bluuebunny/crossref_metadata_2025 huggingface dataset:
Disrupted Maternal Behavior in Morphine-Dependent Pregnant Rats and Anhedonia in their Offspring
Authors: Searles Christopher T. , Vogt Meghan E. , Adedokun Iyanuoluwa , Murphy Anne Z.
Published: January 2025

It is currently estimated that every 15 minutes an infant is born with opioid use disorder and undergoes intense early life trauma due to opioid withdrawal. Clinical research on the long-term consequences of gestational opioid exposure reports increased rates of social, conduct, and emotional disorders in these children. Here, we investigate the impact of perinatal opioid exposure (POE) on behaviors associated with anhedonia and stress in male and female Sprague Dawley rats. Young adult female rats were administered morphine via programmable, subcutaneous micro-infusion pumps before, during, and through one week post gestation. Maternal behavior was examined for fragmentation and entropy for the first two postnatal weeks; offspring were assessed for sucrose preference, social behavior, and stress responsivity. Overall, dams that received morphine across gestation displayed significantly less pup-directed behavior with increased fragmentation for nursing and higher entropy scores. In adolescence, male and female rat offspring exposed to morphine displayed reduced sucrose preference and, as adults, spent significantly less time socially interacting with familiar conspecifics. Changes in social behaviors were linked to increased activity in nondopaminergic mesolimbic reward brain regions. Although no treatment effects were observed in forced swim test performance, corticosterone levels were significantly increased in POE adult males. Together, these results suggest that perinatal morphine exposure results in anhedonic behavior, possibly due to fragmented and unpredictable maternal behavior in opioid-dependent dams.

Significance Statement

Clinical and preclinical research has shown that early life stress can produce lifelong depression-like symptoms. Here, we show that maternal opioid use during pregnancy produces depression-like symptoms in the offspring. We also observed disrupted maternal behavior in morphine-exposed dams that is similar to the changes in maternal behavior reported following other forms of early life stress. We propose that the stress of opioid exposure and suboptimal rearing leads to reduced sucrose preference, increased stress reactivity, and social avoidance behavior in the offspring, all of which are characteristics of anhedonia.
Food for thought: Rosy-faced lovebirds (Agapornis roseicollis) are capable of associative symbol learning and inference-based quantity discrimination
Authors: Wang Shengyu , Lo Kevin Ching Hei , Shiu Verna Wing Ting , Hung Christy Yuen Ching , Poon Emily Shui Kei , Newman Chris , Buesching Christina D. , Sin Simon Yung Wa
Published: January 2025

Cognitive capacity for quantity discrimination is highly adaptive in various ecological contexts and subject to convergent evolution across diverse animal species, yet the underlying mechanism involved is not fully understood. Discrimination accuracy generally increases with the ratio between two quantities; however, this ability is expected to differ across ratio ranges. To test this we presented a novel symbol system to 28 rosy-faced lovebirds (Agapornis roseicollis), associating additive tally marks with symbols representing a one-to-one correspondence with different food quantities. Trained lovebirds could spontaneously infer the relative food quantities represented by other symbols. Lovebirds proved capable of (1) associating symbols (i.e., object-file symbolism); with (2) "more-less" quantity inference, by deducing food quantities based on their knowledge of this symbol-quantity association; and (3) enhancing their performance in relation to disparity ratio (conforming to Weber's law) and absolute difference. Furthermore (4), the influence of food ratio and absolute difference varied with different ratio ranges. Within a small ratio range (<= 3) discrimination performance improved with increments of ratio or absolute difference, whereas within a higher ratio range (> 3), the effect of these factors diminished. We conclude that rosy-faced lovebirds are capable of advanced numeracy and quantity discrimination, similar to larger parrot species.
From Text to Translation: Using Language Models to Prioritize Variants for Clinical Review
Authors: Li Weijiang , Li Xiaomin , Lavallee Ethan , Saparov Alice , Zitnik Marinka , Cassa Christopher
Published: January 2025

Despite rapid advances in genomic sequencing, most rare genetic variants remain insufficiently characterized for clinical use, limiting the potential of personalized medicine. When classifying whether a variant is pathogenic, clinical labs adhere to diagnostic guidelines that comprehensively evaluate many forms of evidence including case data, computational predictions, and functional screening. While a substantial amount of clinical evidence has been developed for these variants, the majority cannot be definitively classified as ‘pathogenic’ or ‘benign’, and thus persist as ‘Variants of Uncertain Significance’ (VUS). We processed over 2.4 million plaintext variant summaries from ClinVar, employing sentence-level classification to remove content that does not contain evidence and removing uninformative summaries. We developed ClinVar-BERT to discern clinical evidence within these summaries by fine-tuning a BioBERT-based model with labeled records. When validated classifications from this model against orthogonal functional screening data, ClinVar-BERT significantly separated estimates of functional impact in clinically actionable genes, includingBRCA1(p =1.90×10−20),TP53(p =1.14×10−47), andPTEN(p =3.82×10−7). Additionally, ClinVar-BERT achieved an AUROC of 0.927 in classifying ClinVar VUS against this functional screening data. This suggests that ClinVar-BERT is capable of discerning evidence from diagnostic reports and can be used to prioritize variants for re-assessment by diagnostic labs and expert curation panels.
Using single-subject morphological networks to elucidate the patterns of disconnection and disconnectome associated with post-stroke deficits and recovery
Authors: Yuan Binke , Zhong Tao , Wang Yaling , Chen Qingwen , Guo Xiaolin , Yang Junjie , Gao Xiaowei , Hu Zhe , Li Junjing , Liu Jiaxuan , Qu Zhiheng , Li Wanchun , Li Zhongqi , Li Wanjing , Huang Yien , Chen Jiali , Wen Hao , Zhang Ye , Li Junle , Gao Han
Published: January 2025

BACKGROUND

The single-subject morphological network (SSMN) provides a new approach for constructing structural connectome. However, its clinical relevance in post-stroke deficits and recovery remains unexplored.

METHODS

This study utilized high-resolution 3D T1-weighted images alongside behavioral and cognitive assessments across multiple domains, including language, motor, memory, and attention, collected at two weeks, three months, and one year post-stroke. The SSMN was constructed using the AAL atlas by evaluating the similarities of regional probability density derived from gray matter volume. Network disconnection and the disconnectome were evaluated by examining changes in network edges and global topological properties. The functional relevance of the SSMN was explored through its associations with post-stroke behavioral and cognitive deficits and recovery, as well as by developing machine-learning-based prediction models.

RESULTS

The findings revealed that the SSMN was sensitive to post-stroke connectional and connectomal disruptions. Domain-specific disruptions in the SSMN were predictable of post-stroke deficits, with correlation pattern aligning with the neurobiological substrates of each domain. Furthermore, the predictive performance of SSMN-based models was comparable to that of other imaging modalities. Notably, normalization of the SSMN within one year post-stroke was significantly associated with functional recovery.

CONCLUSIONS

These results highlight the potential of the SSMN as a novel structural imaging modality for evaluating post-stroke deficits and recovery, offering valuable insights into the neurobiological mechanisms of rehabilitation.
Psilocybin-Assisted Group Psychotherapy + Mindfulness Based Stress Reduction (MBSR) for Frontline Healthcare Provider COVID-19 Related Depression and Burnout: A Randomized Clinical Trial
Authors: Lewis Benjamin R. , Hendrick John , Byrne Kevin , Odette Madeleine , Wu Chaorong , Garland Eric L.
Published: January 2025

Objective

This clinical trial sought to evaluate the safety and preliminary efficacy of psilocybin and MBSR for frontline healthcare providers with symptoms of depression and burnout related to the COVID-19 pandemic.

Methods

This was a randomized controlled trial that enrolled physicians and nurses with frontline clinical work during the COVID-19 pandemic and symptoms of depression and burnout. Participants were randomized in a 1:1 ratio to either an 8-week MBSR curriculum alone or an 8-week MBSR curriculum plus group psilocybin-assisted psychotherapy (PAP) with 25mg psilocybin. Symptoms of depression and burnout were assessed at baseline, and 2-weeks and 6-months post intervention utilizing the Quick Inventory of Depressive Symptoms (QIDS-SR-16) and Maslach Burnout Inventory Human Services Survey for Medical Professionals (MBI-HSS-MP), respectively. Secondary outcome measures included the Demoralization Scale (DS-II) and the Watt’s Connectedness Scale (WCS). Adverse events and suicidality were assessed through 6-month follow-up.

Results

25 participants were enrolled and randomized. There were 12 study-related AEs recorded that were Grade 1-2 and no serious AEs. There was larger decrease in QIDS score for the MBSR+PAP arm compared to MBSR-only from baseline to 2-weeks post-intervention and significant between-group differences favoring MBSR+PAP on subscales of the MBI-HSS-MP as well as the DS-II and WCS.

Conclusions

Group psilocybin-assisted therapy plus MBSR was associated with clinically significant improvement in depressive symptoms without serious adverse events and with greater reduction in symptoms than MBSR alone. Study findings suggest that integrating psilocybin with mindfulness training may represent a promising treatment for depression and burnout among physicians and nurses.
Exploring the possible interventions in children and adolescents with Developmental Coordination Disorder. How far have we come? A Scoping Review
Authors: Chiara Panciroli Maria , Simone Fiore , Andrea Baragetti , Matteo Fascia
Published: January 2025

Background

Developmental Coordination Disorder (DCD) is a common neurodevelopmental disorder. Children with DCD usually need treatment. Indications for intervention are essentially dependent on the influence of the diagnosis on activities of daily life and the proposed treatments are therefore heterogeneous.

Objectives

Identifying and describing the current state of knowledge regarding the treatments available in the literature for the treatment of DCD, defining which of these interventions have been most investigated nowadays, identifying other possible types of intervention that have been introduced in the clinical practice and described by sporadic/anecdotal evidence.

Study design

Scoping review

Eligibility criteria

This review will take in account studies with any type of research design, with no geographical limit, published after 1994. This criterion was defined as corresponding to the date of publication of the DSM-IV, the first document in chronological order to be considered as a reference for the definition of diagnostic criteria in this scoping review.

Inclusion is limited to articles written in either English or Italian language. The population of interest includes children and adolescents (age 0-18 years old) with a diagnose of Developmental Coordination Disorder (DCD) or a probable-DCD (based on DSM-IV or DSM-IV-TR or DSM-V or ICD-10 or ICD-11 criteria) also in possible co-presence of other neurodevelopmental disorders, with the exception of autism spectrum disorder.
Enlarged Perivascular Spaces in the Basal Ganglia Across Epilepsy Subtypes
Authors: Sinclair Benjamin , Yasuda Clarissa Lin , Nicolo John-Paul , Hlauschek Gernot , Bezerra Thais Maria Santos , Chen Zhibin , Vivash Lucy , de Campos Brunno Machado , João Rafael Batista , Brioschi Ricardo , Scardua-Silva Lucas , Alvim Marina Koutsodontis Machado , Kwan Patrick , Cendes Fernando , O’Brien Terence J. , Law Meng
Published: January 2025

Introduction

The glymphatic system is thought to be the brain’s primary waste clearance system, responsible for eliminating soluble metabolites and proteins from the central nervous system. It consists of the cerebrospinal fluid, the interstitial fluid, and a conduit between the two, perivascular spaces (PVS), which are channels formed by astroglial cells surrounding the blood vessels. PVS can be observed on high-resolution T1-weighted MRI images. Small studies have implicated PVS and glymphatics in the pathophysiology of epilepsy, potentially via reduced clearance of excitotoxic substances. This study investigates enlarged PVS burden in a large patient group with various types of epilepsy.

Methods

People with various types of epilepsy were recruited from the Hospital das Clínicas, Unicamp, Brazil. They were matched approximately in age and sex with healthy volunteers as controls. All participants were scanned with T1-weighted MRI on a 3T Phillips MRI scanner, resolution 1.0x1.0x1.0 mm³. A deep-learning algorithm, PINGU, was applied to segment PVS. The volumes of PVS in the White Matter (WM) and Basal Ganglia (BG) were calculated and divided by the respective volumes of WM and BG to derive the volume fractions (PVS-VF). These were used as dependent variables in a general linear model, with the diagnostic group as the independent variable of interest and age and sex included as nuisance covariates.

Results

We recruited 467 people with epilepsy (median age 42 years, 41.5% male), of whom 267 had temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), 71 TLE with no MRI-visible lesions (TLE-NEG), 65 with focal extratemporal epilepsy (ETLE), and 64 with Idiopathic Generalized Epilepsy (IGE)). They were matched with 473 healthy controls (median age 35 years, 38.3% male). All epilepsy subtypes had higher PVS-VF in the BG compared to controls (101-140%, effect size=0.95-1.37, p<1.33x10-15). There was no difference in PVS-VF in the WM between the epilepsy group and healthy controls, or between different epilepsy subtypes. The TLE-HS group had an asymmetry in their PVS distribution, being larger on the contra-lateral side. This was not observed in the healthy controls or any other epilepsy subtypes. There was no association between PVS-VF and duration of illness (median duration 29 years).

Conclusion

Volume of PVS in the BG is enlarged in people with epilepsy. Longitudinal studies are needed to determine whether seizures have a detrimental effect on the brain’s glymphatic system, or whether impaired glymphatics contribute to the development of epilepsy.
Dynamic balance of H3K9me2 heterochromatin by CoREST-2 and RE-1 in growing neurons
Authors: Drube José F. , Cardozo-Gizzi Andrés , Rozés-Salvador Victoria , Martínez Imanol , Ceschin Danilo G. , Giordano Laureano , Serniotti Lucas , Gastaldi Laura , Remedi Mónica , Moyano Ana L. , Cáceres Alfredo , Wilson Carlos
Published: January 2025

A well-balanced chromatin dynamic is vital for the survival and physiology of all cells, including brain neurons. Heterochromatin, commonly associated with transcriptional silencing, also plays significant roles in maintaining genomic stability and facilitating DNA-repair processes. Notably, the bimethylation of histone H3 at lysine 9 (H3K9me2), a hallmark of repressive heterochromatin, supports the axonal specification of neurons. However, neuronal maintenance of H3K9me2 equilibrium remains understudied.

In this work, we unveil a dynamic equilibrium of H3K9me2 regulated by the epigenetic factor CoREST-2 and RE-1 DNA motifs, sustaining axonal and dendritic outgrowth. Using primary cultures of rat hippocampal neurons and a combination of advanced imaging techniques, we observed an enriched nuclear accumulation of CoREST-2 and H3K9me2 along neuronal development. Genetic silencing of CoREST-2 induced axon-dendrite retraction, accompanied by an increase in nuclear levels of H3K9me2. To further investigate heterochromatin structure at the nanoscale, we employed STED nanoscopy and discovered that H3K9me2 is organized into small nanodomains, which were notably enlarged following the suppression of CoREST-2. In contrast, the genetic blockade of RE-1 DNA motifs led to axon-dendrite retraction alongside the disassembly of H3K9me2 nanodomains.

These findings highlight that CoREST-2 and RE-1 sites actively shape neuronal H3K9me2 heterochromatin. Moreover, they uncover that maintaining a precise balance of H3K9me2 is essential for the extension of axons and dendrites, underpinning the connectivity and plasticity of brain neurons.
YX0798 Is a Highly Potent, Selective, and Orally Effective CDK9 Inhibitor for Treating Aggressive Lymphoma
Authors: Jiang Vivian , Xue Yu , Kim Hong , Cai Qingsong , Zhang Tianci , Nie Lei , McIntosh Joseph , Liu Yang , Chen Haiying , Zhou Jia , Wang Michael
Published: January 2025

Non-genetic transcription evolution has been increasingly explored and recognized to drive tumor cell progression and therapeutic resistance. As the regulation hub of transcription machinery, cyclin-dependent kinase 9 (CDK9) is the gatekeeper of RNA polymerase II (Pol II) transcription, and CDK9 dysfunction results in transcriptomic reprogramming and tumor cell progression. We recently reported that the HSP90-MYC-CDK9 network drives therapeutic resistance in mantle cell lymphoma (MCL) through transcriptomic reprogramming. We also showed that targeting CDK9 by AZD4573 and enitociclib is a safe and effective treatment in preclinical MCL models, supporting CDK9 as a valid therapeutic target for MCL. However, current CDK9 inhibitors (CDK9i) under therapeutic development have room for improvement due to limited target selectivity and oral bioavailability. To this end, YX0798 was discovered to be a novel CDK9i through structural optimization. YX0798 demonstrated remarkable target selectivity and high affinity in binding to CDK9. Furthermore, YX0798 showed good oral bioavailability. YX0798, when administrated orally (5 mg/kg, daily), led to an efficacious anti-tumor activityin vivoand showed the potency in overcoming therapeutic resistance. Mechanistically, YX0798 downregulated the short-lived oncoprotein c-MYC and pro-survival protein MCL-1 as a common mechanism of CDK9 inhibition. Moreover, YX0798 disrupted the cell cycle and resulted in transcriptomic reprogramming, eventually leading to cell death. Together, these data demonstrate that YX0798 has oral bioavailability, exquisite selectivity, and anti-tumor potency that results from driving transcription reprogramming towards tumor cell killing.

KEY POINTS

YX0798 showed high selectivity, target binding affinity, and anti-tumor efficacy in overcoming resistance to various therapies.

YX0798 had good oral pharmacokinetics and anti-tumor effects that resulted from transcription reprogramming towards tumor cell killing.
Persistent DNA methylation and downregulation of homeostatic genes in astrocytes after pilocarpine-induced status epilepticus: Implications for epileptogenesis
Authors: Cuautle Dante Gómez , Rossi Alicia , Villarreal Alejandro , D’Alessio Luciana , Ramos Alberto Javier
Published: January 2025

Epilepsy is a debilitating neurological disorder characterized by recurrent seizures, affecting millions of patients worldwide. Retrospective studies in Temporal lobe epilepsy (TLE) patients have shown a high incidence of an initial precipitating event (IPE) in early childhood followed by a silent period where epileptogenesis occurs to end up in chronic epilepsy. Epileptogenesis, the process through which a normal brain undergoes structural and functional changes leading to epilepsy, remains an enigmatic phenomenon. We hypothesized that epigenetics may be involved in epileptogenesis and specifically astrocytes could be affected by pathological remodeling. To study this process, we used three approaches: The lithium-pilocarpine model of TLE in rats, primary astroglial cultures exposed to epileptogenic DAMP named HMGB1, and brain tissue samples resected from TLE patients with drug-resistant epilepsy. We found that the IPE achieved by lithium- pilocarpine treatment (127/30 mg/kg IP) induced the hypermethylation of astrocytes at 7-, 21-, and 35 days post-IPE, indicating persistent epigenetic alterations in astrocytes during the epileptogenic period. In addition, we observed the downregulation of homeostatic astroglial genes AQP4; glutamine synthase (GS), and Kir4.1 with increased proinflammatory genes (C3, MAFG) and DNA methyl transferases (DNMT) expression. These alterations were mimicked in primary astrocyte cultures exposed to the epileptogenic HMGB1 (500 ng/ml; 18 hours) that also induced the hypermethylation of homeostatic astroglial genes. Astrocytes from TLE patients brains showed reactive astrogliosis, increased DNA methylation, and downregulation of homeostatic genes Kir4.1 and GS. These findings show that astrocytes are pathologically altered during the epileptogenic period, combining the proinflammatory gain of function with the loss of homeostatic profile. This may sustain the long-term alterations underlining epileptogenesis.
Nerve Growth Factor Signaling Tunes Axon Maintenance Protein Abundance and Kinetics of Wallerian Degeneration
Authors: Danos Joseph A. , Addemir Merve , McGettigan Lily , Summers Daniel W.
Published: January 2025

Neurotrophic factors are critical for establishing functional connectivity in the nervous system and sustaining neuronal survival through adulthood. As the first neurotrophic factor purified, nerve growth factor (NGF) is extensively studied for its prolific role in axon outgrowth, pruning, and survival. Applying NGF to diseased neuronal tissue is an exciting therapeutic option and understanding how NGF regulates local axon susceptibility to pathological degeneration is critical for exploiting its full potential. Our study identifies surprising connections between NGF signaling and proteostasis of axon maintenance factors. NGF deprivation increases Nmnat2 and Stmn2 protein levels in axon segments with a corresponding delay in Wallerian degeneration. Conversely, acute NGF stimulation reduces local abundance of these axon maintenance factors and accelerates Wallerian degeneration. Pharmacological studies implicate phospholipase C as the key effector in TrkA activation, which drives degradation of palmitoylated Stmn2. While seemingly opposed to neuroprotective activities well-documented for NGF, downregulating Nmnat2 and Stmn2 favors axonal outgrowth over transient hyper-susceptibility to Sarm1-dependent degeneration. This new facet of NGF biology has important implications for axonal remodeling during development and sustained integrity through adulthood.
Predictive routing emerges from self-supervised stochastic neural plasticity
Authors: Nejat Hamed , Sherfey Jason , Bastos André M.
Published: January 2025

Neurophysiology studies propose that predictive coding is implemented via alpha/beta (8-30 Hz) rhythms preparing specific pathways to process predicted inputs. This leads to a state of relative inhibition, reducing feedforward gamma (40-90 Hz) rhythms and spiking for predictable inputs. This is called predictive routing model. It is unclear which circuit mechanisms implement this push-pull interaction between alpha/beta and gamma rhythms. To explore how predictive routing is implemented, we developed a self-supervised learning algorithm we call generalized Stochastic Delta Rule (gSDR). Development of this algorithm was necessary because manual tuning of parameters (frequently used in computational modeling) is inefficient to search through a non-linear parameter space that leads to emergence of neuronal rhythms. We used gSDR to train biophysical neural circuits and validated the algorithm on simple objectives. Then we applied gSDR to model observed neurophysiology. We asked the model to reproduce a shift from baseline oscillatory dynamics (∼<20Hz) to stimulus induced gamma (∼40-90Hz) dynamics recorded in the macaque visual cortex. This gamma oscillation during stimulation emerged by self-modulation of synaptic weights via gSDR. We further showed that the gamma-beta push-pull interactions implied by predictive routing could emerge via stochastic modulation of the local circuitry as well as top-down modulatory inputs to a network. To summarize, gSDR succeeded in training biophysical neural circuits to satisfy a series of neuronal objectives. This revealed the inhibitory neuron mechanisms underlying the gamma-beta push-pull dynamics that are observed during predictive processing tasks in systems and cognitive neuroscience.

Significant Statement

This study contributes to the advancement of self-supervised learning for modeling the behavior of complex neural circuits and specifically, biophysical modeling. We performed simulations in order to examine basic mechanisms in predictive routing framework. Since generalized stochastic delta rule (gSDR) is in the family of evolutionary algorithms and does not rely on specific model-based assumptions, it could improve computational neuroscience studies by adding autonomous approaches in neural network research with emphasis on neurobiology. In addition, it is allows to expand bio-plausibility by defining multiple objectives, making it capable of expanding its neurobiological constraints.
Nurr1 orchestrates claustrum development and functionality
Authors: Yan Kuo , Newman Andrew , Lange Pauline , Mueller Susanne , Foddis Marco , Mantwill Maron , Finke Carsten , Koch Stefan Paul , Boehm-Sturm Philipp , Deng Penghui , Long Melissa , Tarabykin Victor
Published: January 2025

Claustrum is the part of the forebrain known to be most widely interconnected tissue with almost all global regions. It is believed to be involved in coordinating multiple cognitive behaviors including consciousness formation. However, little is known about the molecular mechanisms underlying its development and involvement in behavioral control. Here we show that Nurr1 (Nr4a2) is the key transcription factor orchestrating claustral morphogenesis, functional connectivity and thus behaviors. Nurr1 deficient claustral cells aberrantly migrate into insular cortex, shaping claustrum into an abnormal wing-like structure, and ectopically turn on insular corticex genetic program. Accordingly, functional connectivity of the claustrum is not properly formed and relevant behaviors are dysregulated in Nurr1 deficient mice. We show that Nurr1 regulates claustral neuron positioning by suppressing G-protein signaling.
Detection of HTTex1p by western blot and immunostaining of HD human and mouse brain using neo-epitope antibody P90 highlights impact of CAG repeat expansion on its size, solubility, and response to MSH3 silencing
Authors: Sapp Ellen , Boudi Adel , Iwanowicz Andrew , Belgrad Jillian , Miller Rachael , O’Reilly Daniel , Yamada Ken , Deng Yunping , Joni Marion , Li Xueyi , Kegel-Gleason Kimberly , Khvorova Anastasia , Reiner Anton , Aronin Neil , DiFiglia Marian
Published: January 2025

HTT1ahas been identified in human and mouse HD brain as the pathogenic exon 1 mRNA generated from aberrant splicing between exon 1 and 2 that contributes to aggregate formation and neuronal dysfunction (Sathasivam et al., 2013). Detection of the HTT exon 1 protein (HTTex1p) has been accomplished with surrogate antibodies in fluorescence-based reporter assays (MSD, HTRF), and immunoprecipitation assays, in HD postmortem cerebellum and knock-in mice but direct detection by SDS-PAGE and western blot assay has been lacking. Here proteins in subcellular fractions prepared from human and mouse HD brain were separated by SDS-PAGE and probed by western blot with neo-epitope monoclonal antibodies (P90-1B12 and 11G2) directed to the C-terminal 8 residues of HTTex1p. In human HD putamen and cortex, HTTex1p migrated at 56-60 kD and at higher molecular masses (HMM) consistent with the presence of CAG repeat expansion inHTT1a. HTTex1p in control brain was low or undetectable. Immunofluorescence labeling of human HD cortex using P90-11G2 revealed small aggregates that sparsely populated the neuropil in layers 3 and 5. In caudate putamen of 6 month old HD knock-in mice (Q50, Q80, Q111, Q140 and Q175) HTTex1p migration was inversely correlated with CAG repeat length and appeared as a SDS soluble high molecular mass (HMM) smear in HD Q111, Q140 and Q175 mice but not in Q50 and Q80 mice indicating a CAG repeat size threshold for detecting HTTex1p aggregation. Migration of HTTex1p and HMM smear changed with age in caudate putamen of Q111, Q175 and YAC128 mice. Treating HD Q111 mice with siRNA to MSH3, a modifier of CAG repeat expansion, significantly reduced levels of the HMM smear indicating that the effects of curbing CAG repeat expansion was quantifiable. These results show that P90 antibodies can be used in western blot assays and immunostaining to track and quantify HTTex1p levels, subcellular localization, and solubility.
Cortical responses to conflicting binocular stimuli in mouse primary visual cortex
Authors: Montgomery D. P. , Bowen D. A. , Wu J. , Bear M. F. , Gaier E. D.
Published: January 2025

Binocular vision requires that the brain integrate information coming from each eye. These images are combined (fused) to generate a meaningful composite image. Differences between images, within a range, provide useful information about depth (stereopsis). Interocular disparities that are not effectively combined result in diplopia and rivalry. The neural mechanisms underlying these binocular interactions remain poorly understood. Using a combination of visually evoked potential (VEP) recordings, unit recordings, and 2-photon calcium imaging in the binocular region of mouse primary visual cortex (bV1), we probed the neural mechanisms underlying the processing of two distinct forms of disparate binocular signals. Using a dichoptic display, introduction of a spatial interocular phase disparity in grating stimuli reduced VEP magnitude through decreased neuronal firing in the early phase of the response (40-80 ms after stimulus onset, corresponding to the VEP negativity). Introduction of an interocular orientation disparity also decreased VEP magnitude, but this difference was driven by an increase in firing in the late portion of the visual response (100-200 ms after stimulus onset, corresponding to the VEP positivity). This increase in activity was observed for both regular-spiking (putative excitatory) and fast-spiking (putative parvalbumin-positive inhibitory) units. By contrast, visually evoked calcium responses of somatostatin-positive interneurons decreased with introduction of the interocular orientation disparity. Based on these results, we propose that interocular phase differences largely suppress bV1 responses via feedforward thalamocortical interactions, whereas interocular orientation differences prolong visually evoked activity in bV1 through somatostatin-positive interneuron-mediated disinhibition.
Rotationally Stable Dynamics Over Long Timescales Emerge in Neuronal Development
Authors: Burrows Dominic R.W. , Rosch Richard E.
Published: January 2025

Neuronal networks must balance the need for stable yet flexible dynamics. This is evident during brain development, when synaptic plasticity during critical windows enables adaptability to changing environments whilst ensuring the stability of population dynamics. The emergence of population dynamics that balance stability and flexibility during development is poorly understood. Here, we investigated developmental brain dynamics in larval zebrafish, usingin vivo2-photon imaging to record single-cell activity across major brain regions from 3-8 days post-fertilisation, a highly plastic period in which hunting behaviours are established. Our findings revealed region-specific trajectories in the development of such dynamic regimes: the telencephalon exhibited increased neuronal excitability and long-range correlations, alongside the emergence of scale invariant avalanche dynamics indicative of enhanced flexibility. Conversely, while other regions showed increased state transitions over development, the telencephalon demonstrated a surprising rise in state stability, characterized by slightly longer dwell times and drastically reduced angular velocity in state space. Remarkably, such rotationally stable dynamics persisted up to 5 seconds into the future, indicating the emergence of strong attractors supporting stability over long timescales. Notably, we observed that telencephalon dynamics were maintained near to but not at a phase transition, thus allowing for robust responses while remaining adaptable to novel inputs. Our results highlight regionally-specific trajectories in the relationship between flexibility and stability, illustrating how developing neuronal populations can self-organize to balance these competing demands.

Significance Statement

Brain networks must balance the flexibility to adapt to new stimuli with the need for stability. This trade-off is particularly important during periods of high plasticity in brain development. Our study investigates this balance by recording single-cell activity across the entire brain of developing larval zebrafish. We discovered that brain dynamics become increasingly diverse, characterized by both short and long bursts of activity, reflecting increased flexibility. Simultaneously, we observed the emergence of stable dynamics, linked to consistent activity patterns over time. Using a modelling approach, we showed that this stability was driven by the formation of stable attractors that shape the dynamic trajectories. These findings highlight how population mechanisms can shape the dynamic interplay between flexibility and stability in regional networks in the developing brain.
Impact of Segmentation Errors in Analysis of Spatial Transcriptomics Data
Authors: Mitchel Jonathan , Gao Teng , Cole Eli , Petukhov Viktor , Kharchenko Peter V.
Published: January 2025

Spatial transcriptomics aims to elucidate cell coordination within biological tissues by linking the state of the cell with its local tissue microenvironment. Imaging-based assays are particularly promising for exploring such interdependencies, as they can resolve molecular and cellular features with subcellular resolution in three dimensions. Quantification and analysis of cellular state in such data, however, ultimately depends on the ability to recognize which molecules belong to each cell. Despite computational and experimental progress, this cell segmentation task remains challenging. Here we re-analyze data from multiple tissues and platforms and find that segmentation errors currently confound most downstream analysis of cellular state, including analysis of differential expression, inference of neighboring cell influence, and ligand-receptor interactions. The extent to which mis-segmented molecules impact the results can be striking, often dominating the set of top hits. We show that factorization of molecular neighborhoods can be effective at isolating such molecular admixtures and minimizing their impact on downstream analysis, analogous to doublet filtering of scRNA-seq data. As applications of spatial transcriptomics assays become more widespread, we expect corrections for the confounding effect of segmentation errors to become increasingly important for being able to resolve molecular mechanisms of tissue biology.
Business networking and governance: impact on tourism SMTE performance in Tanzania
Authors: Buzohera Mohamed Issa
Published: January 2025

Purpose

This study investigates the impact of business networking activities and governance mechanisms on the performance of small and medium tourism enterprises in Tanzania’s tourism industry. This study aims to provide insights into how networkig and governance can enhance operational efficiency, market access and overall performance.
Changes in blowfly (Diptera: Calliphoridae) wing morphology during succession in rat carcasses across forest and grassland habitats in South Brazil
Authors: Colares Lucas Ferreira , Herdina Anita da Silva , Bender Mariana , Dambros Cristian de Sales
Published: January 2025

Succession is one of the most extensively studied ecological phenomena, yet debates persist about the importance of dispersal and external factors in driving this process. We aimed to quantify the influence of these factors by investigating how wing‐related traits evolve across succession of blowfly (Diptera: Calliphoridae) communities in South Brazil. Rat carrion was placed in both forest and grassland habitats, and the associated blowfly communities were documented throughout the decomposition process. Using morphometric analysis, we measured wing and thorax traits and assessed trait changes over succession through mixed models. Our findings revealed that carrion succession follows distinct trajectories in forest and grassland environments. Specifically, we observed that Calliphora lopesi predominantly visited carcasses during the final phase of decomposition, resulting in significant differences in species composition and wing size between habitats. In forests, wing size increased toward the later stages of succession, whereas an opposite trend was observed in grasslands. Notably, these trait patterns were only evident at the species level, indicating that intraspecific trait variation is irrelevant. Stronger dispersers tend to arrive during the later stages of succession, suggesting that dispersal has a negligible role in shaping successional dynamics. Instead, environmental differences between habitats drive trait patterns throughout succession. Our results suggest that community composition in ephemeral resources is governed by deterministic processes and that successional stages can be predicted based on blowfly wing traits. Specifically, the presence of the large‐winged C. lopesi indicates late decay, while the small‐winged Chrysomia albiceps and Lucilia eximia are indicative of early decay.
Identifying ENO1 as a protein target of chlorogenic acid to inhibit cellular senescence and prevent skin photoaging in mice
Authors: He Xueling , Wang Chen , Zhang Qianyu , Yang Tong , Guo Qiuyan , Wang Yaxu , Guo Jiayue , Wang Pengjie , Zhang Junzhe , Tang Huan , Zhu Yinhua , Wang Jigang
Published: January 2025

Cellular senescence plays a critical role in repeated ultraviolet (UV) exposure‐induced skin photoaging. Currently, from the perspective of regulating senescent cells, potent compounds or reliable protein targets that could effectively prevent skin photoaging have not yet been reported. Herein, we demonstrated that chlorogenic acid (CGA) significantly inhibited UVA‐induced senescence of human dermis skin fibroblasts (HDF) cells by screening the natural product library. The activity‐based protein profiling (ABPP) result revealed that Enolase 1 (ENO1) is one of the direct targets of CGA in HDF cells. Further mechanism research indicated that CGA covalently binds to ENO1, and prevented UVA‐induced cellular senescence by suppressing the activity of ENO1 protein to block the glycolytic pathway. Importantly, we found that CGA dose‐dependently reduced the skin wrinkle score, alleviated skin pathological features and inhibited senescent characteristics in a photoaging mouse model. The proteomic analysis revealed that CGA treatment effectively inhibited senescence‐associated secretory phenotype (SASP) secretion and glycolysis in skin samples of mice. Collectively, our study not only demonstrated that inhibiting cell senescence is an effective anti‐skin photoaging strategy, but also revealed that ENO1 is a promising protein target to prevent photoaging.
Efficiency of dung beetles (Coleoptera: Scarabaeidae) in improving soil and forage grasses by incorporating nutrients through the removal of cattle dung
Authors: Niero Mariana Mrotskoski , Loss Arcângelo , Brunetto Gustavo , Hernández Malva Isabel Medina
Published: January 2025

Coprophagous dung beetles provide important ecosystem services in improving soil quality and plant development in agricultural environments due to the availability of nutrients from dung removal. The study aimed to compare the effect of dung removal performed by two functional groups, among themselves and with mineral fertiliser, on improving soil and forage grass characteristics. An experiment in mesocosms was conducted in Southern Brazil during the summer/autumn of 2021, sowing Urochloa brizantha in the treatments: (1) telecoprid species (Canthon rutilans cyanescens), (2) paracoprid species (Dichotomius sericeus), (3) both species together, (4) mineral fertiliser and control with cattle dung. Dung removal was quantified weekly. At the end of the experiment, the soil's physical, chemical and microbiological characteristics, dry biomass and macronutrients (N, P and K) of the leaves and roots, and photosynthetic pigments of grasses were analysed. The dung beetle species studied increased total nitrogen and organic matter contents and their particulate fractions of C and N. Paracoprids decreased the soil bulk density and improved its soil aggregation, influencing the pH and Mg contents, with a reduction in Al levels. They were as efficient as mineral fertiliser in incorporating K into the soil. Treatments with beetles had values similar to mineral fertiliser in the foliar concentrations of P, and paracoprids promoted increases in the K concentration in the leaves and roots of the grass. This functional group was also more efficient in removing cattle dung, which was positively related to the amounts of N, organic matter and its particulate fractions, P, macroaggregates and the cation exchange capacity (CECpH7.0) of the soil. Thus, dung removal was associated with improvement in the soil, mainly paracoprids, reinforcing the importance of the ecosystem functions performed by these organisms in agricultural environments, where they can contribute to the increase in nutrient cycling with a consequent decrease in the use of mineral fertilisers.
Gender Under Scrutiny – Whose Gender?
Authors: Mackay Finn
Published: January 2025

This article will argue that there is no war on gender, in the context of the so‐called ‘gender wars’. The dominant binary model of gender as male, masculine, heterosexual or female, feminine, heterosexual is not under scrutiny. There is an old and ongoing attempt to control sex, gender and sexuality and constrain and construct what these mean for the benefit of the patriarchal status quo. Rather than a war on gender, there is a war on identities, relationships and families that are the ‘wrong’ gender, other to the heterosexual nuclear family.
New Insights on Continuous Renal Replacement Therapy for Acute Respiratory Distress Syndrome: A Systematic Review and Meta‐Analysis
Authors: Zeng Siyao , Cui Shanpeng , Li Yue , Yao Zhipeng , Li Yunlong , Cao Yang , Wen Lianghe , Li Ming , Zheng Junbo , Wang Hongliang
Published: January 2025

Background

In recent times, the applications of continuous renal replacement therapy (CRRT) beyond kidney‐related conditions have been progressively increasing, and its implementation in randomized controlled trials (RCTs) specifically for acute respiratory distress syndrome (ARDS) has been documented. This meta‐analysis compiles all existing RCTs to assess whether CRRT benefits ARDS.

Methods

We searched 12 databases in English and Chinese and two clinical trial centers up to November 28, 2023. The main outcome indicator is the mortality rate. Secondary outcome indicators include incidence of ventilator‐associated pneumonia (VAP), ICU length of stay, mechanical ventilation time, oxygenation index (OI) at 24 h (h), OI at 48 h, OI at 72 h, OI at 7 days (d), partial pressure of oxygen (PaO2) at 72 h, Acute Physiology and Chronic Health Evaluation II (APACHE II) score at 24 h, APACHE II score at 48 h, APACHE II score at 72 h, APACHE II score at 7 d, extravascular lung water indexes (EVLWI) at 72 h, TNF‐α at 24 h, TNF‐α at 7 d, IL‐6 at 24 h, IL‐6 at 48 h, IL‐6 at 72 h, and IL‐6 at 7 d. Statistical measures utilized include risk ratios (RR), weighted mean difference (WMD), and 95% confidence intervals (95% CI).

Results

We summarized 36 studies, including 2123 patients. It was found that for ARDS, using CRRT in addition to conventional therapy can reduce the mortality rate (I2 = 0%; RR: 0.40; 95% CI: 0.30–0.53; p < 0.01), the incidence of VAP (I2 = 0%; RR: 0.44; 95% CI: 0.33–0.59; p < 0.01), ICU length of stay, mechanical ventilation time, and EVLWI at 72 h, as well as APACHE II score, TNF‐α, and IL‐6 at various time points. Additionally, it can increase OI during different time intervals and PaO2 at 72 h.

Conclusions

Low‐quality evidence suggests that compared with conventional therapy alone, the use of CRRT may be associated with a lower mortality rate, the incidence of VAP, ICU length of stay, mechanical ventilation time, EVLWI, APACHE II score, TNF‐α, and IL‐6 and may be related to better respiratory function. CRRT may be beneficial for ARDS patients. Future multicenter, well‐designed, high‐quality RCTs are needed to substantiate these findings.
Risk acceleration by gout on major adverse cardiovascular events and all‐cause death in patients with diabetes and chronic kidney disease
Authors: Lee Da Young , Moon Jun Sung , Jung Inha , Chung Seung Min , Park So Young , Yu Ji Hee , Seo Ji A , Han Kyung‐do , Kim Nan Hee
Published: January 2025

Aims

We aimed to examine the impact of gout on cardiovascular disease (CVD) and mortality risk in patients with type 2 diabetes and explore whether chronic kidney disease (CKD) modifies this association.

Materials and Methods

Using the Korean National Health Insurance Service database, 757 378 individuals with type 2 diabetes were classified into the CKD−Gout−, CKD−Gout+, CKD+Gout−, and CKD+Gout+ groups. Cox proportional hazard models were used to assess the risk of myocardial infarction (MI), ischemic stroke, and mortality, after adjusting for cardiometabolic factors.

Results

Over a median follow‐up of 9.3 years, 25 618, 38 691, and 78 628 individuals experienced MI, stroke, and mortality, respectively. The risk of MI or stroke progressively increased across the groups, with the highest adjusted hazard ratio (HR) in the CKD+Gout+ group (HR: 1.57, 95% confidence interval [CI]: 1.46–1.69), followed by the CKD+Gout− group (HR: 1.23, 95% CI 1.20–1.26). The CKD+Gout+ group showed the greatest risks for MI (HR: 1.71), stroke (HR: 1.46), and mortality (HR: 1.78). Individuals with gout alone did not exhibit a significant increase in risk compared with those without gout or CKD. Interaction analyses indicated that the effect of gout on the outcomes was more pronounced in patients with CKD. Subgroup analyses yielded consistent findings across diverse demographic and clinical characteristics.

Conclusions

CKD with or without gout increased the risk of CVD and mortality, with the highest risk observed in the CKD+Gout+ group. The interaction between CKD and gout significantly influenced these outcomes.