bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimisation of surfactin yield inBacillususing active learning and high-throughput mass spectrometry
Authors: Albornoz Ricardo Valencia , Oyarzún Diego , Burgess Karl
Published: January 2024

Integration of machine learning and high throughput measurements are essential to drive the next generation of the design-build-test-learn (DBTL) cycle in synthetic biology. Here, we report the use of active learning in combination with metabolomics for optimising production of surfactin, a complex lipopeptide resulting from a non-ribosomal assembly pathway. We designed a media optimisation algorithm that iteratively learns the yield landscape and steers the media composition toward maximal production. The algorithm led to a 160% yield increase after three DBTL runs as compared to an M9 baseline. Metabolomics data helped to elucidate the underpinning biochemistry for yield improvement and revealed Pareto-like trade-offs in production of other lipopeptides from related pathways. We found positive associations between organic acids and surfactin, suggesting a key role of central carbon metabolism, as well as system-wide anisotropies in how metabolism reacts to shifts in carbon and nitrogen levels. Our framework offers a novel data-driven approach to improve yield of biological products with complex synthesis pathways that are not amenable to traditional yield optimisation strategies.

Graphical abstract
Food web structure mediate positive and negative effects of diversity on ecosystem functioning in a large floodplain river
Authors: Borzone Mas Dalmiro , Scarabotti Pablo A. , Alvarenga Patricio , Vaschetto Pablo A , Arim Matias
Published: January 2024

Research programs on Biodiversity-Ecosystem Functioning (BEF) and Food Web Structure (FWS) have contributed to understanding the impact of biodiversity on the functioning and architecture of ecosystems, but the interconnectedness between these components was seldom attended until recently. Several theoretical hypotheses predict an interconnection between BEF and FWS but were poorly and independently evaluated. We estimated 63 sink food webs of predatory fish in the Paraná River, covering a large gradient of community richness. We evaluated available hypotheses and their interrelationship through path analyses. A well-supported causal structure was identified, supporting that species richness directly increased standing biomass, modularity, and intermodular connection, whereas decreased interaction strength, connectance, and nestedness. A direct positive effect of modularity and connectance on biomass indicates that FWS can determine the BEF. Richness promotes biomass directly and through the increase in modularity but can also decrease biomass due to the decay in connectance, with similar positive and negative effects of richness on biomass. In this sense, the relationship between diversity and ecosystem functioning cannot be blind to FWS. Environmental homogenization and reduction in functional diversity may undermine the conditions for modular food webs, switching positive BEF to negative ones with potential cascading effects in the whole ecosystem.
Diffraction minima resolve point scatterers at tiny fractions (1/80) of the wavelength
Authors: Hensel Thomas A. , Wirth Jan O. , Hell Stefan W.
Published: January 2024

Discerning two or more identical and constantly scattering point sources using freely propagating waves is thought to be limited by diffraction. Here we show both theoretically and experimentally that by employing a diffraction minimum rather than a maximum for resolution, a given number of point scatterers can be discerned at tiny fractions of the employed wavelength. Specifically, we identify an 8 nm distance between two constantly emitting (non-blinking, non-switchable) fluorescent molecules, corresponding to 1/80 of the wavelength. Moreover, we show that contrary to naïve expectations, the measurement precision improves with decreasing distance between the scatterers and with increased scatterer density, thus opening up the prospect of resolving clusters of (optical) point scatterers at tiny fractions of the wavelength.
Joint signatures of morphological and microstructural inter-individual variation in the Alzheimer’s spectrum
Authors: Bussy Aurélie , Patel Raihaan , Parent Olivier , Salaciak Alyssa , Bedford Saashi A. , Farzin Sarah , Tullo Stephanie , Picard Cynthia , Villeneuve Sylvia , Poirier Judes , Breitner John CS , Devenyi Gabriel A. ,   PREVENT-AD Research Group, Tardif Christine L. , Chakravarty M. Mallar
Published: January 2024

Alzheimer’s disease (AD) is primarily characterized by the accumulation of amyloid and tau pathologies. However, alterations in the detailed organization and composition of neural tissue also contribute to the disease’s early stages. Here, we sought to explore whether hippocampal and cortical microstructural changes, such as myelin alterations and inflammation-mediated increases in iron, could serve as indices of AD-related pathophysiology. In this study, we included 158 participants across the AD spectrum: from individuals without cognitive impairment, at high risk for AD, in the prodromal phase with mild cognitive impairment, and suffering from clinical dementia. We measured atrophy using structural magnetic resonance imaging (MRI) and estimated myelin and iron content using quantitative MRI (qMRI) metrics derived from T1 and T2* relaxation, times respectively. We integrated these contrasts to estimate a joint multivariate signature of tissue alterations across the cortex and hippocampus using non-negative matrix factorization. The relevance of these signatures to AD-spectrum measures of medical history, lifestyle, and cognition were further explored using partial least squares correlation. Our results reveal lower disease-related cortical thickness over large areas of the cortex while T2* provided specific variation across the brain (lower in dorsomedial and superior temporal areas, superior frontal cortex, and premotor cortex, and higher in the occipital lobe). Additionally, we observed longer T1 and T2* times in the hippocampus associated with specific lifestyle risk factors like past smoking, high blood pressure, high cholesterol levels, and higher anxiety. These patterns were significantly related to older age, associated with AD progression, being female, and being an APOE-□4 carrier. Taken together, our results suggest that qMRI metrics could serve as a valuable non-invasive tool for exploring the role of myelin and inflammation in AD-related pathophysiology and could be sensitive to modifiable risk factors related to lifestyle and medical history. Future studies may use these signatures to investigate their relationship in investigations related to lifestyle interventions or novel therapeutics.
The Increasing Authorship trend in Neuroscience: A scientometric analysis across 11 countries
Authors: Paul Ann , Segreti Mariella , Pani Pierpaolo , Brunamonti Emiliano , Genovesio Aldo
Published: January 2024

Previous studies have demonstrated an increasing trend of the number of authors across various fields over the years. This trend has been attributed to the necessity for larger collaborations and, at times, to ethical issues regarding authorship attribution. Our study focuses on the evolution of authorship trends in the field of Neuroscience. We conducted our analysis based on a dataset containing 576,647 neuroscience publications produced from 2000 to 2022, focusing on the publications within the Group of ten (G10) countries. Using a matrix-based methodology, we extracted and analyzed the average number of authors per country. Our findings reveal a consistent rise in authorship across all G10 countries over the past two decades. Italy emerged with the highest average number of authors, while the Netherlands stood out for experiencing the most significant increase, particularly in the last decade. The countries with the lowest number of authors per publication were the USA, UK, and Canada.
Spatial proteomics of ER tubules reveals CLMN, an ER-actin tether at focal adhesions that promotes cell migration
Authors: Merta Holly , Isogai Tadamoto , Paul Blessy , Danuser Gaudenz , Henne W Mike
Published: January 2024

The endoplasmic reticulum (ER) is structurally and functionally diverse, yet how its functions are organized within morphological subdomains is incompletely understood. Utilizing TurboID-based proximity labeling and CRISPR knock-in technologies, here we map the proteomic landscape of the human ER and nuclear envelope. Spatial proteomics reveals enrichments of proteins into ER tubules, sheets, and nuclear envelope. We uncover an ER-enriched actin-binding protein, Calmin (CLMN), and define it as an ER-actin tether that localizes to focal adhesions adjacent to ER tubules. CLMN depletion perturbs focal adhesion disassembly, actin dynamics, and cell movement. Mechanistically, CLMN-depleted cells also exhibit defects in calcium signaling near ER-actin interfaces, suggesting CLMN promotes calcium signaling near adhesions to facilitate their disassembly. Collectively, we map the sub-organelle proteome landscape of the ER, identify CLMN as an ER-actin tether, and describe a non-canonical mechanism by which ER tubules engage actin to regulate cell migration.
Identification of sex-biased miRNA markers informative of heat-past events
Authors: van Gelderen Tosca A. , Montfort Jerome , Álvarez-Dios José Antonio , Piferrer Francesc , Bobe Julien , Ribas Laia
Published: January 2024

Elevated temperatures during early developmental stages play a pivotal role in the fate of the final sexual phenotype of fish populations, particularly towards male-skewed sex ratios. This is the case with European sea bass (Dicentrarchus labrax), one of the most important European species in the aquaculture industry. To unveil informative markers of the past thermal events, we investigated changes in the miRNome within the gonads of this species. Consequently, we exposed European sea bass to elevated temperatures during early development and conducted miRNA-sequencing analysis in the ovaries and testes one year post-heat treatment. The examination of miRNA expression levels identified three and twelve miRNAs in ovaries and testes, respectively, reflecting past thermal events. To assess the evolutionary conservation of these identified miRNAs in gonads, we cross-referenced our data with miRNome public information from ovaries and testes in nine additional fish species. This analysis uncovered 43 potential sex-biased markers present in at least five studied species along the evolutionary timeline. For instance, miR-155, miR-429, and miR-140 were female-skewed while miR-184, miR-499, and miR-135 were male-skewed. In addition, among these markers, eight conserved sex-skewed miRNAs proved informative regarding past thermal events in both the ovaries (e.g., miR-192-5p and miR-143-3p) and testes (miR-129-5p, miR-2187a-3p, miR-724-5p, miR-143-3p, miR-194a-5p and miR-223-3p). Notably, miR-223-3p and miR-194a-5p were conserved female-skewed, but showed upregulation in males exposed to high temperature. These miRNAs could serve as markers of heat-induced masculinization of genetic female-prone fish. The current research broadens the inventory of sex-specific miRNAs along evolution in fish and, elucidates thermosensitive miRNAs in the gonads. These findings hold promise as potential tools for predicting historical environmental events associated with masculinization due to high-temperature treatments in cultured species but also perhaps for natural populations exposed to a climate change scenario.
p66Shc Mediates SUMO2-induced Endothelial Dysfunction
Authors: Kumar Jitendra , Uppulapu Shravan K. , Kumari Sujata , Sharma Kanika , Paradee William , Yadav Ravi Prakash , Kumar Vikas , Kumar Santosh
Published: January 2024

Background

Sumoylation is a post-translational modification that can regulate different physiological functions. Increased sumoylation, specifically conjugation of SUMO2/3 (small ubiquitin-like modifier 2/3), is detrimental to vascular health. However, the molecular mechanism mediating this effect is poorly understood.

Methods

We used cell-based assays and mass spectrometry to show that p66Shc is a direct target of SUMO2 and SUMO2 regulates p66Shc function via lysine-81 modification. To determine the effects of SUMO2-p66ShcK81 on vascular function, we generated p66ShcK81R knockin mice and crossbred to LDLr-/-mice to induce hyperlipidemia. Next, to determine p66ShcK81-SUMO2ylation-induced changes in endothelial cell signaling, we performed mass spectrometry followed by Ingenuity Pathway Analysis.

Results

Our data reveal that p66Shc mediates the effects of SUMO2 on endothelial cells. Mass spectrometry identified that SUMO2 modified lysine-81 in the unique collagen homology-2 domain of p66Shc. SUMO2ylation of p66Shc increased phosphorylation at serine-36, causing it to translocate to the mitochondria, a step critical for oxidative function of p66Shc. Notably, sumoylation-deficient p66Shc (p66ShcK81R) was resistant to SUMO2-induced p66ShcS36 phosphorylation and mitochondrial translocation. P66ShcK81R knockin mice were resistant to endothelial dysfunction induced by SUMO2ylation and hyperlipidemia. Ingenuity Pathway Analysis revealed multiple signaling pathways regulated by p66ShcK81-SUMO2ylation in endothelial cells, highlighting Rho-GTPase as a major pathway affected by SUMO2-p66ShcK81.

Conclusions

Collectively, our work reveals SUMO2-p66Shc signaling as a fundamental regulator of vascular endothelial function. We discovered that p66ShcK81 is an upstream modification regulating p66Shc signaling and mediates hyperlipidemia-induced endothelial dysfunction and oxidative stress.
Peripheral monocyte transcriptomics associated with immune checkpoint blockade outcomes in metastatic melanoma
Authors: Cooper Rosalin A , Taylor Chelsea A , Watson Robert A , Tong Orion , Nassiri Isar , Sharma Piyush Kumar , Little Martin , Ye Weiyu , Koturan Surya , Danielli Sara , Middleton Mark , Fairfax Benjamin P
Published: January 2024

Clinical responses to immune checkpoint blockade (ICB) for metastatic melanoma (MM) are variable, with patients frequently developing immune related adverse events (irAEs). The role played by myeloid populations in modulating responses to ICB remains poorly defined. We explored the effect of MM and the response to ICB across a cohort of patients with MM (n=116) and healthy donors (n=45) using bulk and single cell RNA-seq, and flow cytometry. Monocytes from patients with MM exhibit highly dysregulated baseline transcriptional profiles, whilst ICB treatment elicits induction of interferon signaling, MHC class II antigen presentation and CXCR3 ligand expression. Although both combination (cICB - anti-PD-1 and anti-CTLA) and single-agent (sICB - anti-PD1) ICB therapy modulates a shared set of genes, cICB displays a markedly greater magnitude of transcriptional effect. Notably, we find increased baseline monocyte counts correlate with a monocyte proliferation signature and risk of early death, whilst a gene-signature corresponding to a subset of platelet-binding classical monocytes conversely associates with improved outcome. This work demonstrates a central role for monocytes in the modulation of treatment response to ICB, providing insights into inter-individual variation in immune responses to ICB and further highlighting the multifarious immunological consequences of ICB treatment.
Longitudinal progression of blood biomarkers reveals a key role of astrocyte reactivity in preclinical Alzheimer’s disease
Authors: Varma VR , An Y , Kac PR , Bilgel M , Moghekar A , Loeffler T , Amschl D , Troncoso J , Blennow K , Zetterberg H , Ashton NJ , Resnick SM , Thambisetty M
Published: January 2024

Defining the progression of blood biomarkers of Alzheimer’s disease (AD) is essential for targeting treatments in patients most likely to benefit from early intervention. We delineated the temporal ordering of blood biomarkers a decade prior to the onset of AD symptoms in participants in the Baltimore Longitudinal Study of Aging. We show that increased astrocyte reactivity, assessed by elevated glial fibrillary acidic protein (GFAP) levels is an early event in the progression of blood biomarker changes in preclinical AD. In AD-converters who are initially cognitively unimpaired (N=158, 377 serial plasma samples), higher plasma GFAP levels are observed as early as 10-years prior to the onset of cognitive impairment due to incident AD compared to individuals who remain cognitively unimpaired (CU, N=160, 379 serial plasma samples). Plasma GFAP levels in AD-converters remain elevated 5-years prior to and coincident with the onset of cognitive impairment due to AD. In participants with neuropathologically confirmed AD, plasma GFAP levels are elevated relative to cognitively normal individuals and intermediate in those who remain cognitively unimpaired despite significant AD pathology (asymptomatic AD). Higher plasma GFAP levels at death are associated with greater severity of both neuritic plaques and neurofibrillary tangles. In the 5XFAD transgenic model of AD, we observed greater GFAP levels in the cortex and hippocampus of transgenic mice relative to wild-type prior to the development of cognitive impairment. Reactive astrocytosis, an established biological response to neuronal injury, may be an early initiator of AD pathogenesis and a promising therapeutic target.
Characterisation of laminar and vascular spatiotemporal dynamics of CBV and BOLD signals using VASO and ME-GRE at 7T in humans
Authors: Dresbach Sebastian , Huber Renzo , Gulban Omer Faruk , Pizzuti Alessandra , Trampel Robert , Ivanov Dimo , Weiskopf Nikolaus , Goebel Rainer
Published: January 2024

Interpretation of cortical laminar functional magnetic resonance imaging (fMRI) activity requires detailed knowledge of the spatiotemporal haemodynamic response across vascular compartments due to the well-known vascular biases (e.g. the draining veins). Further complications arise from the spatiotemporal hemodynamic response that differs depending on the duration of stimulation. This information is crucial for future studies using depth-dependent cerebral blood volume (CBV) measurements, which promise higher specificity for the cortical microvasculature than the blood oxygenation level dependent (BOLD) contrast. To date, direct information about CBV dynamics with respect to stimulus duration, cortical depth and vasculature is missing in humans. Therefore, we characterized the cortical depth-dependent CBV-haemodynamic responses across a wide set of stimulus durations with 0.9 mm isotropic spatial and 0.785 seconds effective temporal resolution in humans using slice-selective slabinversion vascular space occupancy (SS-SI VASO). Additionally, we investigated signal contributions from macrovascular compartments using fine-scale vascular information from multiecho gradient-echo (ME-GRE) data at 0.35 mm isotropic resolution. In total, this resulted in>7.5h of scanning per participant (n=5). We have three major findings: (I) While we could demonstrate that 1 second stimulation is viable using VASO, more than 12 seconds stimulation provides better CBV responses in terms of specificity to microvasculature, but durations beyond 24 seconds of stimulation may be wasteful for certain applications. (II) We observe that CBV responses show dilation patterns across the cortex. (III) While we found increasingly strong BOLD signal responses in vessel-dominated voxels with longer stimulation durations, we found increasingly strong CBV signal responses in vessel-dominated voxels only until 4 second stimulation durations. After 4 seconds, only the signal from non-vessel dominated voxels kept increasing. This might explain why CBV responses are more specific to the underlying neuronal activity for long stimulus durations.
BBSome-dependent ciliary Hedgehog signaling governs cell fate in the white adipose tissue
Authors: Sieckmann Katharina , Winnerling Nora , Silva Ribeiro Dalila Juliana , Kardinal Ronja , Steinheuer Lisa Maria , Schermann Geza , Klausen Christina , Blank-Stein Nelli , Schulte-Schrepping Jonas , Osei-Sarpong Collins , Becker Matthias , Bonaguro Lorenzo , Beyer Marc , Thurley Kevin , May-Simera Helen Louise , Zurkovic Jelena , Thiele Christoph , Ruiz de Almodovar Carmen , Mass Elvira , Wachten Dagmar
Published: January 2024

The primary cilium has emerged as critical in regulating whole-body energy metabolism, as reflected in the Bardet-Biedl syndrome (BBS), where primary cilia dysfunction leads to obesity due to hyperphagia and white adipose tissue (WAT) remodeling. The regulation of cell fate and differentiation of adipocyte precursor cells (APCs) is key to maintaining WAT homeostasis during obesity. Using mice that recapitulated the BBS patient phenotype (Bbs8−/−), we demonstrate that primary cilia dysfunction reduces the stem-cell-like P1 APC subpopulation by inducing a phenotypic switch into a fibrogenic progenitor state, characterized by extracellular matrix (ECM) remodeling and upregulation of CD9. Single-cell RNA sequencing revealed a direct transition of stem-cell-like P1 cells into fibrogenic progenitors, bypassing the committed P2 cells. Ectopic ciliary Hedgehog signaling upon loss of BBS8 emerged as a central driver of the molecular changes inBbs8−/−APCs, altering differentiation into adipocytes and lipid uptake. These findings unravel a novel role for primary cilia in governing APC fate, determining the delicate balance between adipogenesis and fibrogenesis. The identified molecular mechanisms provide insights into potential therapeutic targets for obesity.
Oviposition status and sugar availability influence measures of transmission potential in malaria-infected mosquitoes
Authors: Shiau Justine C. , Garcia-Diaz Nathan , Kyle Dennis E. , Pathak Ashutosh K.
Published: January 2024

Background

Like other oviparous organisms, the gonotrophic cycle of mosquitoes is not complete until they have selected a suitable habitat to oviposit. In addition to the evolutionary constraints associated with selective oviposition behavior, the physiological demands relative to an organism’s oviposition status also influences their nutrient requirement from the environment. Yet, studies that measure transmission potential (vectorial capacity or competence) of mosquito-borne parasites rarely consider if the rates of parasite replication and development could be influenced by these constraints resulting from whether mosquitoes have completed their gonotrophic cycle.

Methods

Anopheles stephensimosquitoes were infected withPlasmodium bergheithe rodent analog of human malaria and maintained on 1% or 10% dextrose and either provided oviposition sites (‘oviposited’ herein) to complete their gonotrophic cycle or forced to retain eggs (‘non-oviposited’). Transmission potential in the four groups was measured up to 27 days post-infection as 1) the rates of vector survival, 2) rates of sporozoite migration to the salivary glands (‘extrinsic incubation period’ or EIP), and 3), sporozoite densities.

Results

In the two groups of oviposited mosquitoes, rates of sporozoite migration and densities in the salivary glands were clearly higher in mosquitoes fed 10% dextrose. In non-oviposited mosquitoes however, rates of sporozoite migration and densities were independent of sugar concentrations, although both measures were slightly lower than oviposited mosquitoes fed 10% dextrose. Rates of vector survival were higher in non-oviposited mosquitoes.

Conclusions

Taken together, these results suggest vectorial capacity for malaria parasites may be dependent on nutrient availability and oviposition/gonotrophic status and as such, argue for more careful consideration of this interaction when estimating transmission potential; costs to parasite fitness and vector survival were buffered against changes in nutritional availability from the environment in non-oviposited mosquitoes, but not oviposited mosquitoes. In general, however, these patterns suggest parasite fitness may be dependent on complex interactions between physiological (nutrition) and evolutionary (egg-retention) trade-offs in the vector, with potential implications for disease transmission and management. For instance, while reducing availability of oviposition sites and environmental sources of nutrition are key components of integrated vector management strategies, their abundance and distribution is under strong selection pressure from the patterns associated with climate change.

Graphical abstract
Branch-specific clustered parallel fiber input controls dendritic computation in Purkinje cells
Authors: Cirtala Gabriela , Schutter Erik De
Published: January 2024

Most central neurons have intricately branched dendritic trees that integrate massive numbers of synaptic inputs. Intrinsic active mechanisms in dendrites can be heterogenous and be modulated in a branch-specific way. However, it remains poorly understood how heterogenous intrinsic properties contribute to processing of synaptic input. We propose the first computational model of the cerebellar Purkinje cell with dendritic heterogeneity, in which each branch is an individual unit and is characterized by its own set of ion channel conductance densities. When simultaneously activating a cluster of parallel fiber synapses, we measure the peak amplitude of a response (PAR) and observe how changes in P-type calcium channel conductance density shift PAR from a linear one to a bimodal one including dendritic calcium spikes and vice-versa. These changes relate to the morphology of each branch. We show how dendritic calcium spikes propagate and how Kv4 channels block spreading depolarization to nearby branches.
A senescence-specific lncRNA controls metabolic rewiring of senescent cells
Authors: Grossi Elena , Marchese Francesco P. , González Jovanna , Goñi Enrique , Amadoz Alicia , Herranz Nicolás , Montes Marta , Huarte Maite
Published: January 2024

Despite the classical view of senescence as passive growth arrest, it is an active process with profound implications for cellular homeostasis. Senescent cells remain metabolically active to be able to cope with the energetic demand of the senescence program, although the precise mechanisms underlying this metabolic reprogramming are just beginning to emerge. Here we have identifiedsin-lncRNA,a previously uncharacterized lncRNA, highly specific of senescent cells, and transcriptionally induced by C/EBPβ, the master regulator of the senescence-associated secretory phenotype (SASP). While being strongly activated in senescence,sin-lncRNAknockdown reinforces the senescence program by affecting oxidative phosphorylation and mitochondrial function.sin-lncRNAinteracts with the TCA enzyme dihydrolipoamide S-succinyltransferase (DLST) to facilitate its proper. sin-lncRNAdepletion increases DLST nuclear translocation, favoring a metabolic shift from oxidative phosphorylation to a glycolytic phenotype. Moreover, whilesin-lncRNAexpression remains low in highly proliferative cancer cells, it is strongly induced upon cisplatin-induced senescence. Knockdown ofsin-lncRNAin ovarian cancer cells results in deficient oxygen consumption and increased extracellular acidification, sensitizing the cells to cisplatin treatment. Altogether, these results indicate thatsin-lncRNAis specifically induced in cellular senescence to maintain metabolic homeostasis. Our findings reveal a new regulatory mechanism in which a lncRNA contributes to the adaptive metabolic changes in senescent cells, unveiling the existence of an RNA-dependent metabolic network specific to senescent cells.
Generation and characterization of CRISPR-Cas9-MediatedXPCGene Knockout in Human Skin Cells
Authors: Nasrallah Ali , Rezvani Hamid-Reza , Kobaisi Farah , Hammoud Ahmad , Rambert Jérôme , Smits Jos P.H. , Sulpice Eric , Rachidi Walid
Published: January 2024

Xeroderma pigmentosum group C (XPC) is a versatile protein, crucial for sensing DNA damage in the global genome nucleotide excision repair (GG-NER) pathway. This pathway is vital for mammalian cells, acting as their essential approach for repairing DNA lesions stemming from interactions with environmental factors, such as exposure to ultraviolet (UV) radiation from the sun. Loss-of-function mutations in theXPCgene confer a photosensitive phenotype in XP-C patients with the accumulation of unrepaired UV induced DNA damage. This remarkable increase in DNA damage tends to elevate by 10,000-fold the risk of developing melanoma and non-melanoma skin cancers. To date, creating accurate and reproducible models to study human XP-C disease has been an important challenge. To tackle this, we used CRISPR-Cas9 technology in order to knockoutXPCgene in various human skin cells (keratinocytes, fibroblasts, and melanocytes). After validation of theXPCknockout in these edited skin cells, we showed that they recapitulate the major phenotypes of XPC mutations: photosensitivity and the impairment of UV induced DNA damage repair. Moreover, these mutated cells demonstrated a reduced proliferative capacity compared to their respective wild-type controls. Finally, to better mimic the disease environment, we built a 3D reconstructed skin using these XPC knockout skin cells. This model exhibited an abnormal behavior, showing an extensive remodeling of its extracellular matrix compared to normal skin. Analyzing the composition of the fibroblasts secretome revealed a significant augmented shift in the inflammatory response following XPC knockout. Our innovative “disease on a dish” approach can provide valuable insights into the molecular mechanisms underlying XP-C disease, paving the way to design novel preventive and therapeutic strategies to alleviate the disease phenotype. Also, given the high risk of skin cancer onset in XP-C disease, our new approach can also serve as a link to draw novel insights towards this elusive field.
TRESK background potassium channel in MrgprA3+pruriceptors regulates acute and chronic itch
Authors: Llimós-Aubach Júlia , Andres-Bilbe Alba , Pujol-Coma Anna , Pallás Irene , de Anta Josep Maria , Soler Concepció , Comes Núria , Callejo Gerard , Gasull Xavier
Published: January 2024

TRESK (K2P18.1) is a background K+channel expressed in sensory neurons, where it modulates the resting membrane potential, action potential firing and neuronal excitability. A subset of these sensory neurons, which express specific TRPs and Mas-related G protein-coupled receptors (Mrgprs), are activated by pruritogens and mediate itch sensations. Because TRESK is involved in somatosensation and pain transduction, we evaluated the contribution of this channel to pruritic sensitivity and its potential as a target for the treatment of chronic itch pathologies. By combining RNA in situ hybridization, calcium imaging, electrophysiological and behavioral approaches, we found that TRESK is involved in the modulation of non-histaminergic itch. TRESK is coexpressed with MrgprD+and MrgprA3+in sensory neurons and MrgprA3+neurons from TRESK-/-animals display an enhanced firing compared to WT counterparts. Interestingly, acute itch to intradermal injection of chloroquine is significantly enhanced in the absence of TRESK but not the response to histamine, BAM8-22 or LTC4. TRESK deletion also enhanced chronic itch in mice models of Allergic Contact Dermatitis and Dry Skin. In the mouse model imiquimod-induced psoriasiform dermatitis, the absence of TRESK produced a significantly enhanced scratching behavior, which developed earlier and was more robust. Finally, enhancing TRESK function with the channel activator cloxyquin diminished both acute and chronic itch in WT mice but not in KO animals. In summary, our data indicates that TRESK is involved in regulating the excitability of a subset of sensory neurons that mediate histaminergic-independent itch. Enhancing the channel function with specific activators constitutes a novel anti-pruritic therapeutic method that can be combined with other compounds for the treatment of non-histaminergic itch, for which appropriate treatments are lacking.
Superagers resist typical age-related white matter structural changes
Authors: Garo-Pascual Marta , Zhang Linda , Valentí-Soler Meritxell , Strange Bryan A.
Published: January 2024

Superagers are elderly individuals with the memory ability of people 30 years younger and provide evidence that age-related cognitive decline is not inevitable. In a sample of 64 superagers (mean age 81.9; 59% women) and 55 typical older adults (mean age 82.4; 64% women) from the Vallecas Project, we studied, cross-sectionally and longitudinally over 5 years with yearly follow-ups, the global cerebral white matter status as well as region-specific white matter microstructure assessment derived from diffusivity measures. Superagers and typical older adults showed no difference in global white matter health (total white matter volume, Fazekas score, and lesions volume) cross-sectionally or longitudinally. However, analyses of diffusion parameters revealed better white matter microstructure in superagers than in typical older adults. Cross-sectional differences showed higher fractional anisotropy (FA) in superagers mostly in frontal fibres and lower mean diffusivity (MD) in most white matter tracts, expressed as an anteroposterior gradient with greater group differences in anterior tracts. FA decrease over time is slower in superagers than in typical older adults in all white matter tracts assessed, which is mirrored by MD increases over time being slower in superagers than in typical older adults in all white matter tracts except for the corticospinal tract, the uncinate fasciculus and the forceps minor. The better preservation of white matter microstructure in superagers relative to typical older adults supports resistance to age-related brain structural changes as a mechanism underpinning the remarkable memory capacity of superagers, while their regional ageing pattern is in line with the last-in-first-out hypothesis.

SIGNIFICANCE STATEMENT

Episodic memory is one of the cognitive abilities most vulnerable to ageing. Although memory normally declines with age, some older people may have memory performance similar to that of people 30 years younger, and this phenomenon is often conceptualised as superageing. Understanding the superager phenotype can provide insights into mechanisms of protection against age-related memory loss and dementia. We studied the white matter structure of a large sample of 64 superagers over the age of 80 and 55 age-matched typical older adults during 5 years with yearly follow-ups showing evidence of slower age-related changes in the brains of superagers especially in protracted maturation tracts, indicating resistance to age-related changes and a regional ageing pattern in line with the last-in-first-out hypothesis.
Rbpms2 promotes female fate upstream of the nutrient sensing Gator2 complex component, Mios
Authors: Wilson Miranda L. , Romano Shannon N. , Khatri Nitya , Aharon Devora , Liu Yulong , Kaufman Odelya H. , Draper Bruce W. , Marlow Florence L.
Published: January 2024

Reproductive success relies on proper establishment and maintenance of biological sex. In many animals, including mammals, the primary gonad is initially ovary in character. We previously showed the RNA binding protein (RNAbp), Rbpms2, is required for ovary fate in zebrafish. Here, we identified Rbpms2 targets in oocytes(Rbpms2-bound oocyte RNAs; rboRNAs). We identify Rbpms2 as a translational regulator ofrboRNAs, which include testis factors and ribosome biogenesis factors. Further, genetic analyses indicate that Rbpms2 promotes nucleolar amplification via the mTorc1 signaling pathway, specifically through the mTorc1-activating Gap activity towards Rags 2 (Gator2) component, Missing oocyte (Mios). Cumulatively, our findings indicate that early gonocytes are in a dual poised, bipotential state in which Rbpms2 acts as a binary fate-switch. Specifically, Rbpms2 represses testis factors and promotes oocyte factors to promote oocyte progression through an essential Gator2-mediated checkpoint, thereby integrating regulation of sexual differentiation factors and nutritional availability pathways in zebrafish oogenesis.
MRCK-1 activates non-muscle myosin for outgrowth of a unicellular tube inCaenorhabditis elegans
Authors: Popiel Evelyn M. , Derry W. Brent
Published: January 2024

The formation and patterning of unicellular biological tubes is essential for metazoan development. It is well established that vascular tubes and neurons use similar guidance cues to direct their development, but the downstream mechanisms that promote the outgrowth of biological tubes are not well characterized. We show that the conserved kinase MRCK-1 and its substrate the regulatory light chain of non-muscle myosin, MLC-4, are required for outgrowth of the unicellular excretory canal inC. elegans. Structure-function analysis of MRCK-1 indicates that the kinase domain, but not the small GTPase-binding CRIB domain, is required for canal outgrowth. Expression of a phosphomimetic form of MLC-4 rescues canal truncations inmrck-1mutants and shows enrichment at the growing canal tip. Specific depletion of MRCK-1 or MLC-4 in the canal causes severe truncations, with unlumenized projections of the basal membrane. Moreover, our work reveals a novel function for non-muscle myosin downstream of MRCK-1 in excretory canal outgrowth that may be conserved in the development of seamless tubes in other organisms.
Active prokaryotic and eukaryotic viral ecology across spatial scale in a deep-sea brine pool
Authors: Minch Benjamin , Chakraborty Morgan , Purkis Sam , Rodrigue Mattie , Moniruzzaman Mohammad
Published: January 2024

Deep-sea brine pools represent rare, extreme environments that focus biodiversity at bathyal to abyssal depths. Despite their small size and distribution, brine pools represent important ecosystems to study because they provide unique insight into the limits of life on Earth, and by analogy, the plausibility of life beyond it. A distinguishing feature of many brine pools is the presence of thick benthic microbial mats which develop at the brine-seawater interface. While these bacterial and archaeal communities have received moderate attention, little is known about the viral communities and their interactions with host populations in these environments. To bridge this knowledge gap, we leveraged metagenomic and metatranscriptomic data from three distinct zones within the NEOM brine pool system (Gulf of Aqaba) to gain insights into the active viral ecology around the pools. Here, we report a remarkable diversity and activity of viruses of all nucleic acid types and genome sizes that infect prokaryotic and eukaryotic hosts in this environment. These include giant viruses (phylum:Nucleocytoviricota), RNA viruses, jumbo phages, and polinton-like viruses (PLVs). Many of these appeared to form distinct clades showing the possibility of untapped viral diversity in the brine pool ecosystem. Zone-specific differences in viral community composition and infection strategy were also observed with lysogenic phages seeming to dominate the bacterial mat further away from the pool’s center. Through host matching, viruses infecting metabolically important bacteria and archaea were observed – including a linkage between a jumbo phage and a key manganese-oxidizing and arsenic-metabolizing bacterium. Our findings shed light on the role of viruses in modulating the brine pool microbial community dynamics and biogeochemistry through revealing novel viral diversity, host-virus associations, and spatial-scale heterogeneity in viral dynamics in these extreme environments. These results will provide crucial foundation for further investigation into the adaptations of viruses and their microbial hosts in extreme habitats in the marine ecosystem.
Coupled metalipidomics-metagenomics reveal structurally diverse sphingolipids produced by a wide variety of marine bacteria
Authors: Ding Su , von Meijenfeldt F. A. Bastiaan , Bale Nicole J. , Damsté Jaap S. Sinninghe , Villanueva Laura
Published: January 2024

Microbial lipids, used as taxonomic markers and physiological indicators, have mainly been studied through cultivation. However, this approach is limited due to the scarcity of cultures of environmental microbes, thereby restricting insights into the diversity of lipids and their ecological roles. Addressing this limitation, here we apply for the first time metalipidomics combined with metagenomics in the Black Sea, classifying and tentatively identifying 1,623 lipid-like species across 18 lipid classes. We discovered over 200 novel, abundant, and structurally diverse sphingolipids in euxinic waters, including unique 1-deoxysphingolipids with long-chain fatty acids and sulfur-containing groups. Genomic analysis revealed that members of 38 bacterial phyla in the Black Sea can synthesize sphingolipids, representing a fourfold increase from previously known capabilities and accounting for up to 25% of the microbial community. These sphingolipids appear to be involved in oxidative stress response and cell wall remodeling. Our findings underscore the effectiveness of multi-omics approaches in exploring microbial chemical ecology.
Inhibitory control of gait initiation in humans: an electroencephalography study
Authors: Ziri D. , Hugueville L. , Olivier C. , Boulinguez P. , Gunasekaran H. , Lau B. , Welter M-L. , George N.
Published: January 2024

Response inhibition is a crucial component of executive control. Although mainly studied in upper limb tasks, it is fully implicated in gait initiation. Here, we assessed the influence of proactive and reactive inhibitory control during gait initiation in healthy adult participants. For this purpose, we measured kinematics and electroencephalography (EEG) activity (event-related potential [ERP] and time-frequency data) during a modified Go/NoGo gait initiation task in 23 healthy adults. The task comprised Go-certain, Go-uncertain, and NoGo conditions. Each trial included preparatory and imperative stimuli. Our results showed that go-uncertainty resulted in delayed reaction time (RT), without any difference for the other parameters of gait initiation. Proactive inhibition, i.e. Go uncertain versus Go certain conditions, influenced EEG activity as soon as the preparatory stimulus. Moreover, both proactive and reactive inhibition influenced the amplitude of the ERPs (central P1, occipito-parietal N1, and N2/P3) and theta and alpha/low beta band activities in response to the imperative—Go-uncertain versus Go-certain and NoGo versus Go-uncertain—stimuli. These findings demonstrate that the uncertainty context induced proactive inhibition, as reflected in delayed gait initiation. Proactive and reactive inhibition elicited extended and overlapping modulations of ERP and time-frequency activities. This study shows protracted influence of inhibitory control in gait initiation.
Synaptic vesicle release regulates pre-myelinating oligodendrocyte-axon interactions in a neuron subtype-specific manner
Authors: Gronseth James R. , Nelson Heather N. , Johnson Taylor L. , Mallon Taryn A. , Martell Madeline R. , Pfaffenbach Katrina A. , Duxbury Bailey B. , Henke John T. , Treichel Anthony J. , Hines Jacob H.
Published: January 2024

Oligodendrocyte-lineage cells are central nervous system (CNS) glia that perform multiple functions including the selective myelination of some but not all axons. During myelination, synaptic vesicle release from axons promotes sheath stabilization and growth on a subset of neuron subtypes. In comparison, it is unknown if pre-myelinating oligodendrocyte process extensions selectively interact with specific neural circuits or axon subtypes, and whether the formation and stabilization of these neuron-glia interactions involves synaptic vesicle release. In this study, we used fluorescent reporters in the larval zebrafish model to track pre-myelinating oligodendrocyte process extensions interacting with spinal axons utilizing in vivo imaging. Monitoring motile oligodendrocyte processes and their interactions with individually labeled axons revealed that synaptic vesicle release regulates the behavior of subsets of process extensions. Specifically, blocking synaptic vesicle release decreased the longevity of oligodendrocyte process extensions interacting with reticulospinal axons. Furthermore, blocking synaptic vesicle release increased the frequency that new interactions formed and retracted. In contrast, tracking the movements of all process extensions of singly-labeled oligodendrocytes revealed that synaptic vesicle release does not regulate overall process motility or exploratory behavior. Blocking synaptic vesicle release influenced the density of oligodendrocyte process extensions interacting with reticulospinal and serotonergic axons, but not commissural interneuron or dopaminergic axons. Taken together, these data indicate that alterations to synaptic vesicle release cause changes to oligodendrocyte-axon interactions that are neuron subtype specific.
Association between allostatic load and accelerated white matter brain aging: findings from the UK Biobank
Authors: Feng Li , Ye Zhenyao , Du Zewen , Pan Yezhi , Canida Travis , Ke Hongjie , Liu Song , Chen Shuo , Hong L. Elliot , Kochunov Peter , Chen Jie , Lei David K.Y. , Shenassa Edmond , Ma Tianzhou
Published: January 2024

White matter (WM) brain age, a neuroimaging-derived biomarker indicating WM microstructural changes, helps predict dementia and neurodegenerative disorder risks. The cumulative effect of chronic stress on WM brain aging remains unknown. In this study, we assessed cumulative stress using a multi-system composite allostatic load (AL) index based on inflammatory, anthropometric, respiratory, lipidemia, and glucose metabolism measures, and investigated its association with WM brain age gap (BAG), computed from diffusion tensor imaging data using a machine learning model, among 22 951 European ancestries aged 40 to 69 (51.40% women) from UK Biobank. Linear regression, Mendelian randomization, along with inverse probability weighting and doubly robust methods, were used to evaluate the impact of AL on WM BAG adjusting for age, sex, socioeconomic, and lifestyle behaviors. We found increasing one AL score unit significantly increased WM BAG by 0.29 years in association analysis and by 0.33 years in Mendelian analysis. The age- and sex-stratified analysis showed consistent results among participants 45-54 and 55-64 years old, with no significant sex difference. This study demonstrated that higher chronic stress was significantly associated with accelerated brain aging, highlighting the importance of stress management in reducing dementia and neurodegenerative disease risks.