bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuronal TDP-43 aggregation drives changes in microglial morphology prior to immunophenotype in amyotrophic lateral sclerosis
Authors: Swanson Molly E. V. , Mrkela Miran , Turner Clinton , Curtis Maurice A. , Faull Richard L. M. , Walker Adam K. , Scotter Emma L.
Published: October 2024

Microglia are the innate immune cells of the brain with the capacity to react to damage or disease. Microglial reactions can be characterised in post-mortem tissues by assessing their pattern of protein expression, or immunophenotypes, and cell morphologies. We recently demonstrated that microglia have a phagocytic immunophenotype in early-stage ALS but transition to a dysfunctional immunophenotype by end stage, and that these states are driven by TAR DNA-binding protein 43 (TDP-43) aggregation in the human brain. However, it remains unclear how microglial morphologies are changed in ALS. Here we examine the relationship between microglial immunophenotypes and morphologies, and TDP-43 pathology in motor cortex tissue from people with ALS and from a TDP-43-driven ALS mouse model. Post-mortem human brain tissue from 10 control and 10 ALS cases was analysed alongside brain tissue from the bigenicNEFH-tTA/tetO-hTDP-43ΔNLS (rNLS) mouse model of ALS at distinct disease stages. Sections were immunohistochemically labelled for microglial markers (HLA-DR, CD68, and Iba1) and phosphorylated TDP-43 (pTDP-43). Single-cell microglial HLA-DR, CD68, and Iba1 average intensities, and morphological features (cell body area, process number, total outgrowth, and branch number) were measured using custom image analysis pipelines. In human ALS motor cortex, we identified a significant change in microglial morphologies from ramified to hypertrophic, which was associated with increased Iba1 and CD68 levels. In the rNLS mouse motor cortex, the microglial morphological changed from ramified to hypertrophic and increased Iba1 levels occurred in parallel with pTDP-43 aggregation, prior to increases in CD68 levels. Overall, the evidence presented in this study demonstrates that microglia change their morphologies prior to immunophenotype changes. These morphological changes may prime microglia near neurons with pTDP-43 aggregation for phagocytosis, in turn triggering immunophenotype changes; first, to a phagocytic state then to a dysfunctional one.
Deletions Rate-Limit Breast and Ovarian Cancer Initiation
Authors: Houlahan Kathleen E. , Bihie Mahad , Contreras Julián Grandvallet , Fulop Daniel J. , Lopez Gonzalo , Huang Hsin-Hsiung , Van Loo Peter , Curtis Christina , Boutros Paul C. , Huang Kuan-lin
Published: October 2024

Optimizing prevention and early detection of cancer requires understanding the number, types and timing of driver mutations. To quantify this, we exploited the elevated cancer incidence and mutation rates in germlineBRCA1andBRCA2 (gBRCA1/2)carriers. Using novel statistical models, we identify genomic deletions as the likely rate-limiting mutational processes, with 1-3 deletions required to initiate breast and ovarian tumors.gBRCA1/2-driven hereditary and sporadic tumors undergo convergent evolution to develop a similar set of driver deletions, and deletions explain the elevated cancer risk ofgBRCA1/2-carriers. Orthogonal mutation timing analysis identifies deletions of chromosome 17 and 13q as early, recurrent events. Single-cell analyses confirmed deletion rate differences ingBRCA1/2vs. non-carrier tumors as well as cells engineered to harborgBRCA1/2. The centrality of deletion-associated chromosomal instability to tumorigenesis shapes interpretation of the somatic evolution of non-malignant tissue and guides strategies for precision prevention and early detection.
The non-hallucinogenic serotonin 1B receptor is necessary for the antidepressant-like effects of psilocybin in mice
Authors: Fleury Sixtine , Nautiyal Katherine M.
Published: October 2024

Recent studies highlight the promising use of psychedelic therapies for psychiatric disorders, including depression. The persisting clinical effects of psychedelics such as psilocybin are commonly attributed to activation of the serotonin 2A receptor (5-HT2AR) based on its role in the acute hallucinatory effects. However, the active metabolite of psilocybin binds to many serotonin receptor subtypes, including the serotonin 1B receptor (5-HT1BR). Given the known role of 5-HT1BR in mediating depressive phenotypes and promoting neural plasticity, we hypothesized that it mediates the effects of psilocybin on neural activity and behavior. We first examined the acute neural response to psilocybin in mice lacking 5-HT1BR. We found that 5-HT1BR expression influenced brain-wide activity following psilocybin administration, measured by differences in the patterns of the immediate early gene c-Fos, across regions involved in emotional processing and cognitive function, including the amygdala and prefrontal cortex. Functionally, we demonstrated that 5-HT1BR is necessary for the acute and persisting behavioral effects of psilocybin. Although there was no effect of 5-HT1BR expression on the acute head twitch response, mice lacking 5-HT1BRs had attenuated hypolocomotor responses to psilocybin. We also measured the persisting antidepressant-like effects of psilocybin using transgenic and pharmacological 5-HT1BR loss-of-function models and found that 5-HT1B was required for the decreased anhedonia and reduced anxiety-like behavior. Finally, using a network analysis, we identified neural circuits through which 5-H1BR may modulate the response to psilocybin. Overall, our research implicates the 5-HT1BR, a non-hallucinogenic serotonin receptor, as a critical mediator of the behavioral and neural effects of psilocybin in mice.

Significance Statement

Psilocybin, the active ingredient of ‘magic mushrooms’ has emerged as a potential fast-acting and long-lasting antidepressant. As a classic psychedelic, it is unclear what mechanisms of actions underlie its antidepressant effects or if the subjective conscious experience is necessary. While 5-HT2AR-mediated effects are most commonly implicated given its role in the hallucinogenic effect, the polypharmacology of psilocybin is likely critical for its complex behavioral effects. Our studies show the necessity of a non-hallucinatory serotonin receptor, 5-HT1BR, in the antidepressant response to psilocybin, and highlight a potential target for the development of effective non-hallucinogenic pharmacotherapies for the treatment of depressive disorders.
Foamy microglia link oxylipins to disease progression in multiple sclerosis
Authors: van der Vliet Daan , Di Xinyu , Shamorkina Tatiana M. , Pavlovic Anto , van der Vliet Iris A.C.M. , Zeng Yingyu , Macnair Will , van Egmond Noëlle , Chen J.Q. Alida , van den Bosch Aletta M.R. , Engelenburg Hendrik J. , Mason Matthew R.J. , Coulon-Bainier Claire , Gagestein Berend , Dusseldorp Elise , van Eijk Marco , Grether Uwe ,   The Netherlands Brain Bank, Harms Amy C. , Hankemeier Thomas , Collin Ludovic , Heck Albert J.R. , Huitinga Inge , van der Stelt Mario
Published: October 2024

Multiple sclerosis (MS) is a neuroinflammatory disease characterized by expanding demyelinating lesions, leading to severe and irreversible disability. The mechanisms driving lesion expansion, however, remain poorly understood. Here, using a multi-omics approach, we identified foamy microglia as primary contributors to the molecular profile of lesions and disease progression in secondary progressive MS. Lesions with foamy microglia are marked by the accumulation of cholesterol esters, bismonoacylglycerolphosphates (BMP), and oxylipins, along with high B-cell infiltration, increased levels of immunoglobulin G1, and elevated expression of Fcγ- and complement receptors. Lesions with foamy GPNMB+-microglia display markers of enhanced phagocytosis, lipid metabolism, lysosomal dysfunction, and antigen presentation, but lack classical pro-inflammatory markers. Our data suggest that sustained phagocytosis of myelin overwhelms microglial endo-lysosomal capacity, leading to lipid droplet and oxylipin formation. This microglial phenotype may induce further recruitment of adaptive immune cells, axonal damage, drive lesion expansion and prevent remyelination. Monoacylglycerol lipase, involved in producing oxylipin precursors, was identified as a potential therapeutic target to disrupt this cycle and prevent chronic lesion expansion.
Evolutionary macroecology: Incorporating phylogenetic information more explicitly into process-based, forward time, simulation models
Authors: Culshaw Victoria , Rangel Thiago F.L.V.B. , Sanmartín Isabel
Published: October 2024

Abstract

A conceptual and mechanistic approach for bridging the fields of macroecology (ecological biogeography) and historical biogeography has been a long-term aim in Evolutionary Biology. Such a bridge could increase our understanding on the processes governing the spatial and temporal generation of biodiversity distribution patterns. This aim has been recently approached from the perspective of evolutionary biogeographic inferential statistical models, within a maximum likelihood or Bayesian framework, which incorporates the contribution of environmental factors as scaling parameters. Here, we describe a new approach that builds on a spatially-explicit, forward-time, computer simulation (“automat”) model. The model sets a series of rules by which speciation, extinction, and dispersal of lineages are governed within an environmentally heterogeneous, two-dimensional gridded landscape. Unlike some previous approaches, niche conservatism is assumed but the model allows for environmental conditions to vary both spatially and temporally, by letting the model run over three time-series of actual palaeoclimate data, spanning the last 20 million years of geological history. Speciation is governed by a global speciation rate, whereas the background extinction rate is made dependent on abiotic (palaeoenvironmental conditions) and biotic (species density per grid cell) factors, hence giving a local background extinction rate. Also, we propose a novel mechanistic approach in which species are not the result of unique, independent events but linked through evolutionary history from a single evolutionary origin. We set different rules to generate the resulting phylogenies to test different factors (time, environment) that govern the inheritance of range distributions. Dispersal follows a simple Poisson kernel model, with higher probability of migration to contiguous grid cells and rare long-distance movements to distant cells. We also describe ways in which the presence of temporal dispersal barriers could modify the resultant spatial patterns. Evaluation of model accuracy and fit is based on comparison of simulated spatial patterns with observed, empirical ones. We use statistic dependent variables such as the spatial distribution of species in the landscape, species’ geographic range size and location, and the shape of the resultant phylogenies. Finally, we propose that this spatially-explicit simulation model could be used to evaluate the role played by niche conservatism, ecological vicariance and climatic-driven extinction in the generation of disjunct continental patterns, such as the presence of sister-lineages in numerous families of angiosperms forming a ring in the continental margins of the African continent, the Rand Flora pattern.
Simulated climate warming scenarios lead to earlier emergence and increased weight loss but have no effect on overwintering survival in solitary bees
Authors: Möllmann Jannik S. , Lörchner Liv , Hodapp Dean , Knuf Ina , Xu Hongfei , Colgan Thomas J.
Published: October 2024

Insect pollination is critical for both wildflower stability and agricultural yields, with solitary bees being a group of pollinators of fundamental importance. However, documented declines in populations, exacerbated by environmental pressures, including climate change, pose significant threats to the provision of ecosystem services. Exposure to elevated temperatures during periods of dormancy, such as overwintering, is predicted to lead to phenological shifts, changes in condition, and impacts on survival. However, we currently lack studies that inform how such aspects are affected in future climate change scenarios. Using simulated temperature regimes informed by predictions of the Intergovernmental Panel on Climate Change, we exposed overwintering mason bees (Osmiaspecies) to three field-relevant temperature profiles based on either present-day overwintering temperatures or future temperatures predicted under two major climate warming scenarios (SSP2-4.5 and SSP5-8.5) and measured how temperature exposure affected emergence timing, weight loss and survival. We found that exposure to temperatures under intermediate and worst-case climate warming scenarios led to earlier emergence by approximately three and six weeks, respectively, with increasing divergences in timing of emergence between the sexes ofOsmia bicornis, which may lead to intraspecific phenological mismatches. While we found no effect of temperature on overwintering survival rates, we observed increased weight loss prior to emergence but found that in contrast to other studies, it only mildly mediated shifts in emergence timing brought about by temperature exposure, suggesting that weight loss is unlikely to play a major role as a trigger of emergence timing in mason bees. Our study contributes to the growing literature highlighting the impact that temperatures under climate change models will have on the timing of key life events for essential pollinators, which may have consequences at the population and community levels.
Inducible, but not constitutive, pancreaticREG/Regisoforms are regulated by intestinal microbiota and pancreatic diseases
Authors: Zhou Yixuan , Komnick Macy R. , Sepulveda Fabiola , Liu Grace , Nieves-Ortiz Elida , Meador Kelsey , Ndatabaye Ornella , Fatkhullina Aliia , Wu-Woods Natalie J. , Naydenkov Paulina M. , Kent Johnathan , Christiansen Nathaniel , Madariaga Maria L , Witkowski Piotr , Ismagilov Rustem F. , Esterházy Daria
Published: October 2024

TheREG/Reggene locus encodes for a conserved family of potent antimicrobial but also pancreatitis-associated proteins. Here we investigated whetherREG/Regfamily members differ in their baseline expression levels and abilities to be regulated in the pancreas and gut upon perturbations. We found, in human and mouse, pancreas and gut differed inREG/Regisoform levels and preferences, with duodenum most resembling the pancreas. Pancreatic acinar cells and intestinal enterocytes were the dominant REG producers. Intestinal symbiotic microbes regulated the expression of the same, selectRegmembers in gut and pancreas. TheseRegmembers had the most STAT3-binding sites close to the transcription start sites and were partially IL-22 dependent. We thus categorized them as “inducible” and others as “constitutive”. Indeed, also in models of pancreatic-ductal adenocarcinoma and pancreatitis, only inducibleRegmembers were upregulated in pancreas. While intestinalRegexpression remained unchanged upon pancreatic perturbation, pancreatitis altered the microbial composition of the duodenum and feces shortly after disease onset. Our study reveals differential usage and regulation ofREG/Regisoforms as a mechanism for tissue-specific innate immunity, highlights the intimate connection of pancreas and duodenum, and implies a gut-to-pancreas communication axis resulting in a coordinatedRegresponse.
Deficiency of Hv1 Proton Channel Enhances Macrophage Antigen Presentation and Anti-Tumor Responses in Glioma
Authors: Zheng Jiaying , Wang Lingxiao , Zhao Shunyi , Ayasoufi Katayoun , Goddery Emma , Strege Peter R. , Wan Yushan , Zhang Wenjing , Xie Manling , Beyder Arthur , Johnson Aaron J. , Wu Long-Jun
Published: October 2024

In the tumor microenvironment of glioblastoma, myeloid cells act as a double-edged sword—they are a major cellular component modulating the immune response while presenting a potential therapeutic target. Our study highlights the voltage-gated proton channel Hv1, predominantly expressed in myeloid cells, as a crucial regulator of their physiological functions. We discovered a strong correlation between increased Hv1 expression and poor prognosis in glioblastoma patients. Depleting Hv1 significantly extended survival in a mouse model of glioma. Employing multiple novel transgenic mouse lines, we demonstrated that Hv1 is upregulated in response to tumor presence, with glioma-associated macrophages as the principal contributors. Specifically, we identified that Hv1 in infiltrating macrophages as the major driver of survival phenotype differences. Through a combination ofin vivotwo-photon imaging, spectral flow cytometry, and spatial transcriptomic sequencing, we found that Hv1 depletion leads to reduced macrophage infiltration and enhanced antigen presentation, ultimately fostering a stronger adaptive immune response. These findings establish the Hv1 channel as a crucial new immune regulator within the brain tumor milieu, offering a promising target for reprogramming macrophage function to combat glioblastoma.
Associations between Psychological Factors and Long-Term Dizziness Handicap in Vestibular Schwannoma Patients: A Cross-Sectional Study
Authors: Rutenkröger M. , Scheer M. , Rampp S. , Strauss C. , Schönfeld R. , Leplow B.
Published: October 2024

Background

Vestibular schwannoma (VS) often results in persistent dizziness that negatively impacts quality of life (QoL). While physical effects are well-documented, the influence of psychological factors on dizziness severity is less studied. This study investigates how psychological characteristics affect dizziness in VS patients.

Methods

In this cross-sectional study, 93 VS patients were analyzed, with 77 (82.8%) reporting postoperative dizziness. Psychological factors, including premorbid disorders, personality traits, somatization, and current depression and anxiety levels, were assessed using self-report questionnaires. Correlations between these factors and dizziness severity, measured by the Dizziness Handicap Inventory (DHI), were examined.

Results

Patients with postoperative dizziness had higher depression levels and a greater prevalence of preoperative dizziness compared to those without postoperative dizziness. Significant correlations were found between dizziness severity and psychological factors: conscientiousness (r = .30, p = .03), social support (r = .32, p = .03), and the HADS total score (r = .36, p = .01). Emotional aspects of dizziness (DHI-E) were correlated with somatization (r = .27, p = .04) and anxiety (r = .40, p = .01). Functional aspects (DHI-F) were linked to conscientiousness (r = .31, p = .03) and depression (r = .26, p = .06).

Conclusion

Psychological factors significantly impact dizziness severity in VS patients. Incorporating psychological assessments and interventions, such as cognitive-behavioral therapy and combined vestibular and psychological rehabilitation, may improve treatment outcomes and QoL. Further research is needed to assess the effectiveness of these approaches and their impact on the relationship between psychological factors and dizziness.
KRAS G12 mutant alleles differentially control glutamine metabolism via FOXO1
Authors: Ber Suzan , Yang Ming , Sciacovelli Marco , Samarajiwa Shamith , Patel Khushali , Nikitopoulou Efterpi , Howitt Annie , Cook Simon J. , Venkitaraman Ashok R. , Frezza Christian , Esposito Alessandro
Published: October 2024

Mutations in KRAS, particularly at codon 12, are frequent in adenocarcinomas of the colon, lungs and pancreas, driving carcinogenesis by altering cell signalling and reprogramming metabolism. However, the specific mechanisms by which different KRAS G12 alleles initiate distinctive patterns of metabolic reprogramming is unclear. Using isogenic panels of colorectal cell lines harbouring the G12A, G12C, G12D and G12V heterozygous mutations and employing transcriptomics, metabolomics, and extensive biochemical validation, we demonstrate distinctive features of each allele. We also demonstrate that cells harbouring the common G12D and G12V oncogenic mutations significantly alter glutamine metabolism and nitrogen recycling through FOXO1-mediated regulation compared to parental lines. Moreover, with a combination of small molecule inhibitors targeting glutamine and glutamate metabolism, we also identify a common vulnerability that eliminates mutant cells selectively. These results highlight a previously unreported mutant-specific effect of KRAS alleles on metabolism and signalling that could be potentially harnessed for cancer therapy.

In brief

Beret al.reveal common and distinct features of oncogenic KRAS mutant isogenic cell lines. Mutant lines upregulate different nitrogen-recycling metabolic pathways and show sensitivity to combinatorial drugging of glutamine metabolism.

Highlights

Different KRAS mutations trigger distinct metabolic phenotypes in colorectal cell lines

Glutamine metabolism and nitrogen recycling are upregulated in KRAS mutant cells

FOXO1 is a key regulator of KRAS-induced rewiring of glutamine and nitrogen metabolism

Inhibition of glutamine synthetase and glutaminase selectively kills mutant KRAS lines
Genomic diversity and underlying metabolic variations of the human gut microbiome between populations at single nucleotide resolution
Authors: Dong Quanbin , Ma Beining , Zhou Xiaofeng , Huang Pan , Gao Mengke , Yang Shuai , Jiao Yuwen , Zhou Yan , Shi Zhun , Deng Qiufeng , Hua Dongxu , Wang Xiuchao , Liu Lu , Zhang Chengcheng , Zhang Chuan , Kong Mengmeng , He Chang , Wu Tingting , Zou Huayiyang , Shi Jing , Sheng Yanhui , Wang Yifeng , Tang Liming , Hu Shixian , Zhong Huanzi , Sun Wei , Chen Wei , Zhai Qixiao , Kong Xiangqing , Zheng Yan , Chen Lianmin
Published: October 2024

Understanding microbial genomic diversity across populations is crucial for advancing personalized medicine and addressing regional health disparities. However, with 70% of current gut microbial genome data from Europeans and the Americans, regions like East Asia, including China, remain underrepresented, limiting our understanding of global microbial genomic diversity and its health impacts. Here, we present the Global gut Microbiome Reference (GMR), a comprehensive dataset of 478,588 high-quality microbial genomes from Chinese (247,134) and non-Chinese (231,454) populations, covering 6,664 species, 26.4% of which are potential newly classified. Analysis of single nucleotide variations (SNVs) across 304 globally prevalent species revealed that 24.7%, especially from the Lachnospiraceae and Ruminococcaceae families, showed significant genetic differences between Chinese and non-Chinese populations, primarily linked to antibiotic resistance, virulence, and other health-related functions. By integrating these new species into the MetaPhlAn4 database, we enhanced species profiling by up to 22.8%, and established replicable abundance associations to host phenotypic traits between cohorts. Additionally, we found that microbial strain diversity at the SNV level, independent of abundance, was associated with host phenotypic traits, such as cardiometabolic-related risk factors like obesity. In vitro experiments with Bacteroides fragilis_A further highlighted the regulatory role of microbial SNVs in metabolites related to cardiometabolic health. These findings emphasize the need to consider gut microbial genetic diversity in population studies for better insights into regional microbiome differences and their health implications.
Superimposed inhibitory surrounds underlying Saliency-based Stimulus Selection in avian Midbrain isthmi pars magnocellularis
Authors: Qian Longlong , Jia Chongchong , Wang Jiangtao , Li Shi , Wang Songwei
Published: October 2024

In the avian midbrain network, bottom-up spatial attention is directed by saliency-based stimulus selection. However, it remains unclear whether the isthmi pars magnocellularis (Imc), the first site in the midbrain network to represent stimulus selection, can represent stimulus salience and what is the mechanism by which the midbrain network computes salience. Here, we used two separate translational motion stimuli as the main stimulation protocols and conducted in vivo electrophysiological experiments in the pigeon’s Imc. By combining bio-plausible model validation, we found two types of inhibitory surrounds of the Imc neuron receptive field, homogenous inhibitory surrounds (HIS) and non-homogenous inhibitory surrounds (non-HIS), and elucidated the mechanism by which both arise. While HIS is local and depends on stimulus feature similarity, which can be used to compute stimulus saliency, non-HIS is global and doesn’t depend on stimulus feature similarity, which can be used to compute stimulus selection. Moreover, the superimposition of HIS and non-HIS modulates the neural response of Imc. The two inhibitory surrounds of Imc identified in this study more clearly elucidate the full process of achieving bottom-up stimulus selection based on saliency in the midbrain network and show that Imc is a nucleus that can represent both stimulus saliency and stimulus selection.
Artificial Selection and the Skin Microbiome Independently Predict Parasite Resistance
Authors: Kramp Rachael D. , Janecka Mary J. , Tardent Nadine , Jokela Jukka , Kohl Kevin D. , Stephenson Jessica F.
Published: October 2024

Host responses to parasite infection involve several interacting systems. Host genetics determine much of the response, but it is increasingly clear that the host-associated microbiome also plays a role. Genetically determined systems and the microbiome can also interact; for example, the microbiome can modulate the host immune response, andvice versa. However, it remains unclear how such interactions between the host immune system and the microbiome may influence the host’s overall response to parasites.

Host sex is an important source of variation in both immune response and the microbiome across systems, so interactions between them may also therefore differ between males and females, potentially explaining sex-specificity in response to parasites.

To investigate how host genetics and the microbiome interact to shape responses to parasites, we imposed truncation selection on the response of Trinidadian guppies (Poecilia reticulata) to the specialist ectoparasiteGyrodactylus turnbulli. Following experimental infection, we used the 30% of guppies with the lowest parasite load to found the resistant line, the 30% with the highest load to found the susceptible line, and randomly chosen uninfected fish to found the control line. After 3-6 generations of breeding without parasites, we sampled the skin-associated microbiome and then infected fish from each line. We applied machine-learning to identify bacterial community types across lines and evaluated how selection line and community type explained variations in infection severity.

Our findings showed that among females, the resistant line had significantly lower infection severity, while the susceptible line had higher infection severity than other lines. Interestingly, females in the resistant line lost more mass per parasite, i.e., exhibited lower parasite tolerance, than in the control or susceptible lines. Among males, the susceptible line experienced higher infection severity than the other lines, but there was no difference between the resistant and control lines.

We found that the microbiome and host genetics independently explain similar variation in infection severity, highlighting the microbiome’s active role in host-parasite interactions. Our results also indicate sex specificity in the evolution of host defenses.
Targeting the acetyltransferase NAT10 corrects pathologies in human frontotemporal dementia neurons and extends lifespan in an in vivoDrosophilatauopathy model
Authors: Paonessa Francesco , Bizzini Bernardo Delarue , Campbell Tom , Solanki Ravi , Butler Richard , Smith James , Davidson Catherine M. , Larrieu Delphine , Brand Andrea H. , Livesey Frederick J.
Published: October 2024

Disruption of the neuronal nuclear membrane and perturbation of nucleocytoplasmic transport are features of neurodegenerative diseases, including Alzheimer’s disease, that involve the microtubule-associated protein tau (MAPT). We previously identified that missense and splicing mutations in the MAPT gene, causal for frontotemporal dementia, result in nuclear envelope deformation and disrupted nucleocytoplasmic transport in human neurons. This is most likely due to microtubule mechanical stress, similar to that observed in Hutchinson-Gilford Progeria Syndrome (HGPS). A small molecule inhibitor of the acetyltransferase NAT10 has been shown to correct nuclear membrane defects in HGPS by modulating microtubule dynamics. We report here that NAT10 inhibition alters microtubule dynamics and corrects nuclear lamina defects and aberrant nucleocytoplasmic transport in human iPSC-derived FTD-MAPT neurons. Similarly, NAT10 inhibition and haploinsufficiency correct neuronal nuclear shape defects and extend lifespanin vivoin aDrosophilamodel of tauopathy. Our results show that NAT10 mediates neuronal pathologies in tauopathies and is a promising new therapeutic target in these diseases.
Exploiting pathogen defence trade-offs to manage risks of crop pests evolving resistance to biocontrol
Authors: Mangan Rosie , Tinsley Matthew C. , Ferrari Ester , Polanczyk Ricardo A. , Bussière Luc F.
Published: October 2024

Pathogens often exert strong selection, yet host populations maintain considerable genetic variation for resistance, possibly due to environmental heterogeneity causing fitness trade-offs. These trade-offs could help explain genetic variation for pathogen defence, and also constrain resistance evolution to microbial pesticides (an underappreciated risk). However, the presence and strength of such trade-offs remain unclear. We investigate whether pathogen identity or host diet has a stronger effect on the fitness of resistance alleles. We quantify genetic variation and covariation for pathogen resistance in an insect pest across distinct pathogen and plant diet combinations. We demonstrate substantial heritability, indicating considerable risks of biopesticide resistance. Contrary to conventional thinking in host-pathogen biology, we found no strong genetic trade-offs for resisting two fungal pathogen species, but changes in plant diet dramatically altered selection for resistance, revealing diet-mediated genetic trade-offs affecting pest survival. Our data suggest that trade-offs not strictly related to immunocompetence could nevertheless maintain genetic variation for pathogen defence in natural and agricultural landscapes.
Membrane-Dependent Dynamics and Dual Translocation Mechanisms of ABCB4: Insights from Molecular Dynamics Simulations
Authors: Crespi Veronica , Tóth Ágota , Janaszkiewicz Angelika , Falguières Thomas , Di Meo Florent
Published: October 2024

ABCB4 is an ATP-binding cassette transporter expressed at the canalicular membrane of hepatocytes and responsible for translocating phosphatidylcholine into bile. Despite the recent cryo-EM structures of ABCB4, knowledge about the molecular mechanism of phosphatidylcholine transport remains fragmented. In this study, we used all-atom molecular dynamics simulations to investigate ABCB4 dynamics during its transport cycle, leveraging both symmetric and asymmetric membrane models. Our results demonstrate that membrane composition influences the local conformational dynamics of ABCB4, revealing distinct lipid-binding patterns across different conformers, particularly for cholesterol. We explored the two potential mechanisms for phosphatidylcholine translocation: the canonical ATP-driven alternating access model and the “credit-card swipe” model. Critical residues were identified for phosphatidylcholine binding and transport pathway modulation, supporting the canonical mechanism while also indicating a possible additional pathway. The conformer-specific roles of kinking in transmembrane helices (TMH4 and TMH10) were highlighted as key events in substrate translocation. Overall, ABCB4 may utilize a cooperative transport mechanism, integrating elements of both models to facilitate efficient phosphatidylcholine motion across the membrane. This study provides new insights into the relationship between membrane environment and ABCB4 function, contributing to our understanding of its role in bile physiology and susceptibility to genetic and xenobiotic influences.
Understanding the development of enzalutamide resistance based on a functional single-cell approach
Authors: Xue Changhui , Ko Hyun-Kyung , Shi Kasen , Pittsenbarger Janet , Dao Lucien Vu , Shi Kaiyo , Libmann Maximilian , Geng Hao , Qian David Z.
Published: October 2024

Most metastatic prostate cancers (PCa) initially depend on androgen for survival and proliferation. Thus, anti-androgen or castration therapies are the mainstay treatment. Although effective at first, androgen-dependent PCa (ADPC) universally develops therapy resistance, thereby evolving to the incurable disease, called castration resistant PCa (CRPC). Currently, mechanisms underlying the emergence of CRPC from ADPC are largely unclear. We used single-cell RNA-sequencing (scRNA-Seq) to determine how a therapy-naïve ADPC cell line – LNCaP responds to the anti-androgen drug, enzalutamide. We found that most cells expressed the drug-target androgen receptor (AR+), while a small subpopulation (∼12%) expressed low or no AR (ARlow/-). Gene set enrichment analysis (GSEA) revealed that AR+ and ARlow/-cells were enriched with significantly different gene expressions and signaling pathways. Unexpectedly, ARlow/-cells displayed robust transcriptional response, including upregulations of genes and pathways involved in clinical CRPC. Next, we isolate ARlow/-and AR+ cells from the LNCaP cell line, and functionally confirmed the enzalutamide resistant phenotype of ARlow/-cells in vitro and in xenograft models in vivo. Finally, to explore a therapeutic option for ARlow/-cells, we found that ARlow/-cells expressed low levels of NAD+ biosynthesis genes, notably NAPRT, indicating a possible vulnerability to inhibitors blocking NAD+ synthesis. Indeed, treating ARlow/-cells with NAD+ synthesis inhibitors, FK866 and OT-82, significantly inhibited the survival and proliferation of ARlow/-cells, thus suggesting a possible novel therapeutic option for ADT and enzalutamide resistant PCa.

Single-cell RNA-Sequencing reveals heterogeneities of tumor cell populations. In most cases, however, the functional significance of the observed heterogeneity is not tested. In this study, we first identified a possible therapy-resistant prostate cancer cell subpopulation with scRNA-Seq, then confirmed the resistant phenotype with single cell and colony – based cloning and functional testing. In addition, we also identified a therapeutic vulnerability of the resistant cells.
Raising awareness of potential biases in medical machine learning: Experience from a Datathon
Authors: Hochheiser Harry , Klug Jesse , Mathie Thomas , Pollard Tom J. , Raffa Jesse D. , Ballard Stephanie L. , Conrad Evamarie A. , Edakalavan Smitha , Joseph Allan , Alnomasy Nader , Nutman Sarah , Hill Veronika , Kapoor Sumit , Claudio Eddie Pérez , Kravchenko Olga V. , Li Ruoting , Nourelahi Mehdi , Diaz Jenny , Taylor W. Michael , Rooney Sydney R. , Woeltje Maeve , Celi Leo Anthony , Horvat Christopher M.
Published: October 2024

Objective

To challenge clinicians and informaticians to learn about potential sources of bias in medical machine learning models through investigation of data and predictions from an open-source severity of illness score.

Methods

Over a two-day period (total elapsed time approximately 28 hours), we conducted a datathon that challenged interdisciplinary teams to investigate potential sources of bias in the Global Open Source Severity of Illness Score. Teams were invited to develop hypotheses, to use tools of their choosing to identify potential sources of bias, and to provide a final report.

Results

Five teams participated, three of which included both informaticians and clinicians. Most (4/5) used Python for analyses, the remaining team used R. Common analysis themes included relationship of the GOSSIS-1 prediction score with demographics and care related variables; relationships between demographics and outcomes; calibration and factors related to the context of care; and the impact of missingness. Representativeness of the population, differences in calibration and model performance among groups, and differences in performance across hospital settings were identified as possible sources of bias.

Discussion

Datathons are a promising approach for challenging developers and users to explore questions relating to unrecognized biases in medical machine learning algorithms.

Author summary

Disadvantaged groups are at risk of being adversely impacted by biased medical machine learning models. To avoid these undesirable outcomes, developers and users must understand the challenges involved in identifying potential biases. We conducted a datathon aimed at challenging a diverse group of participants to explore an open-source patient severity model for potential biases. Five groups of clinicians and informaticians used tools of their choosing to evaluate possible sources of biases, applying a range of analytic techniques and exploring multiple features. By engaging diverse participants with hands-on data experience with meaningful data, datathons have the potential to raise awareness of potential biases and promote best practices in developing fair and equitable medical machine learning models.
Home and Epigenome: DNA Methylation as a Link Between Poor Housing Quality and Depressive Symptoms
Authors: Sanders Faye , Baltramonaityte Vilte , Lussier Alexandre A. , Smith Andrew D.A.C. , Dunn Erin C , Walton Esther
Published: October 2024

Poor housing quality associates with risk for depression. However, previous research often lacks consideration of socioeconomic status (SES) baseline depressive symptoms and biological processes, leading to concerns of confounding and reverse causation.

In a sample of up to 9,566 adults, we investigated cross-sectional and longitudinal associations between housing quality (assessed at age 28, 1- and 2-year follow-ups) and depressive symptoms (at four intervals between enrolment and 18-year follow-up). In sub-samples (n=871, n=731), we investigated indirect effects via DNA methylation.

Poor housing quality associated with depressive symptoms cross-sectionally (beta range: 0.02 to 0.06, allp-values<.023) after controlling for SES and other factors. Longitudinally, this association persisted at the ∼2-year, but not the ∼18-year follow-up period. Indirect effects linked to genes related to aging, obesity, and brain health.

These results highlight poor housing quality as a risk factor for depression and the potential role of DNA methylation in this association.
Asbestos as contaminant in the mining of non-asbestos minerals: Case of a “marble” waste slurry dump-yard from Rajasthan, India
Authors: Singh Raja , Fitzgerald Sean , Dada Rima , Frank Arthur L
Published: October 2024

Asbestos is fibrous minerals, some of which can naturally occur in certain types of marble, including asbestiform tremolite, actinolite, anthophyllite, and chrysotile, with tremolite the most common among those associated asbestos types. This is of concern as miners and stone workers may not be aware of this and may never be considered by physicians treating them for lung related ailments. Wet marble dust in slurry form is disposed of at designated waste collection points, including in Rajsamand, Rajasthan. unfortunately, this location is now open to the public as a tourist attraction. Dust from this location was tested using Transmission Electron Microscopy (TEM) and tremolite asbestos fibres were found. The presence of tremolite means the workers, bystanders and tourists to the waste collection spots may be exposed to this carcinogen and this may become the etiological factor for mesothelioma or lung cancer among other asbestos related diseases. The marble industry in general should also be subjected to the same regulations as the asbestos industry due to the presence of naturally occurring asbestos in such mines. This is particularly germane in India where asbestos is widely being used and studies show a significant and increasing number of asbestos related lung and pleural, malignant and non-malignant diseases including cancers, such as mesothelioma. This study aims to highlight the occupational and environmental health hazard among workers and the general public.
Home Blood Pressure and Asymptomatic Intracranial and Extracranial Arterial Stenosis in Hypertension Patients
Authors: Cai Enheng , An Dewei , Zhang Jin , Tang Xiaofeng , Li Yan , Wang Yan , Zhu Dingliang
Published: October 2024

Background

We aim to analyze the effect of home blood pressure (HBP) level and variability on both asymptomatic intracranial (aICAS) and extracranial arterial stenosis (aECAS).

Methods

A total of 534 patients completed HBP measurements (HBP) on at least 3 days. The stenoses of ICAS and ECAS were evaluated by CTA. HBP variability (HBPV) was quantified using the standard deviation and maximum--minimum difference between measures. The association of HBP level and variability with both aICAS and aECAS was evaluated using multivariate logistic regression.

Results

Morning HBPV was significantly associated with isolated aICAS, isolated aECAS, and concurrent aICAS and aECAS, respectively, even after being adjusted for HBP level. Besides, HBP were independently related to concurrent aICAS and aECAS (P<0.05). Instead, neither morning nor evening HBP associated with isolated aICAS or aECAS.

Conclusion

The findings of this study confirmed the strong correlation of aICAS/aECAS with HBP in the hypertensive population, particularly morning HBPV.
Ectomycorrhizal symbiosis evolved independently and by convergent gene duplication in rosid lineages
Authors: van Beveren Fabian , Boele Yvet , Puginier Camille , Bianconi Matheus , Libourel Cyril , Bonhomme Maxime , Keller Jean , Delaux Pierre-Marc
Published: October 2024

Many land plants rely on mutualistic symbiotic associations to thrive, starting with their common ancestor associating with arbuscular mycorrhizal (AM) fungi. Similar to AM symbiosis, multiple other intracellular symbiotic interactions have evolved in a variety of land plants. Ectomycorrhizal (ECM) symbiosis contrasts with these relationships as there is no intracellular accommodation of the symbiont inside the plant cell, but only intercellular colonization. This symbiotic relationship is common in a variety of seed plants, mostly trees and shrubs such as pines, willows and oaks.

Although it is known which plant lineages are involved in ECM symbiosis, there has been little investigation into the evolutionary origin of ECM symbiosis in these lineages. Furthermore, the genetic innovations and transcriptomic response related to this symbiosis have been studied largely in a genus or species-specific context, which hinders the study of their evolutionary origins. In this study, we reconstruct the origin of ECM in the rosid clade, showing at least 16 independent origins, resulting in the 17 known extant ECM rosid lineages. Moreover, comparative genomics of these lineages highlight genes involved in cell wall remodeling which underwent duplications in a convergent manner across ectomycorrhizal lineages.
The ecological and economic benefits of sustainable agricultural practices: Evidence from on-farm trials in broad-acre grain crops
Authors: Mata Luis , McGrane Leo , Maino James , Sims Grant , Drum Craig , Umina Paul A.
Published: October 2024

Sustainable agricultural practices are essential for mitigating the negative environmental impacts of conventional agriculture while ensuring food security. However, widespread adoption of these practices requires robust evidence of their efficacy and economic viability.

We co-designed a two-year field trial with farmers and agronomy advisors in Australia, to evaluate the ecological and economic benefits of sustainable agricultural practices for managing the redlegged earth mite, a major pest of Australian grain crops. We compared ‘Novel’ treatments representing long-term farmer-implemented sustainable agricultural practices based on biological control with ‘Conventional’ treatments and ‘Plus’ treatments designed as counterfactuals to disentangle the effects of specific pest control and plant nutrient components.

Redlegged earth mite densities remained below economic thresholds across all treatments and years, demonstrating effective pest control in both conventional and sustainable systems. Notably, the Novel treatment supported higher densities of beneficial arthropods, indicating increased biological control potential.

Yield and gross profit margins were generally similar between the treatments, indicating that sustainable agriculture practices can maintain profitability while fostering biodiversity.

Practical implication. Our study provides evidence that biological control and biofertiliser supplementation can be effectively used to manage agricultural pests and demonstrates the value of close collaboration with farmers and agronomy advisors to conduct ecological field research that has practical applications.
Capicua maintains anterior-posterior axis inBlattella germanicaovaries
Authors: Elshaer Nashwa , Escudero Jorge , Piulachs Maria-Dolors
Published: October 2024

The establishment of the symmetry axis is crucial for the development of all organisms. In insects, this process begins early in oogenesis with the correct distribution of the mRNAs and proteins in the oocyte. One of the proteins that contribute to organizing this distribution is Capicua (Cic). Cic has been studied inDrosophila melanogasteroogenesis and embryo development, it is maternally expressed and is required to establish the dorso-ventral axis, acting as a repressor transcription factor. Although the sequence of Cic is conserved across species, its function in other types of insect ovaries is still unknown. We wondered whether the function of Cic in insects has been maintained through evolution despite the ovary type or if it has been modified in parallel to the ovary evolution. To address this, we studied the Cic function in a phylogenetically basal insect, the cockroachBlattella germanica, a species with panoistic ovaries. The Cic sequence ofB. germanicashares 80% identity withD. melanogasterCic. Our findings indicate that Cic is essential for oocyte development as it is involved in establishing the anterior- posterior axis.
Efficient mutagenesis of maize inbreds using biolistics, multiplex CRISPR/Cas9 editing, and Indel-Selective PCR
Authors: Rai Maruti Nandan , Rhodes Brian , Jinga Stephen , Kanchupati Praveena , Ross Edward , Carlson Shawn R. , Moose Stephen P.
Published: October 2024

CRISPR/Cas9 based genome editing has advanced our understanding of a myriad of important biological phenomena. Important challenges to multiplex genome editing in maize include assembly of large complex DNA constructs, few genotypes with efficient transformation systems, and costly/labor-intensive genotyping methods. Here we present a ‘fast-edit’ approach for multiplex CRISPR/Cas9 genome editing system that delivers a single compact DNA constructviabiolistics to type I embryogenic calli, followed by a novel efficient genotyping assay to identify desirable editing outcomes. We first demonstrate the creation of heritable mutations at multiple target sites within the same gene. Next, we successfully created individual and stacked mutations for multiple members of a gene family. Genome sequencing found off-target mutations are rare. Multiplex genome editing was achieved for both the highly transformable inbred line H99 and Illinois Low Protein1 (ILP1), a genotype where transformation has not previously been reported. In addition to screening transformation events for deletion alleles by PCR, we also designed PCR assays that selectively amplify deletion or insertion of a single nucleotide, the most common outcome from DNA repair of CRISPR/Cas9 breaks by non-homologous end-joining. The Indel- Selective PCR (IS-PCR) method enabled rapid tracking of multiple edited alleles in progeny populations. The ‘end to end’ pipeline presented here for multiplexed CRISPR/Cas9 mutagenesis can be applied to accelerate maize functional genomics in a broader diversity of genetic backgrounds.