abnormalities in contributing to the manifestation of opposing polarities within a single disorder was discussed, offering insights into the potential physiological mechanisms and genesis of BPD. The framework of dialectic neuroscience may provide a valuable approach for developing guiding brain theories in psychiatric disorders.
Spatially regulated mRNA decay sharpens expression patterns in theDrosophilaembryo
Authors: Love Jennifer C. , Beadle Lauren Forbes , Sutcliffe Catherine , Rattray Magnus , Ashe Hilary L.
Published: February 2025

The regulation of mRNA decay is important for numerous cellular and developmental processes. Here, we use the patterning geneeven-skipped(eve) in the earlyDrosophilaembryo to investigate the contribution of mRNA decay to shaping mature expression patterns. Through P-body colocalisation analysis and mathematical modelling of live and fixed imaging data, we present evidence thatevemRNA stability is regulated across stripe 2, with enhanced mRNA decay at the edges of the stripe. To manipulate mRNA stability, we perturbed mRNA decay in the embryo by optogenetic degradation of the 5’ to 3’ exoribonuclease Pacman (Pcm). Depleting Pcm results in larger P-bodies, which accumulateevemRNAs, and disruptedeveexpression patterns. Overall, these data show howevemRNA instability can function with transcriptional regulation to define sharp expression domain borders. We discuss how spatially regulated mRNA stability may be widely used to sculpt expression patterns during development.
Diverse mechanisms of DDX3Y suppression by DDX3X
Authors: Xu Xiaolu , Wei Shuo
Published: February 2025

The DEAD-box RNA helicase DDX3X has important roles in development and disease. Loss of DDX3X during developmental and pathological processes such as tumorigenesis can lead to compensatory upregulation of the close paralog DDX3Y in males, which may underlie the sexual dimorphism displayed by some DDX3X-associated diseases. However, how DDX3X cross-regulates DDX3Y remains largely unknown. Here, we investigated the regulation of DDX3Y by DDX3X in two male-derived human cancer cell lines, HCT116 and U87MG. Depletion of DDX3X in HCT116 cells results in moderately increased DDX3Y mRNA and protein, in part due to stabilization ofDDX3Ytranscripts. Conversely, reduction of DDX3X in U87MG cells markedly upregulates DDX3Y protein without affecting its mRNA, mainly by enhancing DDX3Y protein stability. We further show that DDX3X physically interacts with DDX3Y. DDX3Y is much less stable than DDX3X in U87MG cells, and substitution of two lysine residues in DDX3Y with the corresponding arginine in DDX3X stabilizes DDX3Y. Thus, the compensatory upregulation of DDX3Y following DDX3X loss can occur at either transcript or protein level, suggesting complex and cell type-specific cross-regulation between these X- and Y-linked paralogs to keep the total DDX3 dosage in check.
Wastewater metaproteomics: tracking microbial and human protein biomarkers
Authors: Tugui Claudia G. , Cordesius Filine , van Holthe Willem , van Loosdrecht Mark C.M. , Pabst Martin
Published: February 2025

Wastewater-based surveillance has become a powerful tool for monitoring the spread of pathogens, antibiotic resistance genes, and measuring population-level exposure to pharmaceuticals and chemicals. While surveillance methods commonly target small molecules, DNA, or RNA, wastewater also contains a vast spectrum of proteins. However, despite recent advances in environmental proteomics, large-scale monitoring of protein biomarkers in wastewater is still far from routine. Analyzing raw wastewater presents a challenge due to its heterogeneous mixture of organic and inorganic substances, microorganisms, cellular debris, and various chemical pollutants. To overcome these obstacles, we developed a wastewater metaproteomics approach including efficient protein extraction and an optimized data-processing pipeline. The pipeline utilizes de novo sequencing to customize large public sequence databases to enable comprehensive metaproteomic coverage. Using this approach, we analyzed wastewater samples collected over three months from two urban locations. This revealed a core microbiome comprising a broad spectrum of microbes, gut bacteria and potential opportunistic pathogens. Additionally, we identified nearly 200 human proteins, including promising population-level health indicators, such as immunoglobulins, uromodulin, and cancer-associated proteins.
Evaluation of Antioxidant Anticancer and Antimicrobial Activities of Datura Leaf Extracts: A Microbiological Perspective
Authors: Sheoran Sumit , Arora Swati
Published: February 2025

Datura, a genus of flowering plants, has long been used in traditional medicine owing to its pharmacological properties. This study investigated the antioxidant and antimicrobial activities of Datura leaf extracts by using in vitro assays. Antioxidant potential was evaluated using standard methods, while antimicrobial activity was assessed against various bacterial and fungal strains using the disk diffusion method. The results demonstrated significant antioxidant properties and broad-spectrum antimicrobial activity, supporting the potential of Datura as a source of bioactive compounds for pharmaceutical applications. The findings of this study elucidate the potential of datura leaf extracts as natural alternatives to synthetic antioxidants and antimicrobial agents in various industries. Further research is warranted to explore the specific bioactive compounds responsible for these properties and to investigate their mechanisms of action. Additionally, future studies should focus on optimizing extraction methods to enhance the potency and efficacy of Datura-derived products for potential therapeutic applications.
Enhanced Computational and Experimental Approaches for Comparative Analysis of the Human Mycobiome
Authors: Begum Neelu , Lee Sunjae , Almeida Mathieu , Engstrand Lars , Patel S. Vishal C. , Uhlen Mathias , Ehrlich Dusko , Shoiae Saeed , Moyes David L.
Published: February 2025

The mycobiome is now recognized as a critical part of the human microbial ecosystem, playing a significant role in both health and disease. Mycobiome research is currently in its infancy and relies on fungal-specific primers with challenges in bioinformatics to accurately determine the structure of the mycobiota community. In addition, the majority of computational and experimental methods currently in use have been optimized for bacteria rather than for fungi. Here, we provide a comparative analysis of extraction methodologies for metagenome sequencing and subsequent bioinformatic analysis that will enhance fungal species identification. We utilized cultured mock fungal communities, including both yeast and mold species, to evaluate the efficiency of extraction protocols. We further enhanced computational analysis of the mycobiome, using mock and human metagenome data together with our curated catalogue consisting of 984 fungal genomes specific to the human mycobiome. Application of this optimised workflow for oral and gut samples of healthy individuals detected of novel species fromPucciniaandLentinusgenera among the established presence ofMalassezia,Rhizophagus,CandidaandSaccharomycesgenera. In addition,Enterocytozoon,was identified specifically in the gut mycobiome. Our pipeline enabled the comprehensive sampling of all fungal genes in a microbial community within a human sample minimising bias, reducing errors and artefacts from amplification, and providing accurate diversity and abundance data for the human mycobiome.
Structural basis for HIV-1 capsid adaption to rescue IP6-packaging deficiency
Authors: Zhu Yanan , Kleinpeter Alex B , Rey Juan S. , Shen Juan , Shen Yao , Xu Jialu , Hardenbrook Nathan , Chen Long , Lucic Anka , Perilla Juan R. , Freed Eric O. , Zhang Peijun
Published: February 2025

Inositol hexakisphosphate (IP6) promotes HIV-1 assembly via its interaction with the immature Gag lattice, effectively enriching IP6 within virions. During particle maturation, the HIV-1 protease cleaves the Gag polyproteins comprising the immature Gag lattice, releasing IP6 from its original binding site and liberating the capsid (CA) domain of Gag. IP6 then promotes the assembly of mature CA protein into the capsid shell of the viral core, which is required for infection of new target cells. Recently, we reported HIV-1 Gag mutants that assemble virions independently of IP6. However, these mutants are non-infectious and unable to assemble stable capsids. Here, we identified a mutation in the C-terminus of CA – G225R – that restores capsid formation and infectivity to these IP6-packaging-deficient mutants.

Furthermore, we show that G225R facilitates thein vitroassembly of purified CA into capsid-like particles (CLPs) at IP6 concentrations well below those required for WT CLP assembly. Using single-particle cryoEM, we solved structures of CA hexamer and hexameric lattice of mature CLPs harbouring the G225R mutation assembled in low-IP6 conditions. The high-resolution (2.7 Å) cryoEM structure combined with molecular dynamics simulations of the G225R capsid revealed that the otherwise flexible and disordered C-terminus of CA becomes structured, extending to the pseudo two-fold hexamer-hexamer interface, thereby stabilizing the mature capsid. This work uncovers a structural mechanism by which HIV-1 adapts to a deficiency in IP6 packaging. Furthermore, the ability of G225R to promote mature capsid assembly in low-IP6 conditions provides a valuable tool for capsid-related studies and may indicate a heretofore unknown role for the unstructured C-terminus in HIV-1 capsid assembly.
Linking acoustic telemetry data to spatial covariates in river networks with spatially explicit capture-recapture models
Authors: Bottoms Joseph R. , Auger-Méthé Marie , O’Connor Bryce , Power Michael , Patterson David A. , Shrimpton J. Mark , Cooke Steven J. , Martins Eduardo G.
Published: February 2025

Spatially explicit capture-recapture (SECR) models extend classical capture-recapture models to include spatially-explicit animal locations and environmental covariates. SECR models have been widely employed in terrestrial studies to predict the population size and densities of animals assuming a closed population over a defined area. In this work, we extend and apply SECR models to a novel use-case that both uses a relative density formulation and accounts for biased tagging distributions to estimate parameters of habitat use from acoustic telemetry data in a branching river network.

Using SECR models, we predict how temperature distributions during the summer feeding season influenced how tagged Arctic grayling (Thymallus arcticus) distributed themselves through the Parsnip watershed in northcentral British Columbia, Canada. We found that the relative density of tagged Arctic grayling peaked at water temperatures of 12.4 °C. In warm years, relative densities were constricted as parts of the watershed became unfavorably warm. In cool years, fish were distributed widely throughout the watershed.

In acoustic telemetry, only the tagged population is available for detection. We highlight several specific considerations and assumptions for using this approach: i.e. (a) activity centres are assumed to remain in the same location throughout the study period, thus the time window of the study should be selected accordingly (e.g., exclude migratory periods); (b) inferences from acoustic telemetry data depict relative (not absolute) densities; and (c) spatial tagging effort must be defined in the model to ensure that predictions are not merely an artefact of tagging effort across space and time. When applied following these assumptions, this method is broadly useful for ecologists as it presents a quantitative way to merge automated telemetry datasets with discrete habitat parameters that drive population distributions through time and are relevant to managers and conservation professionals. Further, this method can be applied to branching river networks in which topological challenges have hindered other statistical approaches.
Macroinvertebrate diversity patterns in a guano-rich temperate cave
Authors: Dainelli Luisa , Martínez Alejandro , Serena Fabrizio , Gammuto Leandro , Graco-Roza Caio , Langeneck Joachim , Mammola Stefano , Petroni Giulio
Published: February 2025

Most caves in temperate regions are energy-poor, leading to low richness and abundances of terrestrial macroinvertebrates. However, caves with abundant bat populations may represent a notable exception, as bat guano serves as a significant source of organic matter, supporting diverse specialized invertebrates. Yet, given the overall rarity of guano-rich caves in temperate region, their ecological dynamics are poorly understood. We conducted a year-long monthly standardized monitoring of the macroinvertebrates of the Buca dei Ladri cave, a guano-rich cavity in Tuscany, Italy. At each survey, we counted species within different sampling quadrats and collected environmental variables such as temperature, structural heterogeneity of the substrate, dominant substrate, and presence of bats. Over the year, we identified 31 macroinvertebrate species in the cave as both morphospecies and molecular lineages, based on mitochondrial COI and nuclear 18S genes. The latter approach hinted at the presence of cryptic diversity in some species. We observed an increase in species diversity with increasing structural complexity and the presence of bats, whereas a lower species diversity was found in guano-dominated substrates, probably due to the old age and subsequent low nutritional value of the historical guano deposits. Changes in the abundance of species within the cave were primarily explained by differences in structural complexity across sampling quadrats, whereas the distance from the cave entrance mostly explained species replacement. Our results underscore the importance of preserving healthy bat populations and a high habitat heterogeneity within the cave for the long-term conservation of the unique macroinvertebrate assemblages of the cave.