bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and Efficacy of Chimeric Antigen Receptor T-cell Therapy for Recurrent Glioblastoma: An Augmented Meta-analysis of Phase 1 Clinical Trials
Authors: Azzam Ahmed Y. , Morsy Mahmoud M. , Azab Mohammed A. , Elamin Osman , Elswedy Adam , Ahmed Omar S. , Nassar Mahmoud , Zomia Ahmed Saad Al , Mohamed Adham A. , Atallah Oday , Alamoud Ahmed , Alotaibi Hammam A. , Abukhadijah Hana J. , Nashwan Abdulqadir J
Published: October 2024

Introduction

Glioblastoma is a devastating brain tumor with poor prognosis despite current treatment modalities. Chimeric antigen receptor T-cell (CAR T-cell) therapy has shown promise in other cancers but has yielded mixed results in glioblastoma. This augmented meta-analysis aims to address the limitations of previous studies and evaluate the safety and efficacy of CAR T-cell therapy for recurrent glioblastoma.

Methods

We followed PRISMA guidelines, including specific inclusion and exclusion criteria, for our literature review. Eight studies with 108 patients were included. We used standard and augmented meta-analyses to assess outcomes, complications, and publication bias.

Results

It was found that the mean overall survival for glioblastoma patients who underwent CAR T-cell therapy was 6.49 months, demonstrating no significant deviation from the median survival observed in those following the standard protocol. CAR T-cell therapy did not lead to a statistically significant improvement in achieving complete responses, with only 80% of patients exhibiting this outcome. Conversely, 44% of patients experienced stable disease, while 58% faced disease progression after CAR T-cell therapy. Adverse events were notable, with CAR T cell therapy-related encephalopathy affecting 37% of treated patients, while cytokine release syndrome was a rare event, observed in only 3% of cases.

Conclusions

To our knowledge, this is the first study that utilizes this novel statistical technique to predict the outcomes of CAR T-cell therapy for recurrent glioblastoma. The results of this study are predictive rather than confirmatory. CAR T-cell therapy for glioblastoma was not predicted to significantly improve survival or achieve substantial complete responses. Stable disease rates are modest, while disease progression is notable. Adverse events, especially CAR T-cell therapy-related encephalopathy, raise safety concerns. Further trials and refinements are needed to enhance CAR T-cell therapy’s effectiveness and safety in glioblastoma treatment, Manuscript Click here to view linked References potentially through optimizing administration routes and target antigens or combining it with other therapies. This challenging disease necessitates continued research to improve patient outcomes.
Prevalence and Diversity of Haemosporidian-Associated Matryoshka RNA Viruses in a Natural Population of Wild Birds
Authors: Esperanza Carlos W. , Faircloth Caroline E. , Roy Scott W. , Sehgal Ravinder N.M.
Published: October 2024

Matryoshka RNA viruses (MaRNAV) have previously been detected using bioinformatics and limited PCR approaches. They are associated with haemosporidian parasite infections, yet their prevalence and diversity in wild bird populations remains largely unknown. To investigate the prevalence of MaRNAV, we examined blood samples collected from wild passerine birds and raptors in the San Francisco Bay Area. Samples were first screened for haemosporidian infections followed by RNA sequencing (RNAseq) and reverse transcriptase (RT) PCR to detect MaRNAV. Our analyses identified two novel MaRNAV (MaRNAV-5 and −6) infecting various bird species harboring diverseHaemoproteusandLeucocytozoonspecies and lineages. MaRNAV-5, associated withHaemoproteus, exhibited 71.3% amino acid identity to MaRNAV-4, also associated withHaemoproteus, and was found across 15 different passerine species. MaRNAV-6, linked toLeucocytozoon, shared 72.9% identity withLeucocytozoon-associated MaRNAV-3 and was exclusively found in 4 raptor species. Prevalence was 44.79% for MaRNAV-5 in haemosporidian-infected passerines and 22.22% for MaRNAV-6 in haemosporidian-infected raptors. These viruses were not found in uninfected birds similarly tested via RNAseq and RT-PCR and were consistently only found in birds infected with haemosporidia. Sanger sequencing revealed high similarity of viral sequences across different bird species, even of different orders. Our findings indicate a high prevalence of MaRNAV among local wild birds, as well as their potential specificity to haemosporidia genera, suggesting potential impacts on their health and ecology. We propose a potential life-cycle model for this group of viruses where the insect vector is the primary host, and the haemosporidian parasite acts as the virus’ “vector” to reach its next host. Further research is needed to determine the impact of these viruses in avian systems.
40 Hz sensory stimulation enhances CA3-CA1 coordination and prospective coding during navigation in a mouse model of Alzheimer’s disease
Authors: Paulson Abigail L. , Zhang Lu , Prichard Ashley M. , Singer Annabelle C.
Published: October 2024

40 Hz sensory stimulation (“flicker”) has emerged as a new technique to potentially mitigate pathology and improve cognition in mouse models of Alzheimer’s disease (AD) pathology. However, it remains unknown how 40 Hz flicker affects neural codes essential for memory. Accordingly, we investigate the effects of 40 Hz flicker on neural representations of experience in the hippocampus of the 5XFAD mouse model of AD by recording 1000s of neurons during a goal-directed spatial navigation task. We find that an hour of daily exposure to 40 Hz audio-visual stimulation over 8 days leads to higher coordination between hippocampal subregions CA3 and CA1 during navigation. Consistent with CA3’s role in generating sequential activity that represents future positions, 40 Hz flicker exposure increased prospective coding of future positions. In turn, prospective coding was more prominent during efficient navigation behavior. Our findings show how 40 Hz flicker enhances key hippocampal activity during behavior that is important for memory.

Significance Statement

Brain stimulation has emerged as a new potential therapeutic approach to potentially correct or improve altered neural activity in Alzheimer’s disease. One such approach, 40 Hz sensory stimulation, or flicker, has been shown to improve cognition in disease models. However, it is not clear how 40 Hz flicker affects neural activity underlying memory processes. Here, we investigate how 40 Hz flicker exposure affects neural activity patterns that are crucial for memory. We find 40Hz flicker increases neural coordination in memory circuits, indicating better communication. Furthermore, 40Hz flicker increased neural representations of future positions, patterns theorized to support memory-based planning. These results indicate that 40 Hz flicker increases key neural activity that is important for memory.
The YTHDF Proteins Shape the Brain Gene Signatures of Alzheimer’s Disease
Authors: Tasaki Shinya , Avey Denis R. , Kearns Nicola A. , Iatrou Artemis , Yu Chunjiang , De Tissera Sashini , Vyas Himanshu , Xu Jishu , Flood Daniel J. , Rothamel Katherine , Wingo Aliza P , Wingo Thomas S , Seyfried Nicholas T. , De Jager Philip L. , Yeo Gene , Gaiteri Chris , Bennett David A. , Wang Yanling
Published: October 2024

The gene signatures of Alzheimer’s Disease (AD) brains reflect an output of a complex interplay of genetic, epigenetic, epi-transcriptomic, and post-transcriptional regulations. To identify the most significant factor that shapes the AD brain signature, we developed a machine learning model (DEcode-tree) to integrate cellular and molecular factors explaining differential gene expression in AD. Our model indicates that YTHDF proteins, the canonical readers of N6-methyladenosine RNA modification (m6A), are the most influential predictors of the AD brain signature. We then show that protein modules containing YTHDFs are downregulated in human AD brains, and knocking out YTHDFs in iPSC-derived neural cells recapitulates the AD brain gene signaturein vitro. Furthermore, eCLIP-seq analysis revealed that YTHDF proteins influence AD signatures through both m6A-dependent and independent pathways. These results indicate the central role of YTHDF proteins in shaping the gene signature of AD brains.
Decoding the transcriptomic signatures of psychological trauma in human cortex and amygdala
Authors: Hicks Emily M. , Seah Carina , Deans Michael , Lee Seoyeon , Johnston Keira J.A. , Cote Alanna , Ciarcia Julia , Chakka Akash , Collier Lily , Holtzheimer Paul E. , Young Keith A. ,   Traumatic Stress Brain Research Group, Krystal John H. , Brennand Kristen J. , Nestler Eric J. , Girgenti Matthew J. , Huckins Laura M.
Published: October 2024

Psychological trauma has profound effects on brain function and precipitates psychiatric disorders in vulnerable individuals, however, the molecular mechanisms linking trauma with psychiatric risk remain incompletely understood. Using RNA-seq data postmortem brain tissue of a cohort of 304 donors (N=136 with trauma exposure), we investigated transcriptional signatures of trauma exposures in two cortical regions (dorsolateral prefrontal cortex, and dorsal anterior cingulate cortex) and two amygdala regions (medial amygdala and basolateral amygdala) associated with stress processing and regulation. We focused on dissecting heterogeneity of traumatic experiences in these transcriptional signatures by investigating exposure to several trauma types (childhood, adulthood, complex, single acute, combat, and interpersonal traumas) and interactions with sex. Overall, amygdala regions were more vulnerable to childhood traumas, whereas cortical regions were more vulnerable to adulthood trauma (regardless of childhood experience). Using cell-type-specific expression imputation, we identified a strong transcriptional response of medial amygdala excitatory neurons to childhood trauma, which coincided with dysregulation observed in a human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons exposed to hydrocortisone. We resolved multiscale coexpression networks for each brain region and identified modules enriched in trauma signatures and whose connectivity was altered with trauma. Trauma-associated coexpression modules provide insight into coordinated functional dysregulation with different traumas and point to potential gene targets for further dissection. Together, these data provide a characterization of the long-lasting human encoding of traumatic experiences in corticolimbic regions of human brain.
Immune History Modifies Disease Severity to HPAI H5N1 Clade 2.3.4.4b Viral Challenge
Authors: Brigleb Pamela H. , Sharp Bridgett , Roubidoux Ericka Kirkpatrick , Meliopoulos Victoria , Tan Shaoyuan , Livingston Brandi , Morris Dorothea , Ripperger Tyler , Lazure Lauren , Balaraman Velmurugan , Thompson Alexis C. , Kleinhenz Katie , Dimitrov Kiril , Thomas Paul G. , Schultz-Cherry Stacey
Published: October 2024

The most recent outbreak of highly pathogenic avian H5 influenza (HPAI) virus in cattle is now widespread across the U.S. with spillover events happening to other mammals, including humans. Several human cases have been reported with clinical signs ranging from conjunctivitis to respiratory illness. However, most of those infected report mild to moderate symptoms, while previously reported HPAI H5Nx infections in humans have had mortality rates upwards of 50%. We recently reported that mice with pre-existing immunity to A/Puerto Rico/08/1934 H1N1 virus were protected from lethal challenge from highly pathogenic clade 2.3.4.4b H5N1 influenza virus. Here, we demonstrate that mice infected with the 2009 pandemic H1N1 virus strain A/California/04/2009 (Cal09) or vaccinated with a live-attenuated influenza vaccine (LAIV) were moderately-to-highly protected against a lethal A/bovine/Ohio/B24OSU-439/2024 H5N1 virus challenge. We also observed that ferrets with mixed pre-existing immunity—either from LAIV vaccination and/or from Cal09 infection—showed protection against a HPAI H5N1 clade 2.3.4.4b virus isolated from a cat. Notably, this protection occurred independently of any detectable hemagglutination inhibition titers (HAIs) against the H5N1 virus. To explore factors that may contribute to protection, we conducted detailed T cell epitope mapping using previously published sequences from H1N1 strains. This analysis revealed a high conservation of amino acid sequences within the internal proteins of our bovine HPAI H5N1 virus strain. These data highlight the necessity to explore additional factors that contribute to protection against HPAI H5N1 viruses, such as memory T cell responses, in addition to HA-inhibition or neutralizing antibodies.
Enhanced immune evasion of SARS-CoV-2 KP.3.1.1 and XEC through NTD glycosylation
Authors: Liu Jingyi , Yu Yuanling , Jian Fanchong , Yang Sijie , Song Weiliang , Wang Peng , Yu Lingling , Shao Fei , Cao Yunlong
Published: October 2024

KP.3.1.1 has surpassed KP.3 to become the new globally dominant strain, while XEC, a recombinant variant of KS.1.1/KP.3.3, is rapidly expanding across Europe and North America. Notably, both variants carry mutations, S31del of KP.3.1.1 and T22N of XEC, that could introduce new N-linked glycans on the Spike N-terminal domain (NTD), emphasizing the urgent need to assess their potential changes in viral characteristics. Here, we found that both KP.3.1.1 and XEC maintained the high ACE2-Spike binding affinity and pseudovirus infectivity of KP.3. Importantly, compared to KP.3, KP.3.1.1, and especially XEC, could further evade the neutralizing antibodies in convalescent plasma, even those elicited by KP.2-like breakthrough infections. Interestingly, both variants demonstrated increased resistance against monoclonal neutralizing antibodies targeting various epitopes on the receptor-binding domain (RBD). These suggest that the additional NTD glycosylation of KP.3.1.1 and XEC could enhance immune evasion via allosteric effects, and supports the future prevalence of XEC.
Size Selection of Giant Unilamellar Vesicles (GUVs) via Modified cDICE Method
Authors: Chen Ariel , Gat Shachar , Ohana Lior , Yekimov Evgeni , Tsori Yoav , Bernheim-Groswasser Anne
Published: October 2024

The production of giant unilamellar vesicles (GUVs) plays a pivotal role in various scientific disciplines, particularly in the development of synthetic cells. While numerous methods exist for GUV preparation, the modified continuous droplet interface crossing encapsulation (cDICE) method offers the advantages of simplicity and high encapsulation efficiency. However, a significant limitation of this technique is the generation of vesicles with a broad size distribution and the inability to control the desired size range. This raises a key question: Can the modified cDICE method be optimized to produce GUVs with controlled size distribution? In this study, we examined the effects of two experimental parameters—rotation time (tROT) and the angular frequency (ω) of the cDICE chamber—on the size distribution of GUVs. Our results show that reducing either the angular frequency or rotation time shifts the size distribution toward larger vesicles, enabling effective size selection. These findings are further supported by a physical model, which provides insights into the mechanisms underlying size selection. This work demonstrates that control over GUV size distribution can be achieved through straightforward adjustments of system parameters. The ability to fine-tune vesicle size offers researchers a powerful tool for developing customizable experimental systems for synthetic biology and related fields.
The role of dopaminergic, cholinergic and noradrenergic networks in hyposmia in Parkinson’s disease
Authors: Pérot Jean-Baptiste , Kozlowski Esther , Fraysse Audrey , Ouarab Salim , Valabregue Romain , Rebbah Sana , Lejeune François-Xavier , Massy Emma , Gaurav Rahul , Arnulf Isabelle , Corvol Jean-Christophe , Vidailhet Marie , Pyatigorskaya Nadya , Galléa Cécile , Lehéricy Stéphane
Published: October 2024

Background

Olfactory impairment is frequently observed in Parkinson’s disease (PD) before motor symptom onset. Patients with isolated rapid eye movement sleep behaviour disorder (iRBD) are at risk to develop PD and present olfactory dysfunction. Subcortical neuromodulatory nuclei including the substantia nigra, the nucleus basalis of Meynert, and the locus coeruleus, may all contribute to olfactory dysfunction.

Objective

The objective of this study was to understand the network alterations underlying olfactory dysfunction in PD and in the early prodromal iRBD patients using multimodal MRI.

Methods

PD (n = 107), iRBD patients (n = 35) and healthy controls (HC, n = 39) were recruited from the ICEBERG cohort for a cross-sectional study. We separated subjects in Healthy Controls, iRBD patients, and PD patients with or without RBD and with or without anosmia. Olfactory, motor, and cognitive scores were assessed and combined with multimodal imaging.

Results

We found that olfaction positively correlated with (i) striatal DaT signal in PD patients; (ii) neuromelanin contrast in the locus coeruleus and (iii) Nucleus Basalis of Meynert grey matter (GM) volume in all patients. These signals were uncorrelated with motor and cognitive scores. Functional connectivity was reduced in regions of the cholinergic olfactory network in anosmic patients. Functional connectivity was also reduced in the noradrenergic network of patients with RBD.

Discussion

Our results indicate the implication of the cholinergic network in PD patients with anosmia and a contribution of the noradrenergic network to olfactory dysfunction, only in patients with RBD.
Distractor anticipation during working memory is associated with theta and beta oscillations across spatial scales
Authors: Jung Dennis Y. , Sahoo Bikash C. , Snyder Adam C.
Published: October 2024

Anticipating distractors during working memory maintenance is critical to reduce their disruptive effects. In this study, we aimed to identify the oscillatory correlates of this process across different spatial scales of neural activity. We simultaneously recorded local field potentials (LFP) from the LPFC and electroencephalograms (EEG) from the scalp of monkeys performing a modified memory-guided saccade (MGS) task. The monkeys were required to remember the location of a target visual stimulus while anticipating distracting visual stimulus, flashed at 50% probability during the delay period. We found significant theta-band activity across spatial scales during anticipation of a distractor, closely linked with underlying working memory dynamics, through decoding and cross-temporal generalization analyses. EEG particularly reflected reactivation of memory around the anticipated time of a distractor, even in the absence of stimuli. During this anticipated time, beta-band activity exhibited transiently enhanced intrahemispheric communication between the LPFC and occipitoparietal brain areas. These oscillatory phenomena were observed only when the monkeys successfully performed the task, implicating their possible functional role in mitigating anticipated distractors. Our results demonstrate that distractor anticipation recruits multiple oscillatory processes across the brain during working memory maintenance, with a key activity observed predominantly in the theta and beta bands.
Soil properties in agricultural systems affect microbial genomic traits
Authors: Goodall Tim , Busi Susheel Bhanu , Griffiths Robert I. , Jones Briony , Pywell Richard F. , Richards Andrew , Nowakowski Marek , Read Daniel S.
Published: October 2024

Understanding the relationships between bacterial taxa, their ecological and genomic traits, and their environment, is important for elucidating the mechanisms that drive microbial community dynamics and their roles in ecosystem functioning. This is especially true for soils, where dramatic shifts in resource input or physicochemical properties occur through land use and agricultural practices. Here, we examined the relationships between soil properties and bacterial traits within highly managed agricultural soil systems subjected to arable crop rotations or management as permanent pasture. We assessed the bacterial communities within these soils using amplicon sequencing and assigned each amplicon trait scores for rRNA copy number, genome size, and GC content, which are classically associated with potential growth rates and specialisation. We also calculated the niche breadth trait of each amplicon as a measure of social ubiquity within the examined samples. Within this soil system, we demonstrated that pH was the primary driver of bacterial traits. The weighted mean trait scores of the samples revealed that bacterial communities associated with soils at lower pH (<7) tended to have larger genomes (possess more potential plasticity), have more rRNA (higher growth rate potential), and are more ubiquitous (have less niche specialisation) than the bacterial communities from higher pH soils. Our findings highlight not only the association between pH and bacterial community composition but also the importance of pH in driving community functionality by directly influencing genomic and niche traits.
Equivalence between representational similarity analysis, centered kernel alignment, and canonical correlations analysis
Authors: Williams Alex H.
Published: October 2024

Centered kernel alignment (CKA) and representational similarity analysis (RSA) of dissimilarity matrices are two popular methods for comparing neural systems in terms of representational geometry. Although they follow a conceptually similar approach, typical implementations of CKA and RSA tend to result in numerically different outcomes. Here, I show that these two approaches are largely equivalent once one incorporates a mean-centering step into RSA. This equivalence holds for both linear and nonlinear variants of these methods. These connections are simple to derive, but appear to have been thus far overlooked in the context of comparing neural representations. By unifying these measures, this paper hopes to simplify a complex and fragmented literature on this subject.
Cortex-wide characterization of decision-making neural dynamics during spatial navigation
Authors: Haley Samuel P. , Surinach Daniel A. , Nietz Angela K. , Carter Russell E. , Zecker Lucas S. , Popa Laurentiu S. , Kodandaramaiah Suhasa B. , Ebner Timothy J.
Published: October 2024

Decision-making during freely moving behaviors involves complex interactions among many cortical and subcortical regions. However, the spatiotemporal coordination across regions to generate a decision is less understood. Using a head-mounted widefield microscope, cortex-wide calcium dynamics were recorded in mice expressing GCaMP7f as they navigated an 8-maze using two paradigms. The first was an alternating pattern that required short term memory of the previous trial to make the correct decision and the second after a rule change to a fixed path in which rewards were delivered only on the left side. Identification of cortex-wide activation states revealed differences between the two paradigms. There was a higher probability for a visual/retrosplenial cortical state during the alternating paradigm and higher probability of a secondary motor and posterior parietal state during left-only. Three state sequences (motifs) illustrated both anterior and posterior activity propagations across the cortex. The anterior propagating motifs had the highest probability around the decision and posterior propagating motifs peaked following the decision. The latter, likely reflecting internal feedback to influence future actions, were more common in the left-only paradigm. Therefore, the probabilities and sequences of cortical states differ when working memory is required versus a fixed trajectory reward paradigm.
Pseudomonas aeruginosaAlkyl Quinolone Response is dampened by Enterococcus faecalis
Authors: Fink Maggie M. , Weaver Abigail A. , Parmar Dharmeshkumar , Paczkowski Jon E. , Li Lingyun , Klaers Maggie K. , Junker Ella A. , Jarocki Elizabeth A. , Sweedler Jonathan V. , Shrout Joshua D.
Published: October 2024

The bacteriumPseudomonas aeruginosais an opportunistic pathogen that can cause lung, skin, wound, joint, urinary tract, and eye infections. WhileP. aeruginosais known to exhibit a robust competitive response towards other bacterial species, this bacterium is frequently identified in polymicrobial infections where multiple species survive. For example, in prosthetic joint infections (PJIs),P. aeruginosacan be identified along with other pathogenic bacteria includingStaphylococcus aureus, Enterococcus faecalis,andCorynebacterium striatum.Here we have explored the survival and behavior of such microbes and find thatE. faecalisreadily survives culturing withP. aeruginosawhile other tested species do not. In each of the tested conditions,E. faecalisgrowth remained unchanged by the presence ofP. aeruginosa,indicating a unique mutualistic interaction between the two species. We find thatE. faecalisproximity leadsP. aeruginosato attenuate competitive behaviors as exemplified by reduced production ofPseudomonasquinolone signal (PQS) and pyocyanin. Reduced alkyl quinolones is important toE. faecalisas it will grow in supernatant from a quinolone mutant but not P. aeruginosa wildtype in planktonic culture. The reduced pyocyanin production ofP. aeruginosais attributable to production of ornithine byE. faecalis, which we recapitulate by adding exogenous ornithine toP. aeruginosamono-cultures. Similarly, co-culture with an ornithine-deficient strain ofE. faecalisleadsP. aeruginosato yield near mono-culture amounts of pyocyanin. Here, we directly demonstrate how notorious pathogens such asP. aeruginosamight persist in polymicrobial infections under the influence of metabolites produced by other bacterial species.

Importance

While we now appreciate that many infections are polymicrobial, we understand little of the specific actions between a given set of microbes to enable combinatorial survival and pathogenesis. The bacteriaPseudomonas aeruginosaandEnterococcus faecalisare both prevalent pathogens in wound, urinary tract, and bacteremic infections. WhileP. aeruginosaoften kills other species in standard laboratory culture conditions, we present here thatE. faecaliscan be reliably co-cultured withP. aeruginosa.We specifically detail that ornithine produced byE. faecalisreduces the Pseudomonas Quinolone Signal response ofP. aeruginosa. This reduction of the Pseudomonas Quinolone Signal response aidsE. faecalisgrowth.
RTL4,a retrovirus-derived gene implicated in autism spectrum disorder, is a microglial gene that responds to noradrenaline in the postnatal brain
Authors: Ishino Fumitoshi , Itoh Johbu , Matsuzawa Ayumi , Irie Masahito , Suzuki Toru , Hiraoka Yuichi , Yoshikawa Masanobu , Kaneko-Ishino Tomoko
Published: October 2024

RTL4, a gene acquired from a retrovirus, is a causative gene in autism spectrum disorder. Its KO mice exhibit increased impulsivity, impaired short-term spatial memory, failure to adapt to novel environments, and delayed noradrenaline (NA) recovery in the frontal cortex. However, due to its very low expression in the brain, it remains unknown which brain cells express RTL4 and its dynamics in relation to NA. Here, using knock-in mice carrying endogenousRtl4fused toVenus, we demonstrated thatRTL4is a microglial gene with several important properties. The RTL4-Venus fusion protein was detected as a secreted protein in the midbrain, hypothalamus, hippocampus and amygdala in the postnatal brain. Its signal intensity was high during critical periods of neonatal adaptation to novel environments and was upregulated by various stimuli, such as handling the mice, mild environmental changes and administration of isoproterenol, an agonist of adrenergic beta receptors. It was decreased by anesthesia but was maintained by the administration of milnacipran, an NA reuptake inhibitor. These results suggest that RTL4 intensity depends on the arousal state via NA and is somehow related to the NA reuptake process.In vitromixed glial culture experiments demonstrated thatRtl4is a microglial gene and suggested that RTL4 secretion responds rapidly to isoproterenol. Taken together with previous results fromRtl4KO mice, microglial RTL4 plays an important role in the NA response and it is likely involved in the development of the NAergic neuronal network in the brain.
Depletion of BBSome Subunits Alters Receptor Endocytosis and Promotes EMT via TGF-β Signaling
Authors: Solarat C. , Barra-Carneiro J. , Vila-Almuíña S. , Barbeito P. , Schrøder Holm M. , Gammoh N. , Christensen S.T. , Valverde D.
Published: October 2024

Ciliopathies are genetic disorders caused by defects in the structure or function of the cilia and their related structures. Bardet-Biedl syndrome (BBS) is a complex ciliopathy with varied symptoms, probably due to altered membrane receptor signalling pathways. This study explores the role ofBBS1andBBS4gene deficiencies in receptor trafficking and epithelial-mesenchymal transition (EMT) in retinal epithelial cells. Deficiencies in these genes, key components of the BBSome complex, led to shorter cilia and disrupted receptor endocytosis.BBS1knockout (KO) cells showed delayed transferrin internalisation and increased recycling of TGFBR1, promoting EMT. On the contrary,BBS4KO cells had higher receptor degradation but no affected recycling. These disruptions suggest that BBSome regulates both ciliary and nonciliary pathways. Increased EMT markers inBBS1KO cells were associated with higher cell migration and reduced proliferation, highlighting the role in receptor trafficking and potential therapeutic targets for retinal degeneration in BBS.

Highlights

Depletion of BBS1 and BBS4 alters endocytic trafficking as well as length and/or frequency of primary cilia, affecting the internalisation of receptors at the ciliary pocket.

BBS1knockout cells show increased EMT, up-regulation of mesenchymal markers, enhanced migration, and reduced proliferation after TGF-β stimulation.

BBS1knockout cells exhibit increased TGFBR1 recycling, whileBBS4KO cells exhibit balanced receptor degradation and recycling, indicating distinct roles of these two BBSome components in receptor trafficking.

Targeting the TGF-β pathway and EMT may provide therapeutic options for retinal degeneration in Bardet-Biedl syndrome.
Comparative genomic analysis reveals reduced pathogenicity ofRalstoniaspp. in water
Authors: Liu Gaopeng , Mao Chengzhi , Li Qi , Huo Da , Li Tao
Published: October 2024

Ralstoniaspp., known for their adaptability across various habitats, are known to cause infections. The adaptive metabolic diversity of those inhabiting aquatic ecosystems remains poorly understood. We report four newRalstonia pickettiigenomes enriched in the cyanobacterial culture derived from bloom-forming cyanobacteria,Dolichospermum. A total of 228 complete genomes from theRalstoniagenus were utilized for phylogenetic inference, categorizing them based on isolation environment and host: water, soil, plant, and human groups. Meanwhile, the abundance of carbohydrate-active enzymes and secondary metabolites in water and human groups differed from the plant-host associate habitat.CeoBand two β-lactamases types ofOXAwere identified in the water habitat, showing similarities to certain strains in the human-host but differences from other habitats. The infectivity within water habitats seems to diminish, as evidenced by the decreased abundance of T3SS virulence proteins. Moreover, a distinctive pyrimidine degradation pathway in water degrades exogenous pyrimidines to supply nitrogen and other compounds for energy metabolism to provide a potential for broader habitat adaptability. Fluorescence in situ hybridization results confirmed thatR. pickettiirarely attached to cyanobacterial cells, indicating that they are not parasitic relationships. We postulate that the absence of T3SS and the unique metabolic profile represent adaptations ofRalstoniato an aquatic free-living lifestyle.
Human gut commensalAlistipes timonensismodulates the host lipidome and delivers anti-inflammatory outer membrane vesicles to suppress colitis in anIl10-deficient mouse model
Authors: Older Ethan A. , Mitchell Mary K. , Campbell Andrew , Lian Xiaoying , Madden Michael , Wang Yuzhen , van de Wal Lauren E. , Zaw Thelma , VanderVeen Brandon N. , Tatum Rodney , Murphy E. Angela , Chen Yan-Hua , Fan Daping , Ellermann Melissa , Li Jie
Published: October 2024

Correlative studies have linked human gut microbes to specific health conditions.Alistipesis one such microbial genus negatively linked to inflammatory bowel disease (IBD). However, the protective role ofAlistipesin IBD has not been studied and the underlying molecular mechanisms also remain unknown. In this study, colonization ofIl10-deficient mice withAlistipes timonensisDSM 27924 delays the development of colitis. Colonization withAlistipesdoes not significantly alter the gut microbiome composition during colitis development, but instead shifts the host plasma lipidome, increasing phosphatidic acids while decreasing triglycerides. Outer membrane vesicles (OMVs) derived fromAlistipesare also detected in the plasma of colonized mice, which carry metabolites with immunomodulatory potential into the host circulatory system. We further demonstrate that fractions ofA. timonensisOMVs suppress LPS-inducedIl6,Il1b, andTnfaexpressionin vitroin murine macrophages. We detect immunomodulatory sulfonolipids (SoLs) in the active fraction, which are also increased in the blood ofA. timonensis-colonized mice; and we identify other putative bioactive lipids in theA. timonensisOMVs. Thus,A. timonensisOMVs represent a potential mechanism forAlistipes-mediated delay of colitis progression inIl10-deficient mice through the delivery of immunomodulatory lipids, including SoLs, and modulation of the host plasma lipidome.
Transcriptome-driven Health-status Transversal-predictor Analysis (THTA) using the PBMC transcriptome for health, food, microbiome and disease markers for understanding the background and development of lifestyle diseases
Authors: Todt Tilman , van Bussel Inge , Afmann Lydia , Brennan Lorraine , Ivanova Diana G. , Kiselova-Kaneva Yoana , Louise Thomas E. , Rühl Ralph
Published: October 2024

We developed a novel machine-learning artificial intelligence (AI) approach to predict general health and food-intake parameters named Transcriptome-driven Health-status Transversal-predictor Analysis (THTA) with relevance for diabesity markers based on a mathematics-driven and non-transcriptomic biomarker driven approach. The prediction was based on values from food consumption, dietary lipids and their bioactive metabolites, peripheral blood mononuclear cells (PBMC) mRNA-based transcriptome signatures, magnetic resonance imaging (MRI), energy metabolism measurements, microbiome analyses, and baseline clinical parameters in a cohort of 72 subjects. Our novel machine learning approach included transcriptome data from PBMCs as a “one-method” approach to predict 77 general health-status markers for broad stratification of the diabesity phenotype, which are usually necessitating measurements using 16 different methods. The PBMC transcriptome was used to determine these selected 77 basic and background health-status markers in a transversal-predictor establishment group with very high accuracy (Pearson correlations are r = 0,94 ranging from 0,88 to 0,98). These collected variables offer a valuable indication to identify which individual factor(s) are mainly targeting diabesity. Based on the “establishment group“ prediction approach a further “confirmation group” prediction approach was performed with a predictive potential for these 77 variables of r = 0,62 (ranging from 0,30 to 0,99). This “one-method” approach allows monitoring of a large number of health-status variables with relevance for diabesity simultaneously and may enable monitoring of therapeutic and preventive strategies. In summary, this novel technique based on PBMC transcriptomics from human blood offers prediction of a large range of health-related markers, which independently would be obtained in different clinical / research centres at a much higher price.
An exposome-wide assessment of 6600 SomaScan proteins with non-genetic factors in Chinese adults
Authors: Chan Ka Hung , Clarke Jonathan , Kakkoura Maria G. , Iona Andri , Wang Baihan , Clarke Charlotte , Wright Neil , Yao Pang , Mazidi Mohsen , Im Pek Kei , Rahmati Maryam , Kartsonaki Christiana , Morris Sam , Fry Hannah , Millwood Iona Y , Walters Robin G , Chen Yiping , Du Huaidong , Yang Ling , Avery Daniel , Schmidt Dan Valle , Liu Yongmei , Yu Canqing , Sun Dianjianyi , Lv Jun , Hill Michael , Li Liming , Clarke Robert , Bennett Derrick A , Chen Zhengming
Published: October 2024

Background

Proteomics offer new insights into human biology and disease aetiology. Previous studies have explored the associations of SomaScan proteins with multiple non-genetic factors, but they typically involved Europeans and a limited range of factors, with no evidence from East Asia populations.

Methods

We measured plasma levels of 6,597 unique human proteins using SomaScan platform in ∼2,000 participants in the China Kadoorie Biobank. Linear regression was used to examine the cross-sectional associations of 37 exposures across several different domains (e.g., socio-demographic, lifestyle, environmental, sample processing, reproductive factors, clinical measurements and frailty indices) with plasma concentrations of specific proteins, adjusting for potential confounders and multiple testing.

Findings

Overall 12 exposures were significantly associated with levels of >50 proteins, with sex (n=996), age (n=982), ambient temperature (n=802) and BMI (n=1035) showing the largest number of associations, followed by frailty indices (n=465) and clinical measurements (e.g., RPG, SBP), but not diet and physical activity which showed little associations. Many of these associations varied by sex, with a large number of age-related proteins in females also associated with menopausal status. Of the 6,597 proteins examined, 43% were associated with at least one exposure, with the proportion higher for high-abundance proteins, but certain biologically-important low-abundance proteins (e.g., PSA, HBD-4) were also associated with multiple exposures. The patterns of associations appeared generally similar to those with Olink proteins.

Interpretation

In Chinese adults an exposome-wide assessment of SomaScan proteins identified a large number of associations with exposures and health-related factors, informing future research and analytic strategies.
Accuracy of menu calorie labelling in the England out-of-home food sector during 2024: Assessment of a national food policy
Authors: Finlay Amy , Jones Andrew , Thorp Paula , Putra I Gusti Ngurah Edi , Polden Megan , Adams Jean , Brealey Jane , Robinson Eric
Published: October 2024

Mandatory calorie labelling was introduced in out-of-home (OOH) food sector outlets during 2022 in England. Previous research in North America has found labelled energy content can be underestimated for packaged and quick-serve foods, but no study has evaluated the accuracy of out-of-home food sector menu calorie labelling in response to the mandatory policy introduced in England. N=295 menu items from a range of outlet types (e.g. cafes, pubs, restaurants) and menu categories (e.g., starters and sides, main, dessert) were sampled. Bomb calorimetry was used to quantify energy content and the reported energy content on menus was recorded. Consistency of measured energy was assessed by sampling the same items across outlets of the same business (N=50 menu items). Differences between reported and measured energy content were tested through Wilcoxon Signed Rank tests, and a linear model examined correlates of the difference. Mean measured kilocalories (kcal) were significantly lower than reported kcal (−16.70kcal (±149.19), V=16920, p<.01, r=0.182). However, both over- and under-estimation of measured energy content was common and the averaged absolute percentage difference between reported and measured values was 21% (±29%). Discrepancy between measured and reported energy content was more common in some outlet types (pubs) and reported energy content was substantially different (>20%) to measured energy content for 35% of sampled menu items. There were significant inaccuracies in reported energy content of calorie labelled menu items in English food outlets subject to mandatory calorie labelling and this appears to be caused by both over- and under-estimation of reported energy content.

Highlights

-

Energy content measured by bomb calorimetry was significantly higher than on menus.

-

Both under and over estimation of food energy content were frequently observed.

-

Measured energy content was consistent across chain outlets in different locations.
Efficacy of lightweight Vision Transformers in diagnosis of pneumonia
Authors: Bukhari Muhammad Tayyeb
Published: October 2024

1

Abstract

Pneumonia is one of the leading causes of death in children under five, particularly in resource-limited settings. The timely and accurate detection of pneumonia, often conducted through chest X-rays, remains a challenge due to the scarcity of trained professionals and the limitations of traditional diagnostic methods. In recent years, Artificial Intelligence (AI) models, especially Convolutional Neural Networks (CNNs), have been increasingly applied to automate pneumonia detection. However, CNN models are often computationally expensive and lack the ability to capture long-range dependencies in images, limiting their efficacy in certain medical applications. To address these limitations, lightweight hybrid models such as Vision Transformers (ViTs), which combine the strengths of CNNs and transformers, offer a promising solution. This study compares the efficacy of two lightweight CNNs (EfficientNet Lite0 and MobileNetV3 Large) with two hybrid ViTs (MobileViT Small and EfficientFormerV2 S0) for pneumonia detection. The models were evaluated on a publicly available chest X-ray dataset using metrics such as accuracy, F1 score, precision, and recall. Results show that the hybrid models, particularly MobileViT Small, outperformed their CNN counterparts in both accuracy (97.50%) and F1 score (0.9664), demonstrating the potential of ViT-based models for medical imaging tasks. The findings suggest that hybrid models provide superior recall, reducing false negatives, which is crucial for medical diagnostics. Further research should focus on optimizing these hybrid models to improve computational efficiency while maintaining high diagnostic performance.
Contextualising transcription factor binding during embryogenesis using natural sequence variation
Authors: Sigalova Olga M. , Forneris Mattia , Stojanovska Frosina , Zhao Bingqing , Viales Rebecca R. , Rabinowitz Adam , Hamal Fayrouz , Ballester Benoît , Zaugg Judith B , Furlong Eileen E.M.
Published: October 2024

Understanding how genetic variation impacts transcription factor (TF) binding remains a major challenge, limiting our ability to model disease-associated variants. Here, we used a highly controlled system of F1 crosses with extensive genetic diversity to profile allele-specific binding of four TFs at several embryonic time-points, usingDrosophilaas a model. Using a combined haplotype test, we identified 9-18% of TF bound regions impacted by genetic variation. By expanding WASP (a tool for allele-specific read mapping) to examine INDELs, we increased detection of allele imbalanced (AI) peaks by 30-50%. This fine-grained ‘mutagenesis’ could reconstruct functionalized binding motifs of all factors. To prioritise potential causal variants, we trained a convolutional neural network (Basenji) to predict TF binding from DNA sequence. The model could accurately predict experimental AI for strong effect variants, providing a mechanistic interpretation for how genetic variation impacted TF binding. This revealed unexpected relationships between TFs, including potential cooperative pairs, and mechanisms of tissue specific recruitment of the ubiquitous factor CTCF.
Ion-chain sympathetic cooling and gate dynamics
Authors: Paul A. , Noel C.
Published: October 2024

Sympathetic cooling is a technique often employed to mitigate motional heating in trapped-ion quantum computers. However, choosing system parameters such as number of coolants and cooling duty cycle for optimal gate performance requires evaluating trade-offs between motional errors and other slower errors such as qubit dephasing. The optimal parameters depend on cooling power, heating rate, and ion spacing in a particular system. In this study, we aim to analyze best practices for sympathetic cooling of long chains of trapped ions using analytical and computational methods. We use a case study to show that optimal cooling performance is achieved when coolants are placed at the center of the chain and provide a perturbative upper bound on the cooling limit of a mode given a particular set of cooling parameters. In addition, using computational tools, we analyze the trade-off between the number of coolant ions in a chain and the center-of-mass mode heating rate. We also show that cooling as often as possible when running a circuit is optimal when the qubit coherence time is otherwise long. These results provide a roadmap for how to choose sympathetic cooling parameters to maximize circuit performance in trapped-ion quantum computers using long chains of ions.

Published by the American Physical Society
2024
Fading ergodicity
Authors: Kliczkowski Maksymilian , Świętek Rafał , Hopjan Miroslav , Vidmar Lev
Published: October 2024

Eigenstate thermalization hypothesis (ETH) represents a breakthrough in many-body physics since it allows us to link thermalization of physical observables with the applicability of random matrix theory (RMT). Recent years were also extremely fruitful in exploring possible counterexamples to thermalization, ranging, among others, from integrability, single-particle chaos, many-body localization, many-body scars, to Hilbert-space fragmentation. In all these cases the conventional ETH is violated. However, it remains elusive how the conventional ETH breaks down when one approaches the boundaries of ergodicity, and whether the range of validity of the conventional ETH coincides with the validity of RMT-like spectral statistics. Here we bridge this gap and we introduce a scenario of the ETH breakdown in many-body quantum systems, dubbed fading ergodicity regime, which establishes a link between the conventional ETH and nonergodic behavior. We conjecture this scenario to be relevant for the description of finite many-body systems at the boundaries of ergodicity, and we provide numerical and analytical arguments for its validity in the quantum sun model of ergodicity-breaking phase transition. For the latter, we provide evidence that the breakdown of the conventional ETH is not associated with the breakdown of the RMT-like spectral statistics.

Published by the American Physical Society
2024
Magnetic structures of
PrMn7O12
: Intersublattice magnetoelastic coupling and incommensurate spin canting
Authors: Behr Dylan , Liu Ran , Yamaura Kazunari , Belik Alexei A. , Khalyavin Dmitry D. , Johnson Roger D.
Published: October 2024

We report on the magnetic structures of PrMn7O12, resolving both a high-temperature structure in common with the other R3+Mn7O12 systems and an additional low-temperature phase characterized by a superposed incommensurate (ICM) spin canting. A phenomenological model is developed to account for large magnetoelastic coupling immediately below the Curie temperature, demonstrating that A′B exchange is primarily responsible for the ferrimagnetic structures observed across the R3+Mn7O12 family. Finally, an analytical mean-field minimal model is presented that successfully accounts for all magnetic structures observed in this family of materials, including the canted commensurate and ICM ground states.

Published by the American Physical Society
2024