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A role for the male germline in the expansion of the mammalian brain
Get PDFThe brain and testis share a surprisingly high number of molecular and cellular similarities. We have previously hypothesised that, throughout evolution, many genetic variants contributing to brain size expansion first arose in spermatogonia where they conferred a selective advantage to the male germline stem cells via a process analogous to oncogenesis – known as ‘selfish spermatogonial selection’. Once transmitted to the next generation, these selfish variants became constitutive, disproportionately accumulating in signalling pathways active in both spermatogenesis and neurogenesis and which regulate stem cell proliferation. Although the evidence supporting a close molecular relationship between the germline and brain is compelling, research in this area is stymied by the relative scarcity of spermatogonia and the inherent stochasticity of single-cell transcriptomic profiling. Accordingly, the molecular signatures of spermatogonia are incompletely understood, and their similarity with neural programs difficult to assess. To address this, we combine re-analyses of 34 adult human single-cell testis datasets with data from the Human Protein Atlas to assess the extent to which genes functionally associated with brain growth and development are expressed within testicular cell types. Consistent with our hypothesis, we find that among thousands of proteins with brain-associated functions, the majority are not only expressed in male germ cells, but show particular enrichment in spermatogonia. We contextualise these results with an extensive literature survey and conclude that further enquiry into the testis-brain connection may yield novel insight into the evolutionary processes that shaped the human condition.
Significance statement The human brain and testis share unexpected molecular similarities, yet the evolutionary and biomedical implications of this overlap remain poorly understood. By integrating single-cell transcriptomic datasets with large-scale proteomic data, we show that genes implicated in neurodevelopment are widely expressed in the male germline and particularly enriched in spermatogonia. These findings support the idea that ‘selfish’ mutations arising in spermatogonial stem cells not only promote their own propagation in the testis but may also influence neural progenitor biology once inherited. Our results provide a systematic foundation for understanding how male germline-specific evolutionary forces could have contributed to the emergence of the large and complex human brain, while also offering insight into the origins of susceptibility to some congenital neurodevelopmental diseases
ALARUM: Active One Health surveillance in LMICs to monitor and predict Antimicrobial Resistance Using Metagenomics – a cross-sectional study protocol
Get PDFBackground
In rural sub-Saharan Africa (sSA), the burden of antimicrobial resistance (AMR) remains high. As AMR continues to rise, there is a strong need for practical, implementable surveillance to monitor and mitigate risks, as well as inform timely, evidence-based clinical decision-making. Emerging evidence points to possible community-level drivers, such as transmission between human, animal and environmental reservoirs as contributing factors, yet microbiological surveillance or opportunities for wastewater-based surveillance are often limited and insufficient in these settings. Therefore, alternative sustainable and affordable approaches are needed. We intend to build on the demonstrated potential of metagenomic profiling of pooled faecal material, which accurately predicted population-level AMR prevalence in invasive
Enterobacterales
infections.
Methods and analysis
We aim to validate this metagenomic pooled approach on additional populations, and to evaluate whether AMR patterns could be similarly predicted from surveillance of community One Health reservoirs. We will assemble existing data from hospital-based microbiology diagnostic laboratories in rural Burkina Faso and Kenya, and determine to what extent community-level metagenomic data, and/or faecal material of patients on hospital admission, can predict AMR in clinical isolates. We will perform community-level surveys in eight clusters per country, randomly selecting 15 households per cluster. We will systematically sample suspected environmental AMR exposure sites in and around households (soil, drinking water, latrines, chicken faeces) and collect data on community-level antibiotic use, hygiene practices, contact with domestic animals and sanitary facilities. Samples and data will be collected twice: during the dry and during the rainy season.
In addition to evaluating the accuracy of predicting resistance in clinical isolates, we will quantify community-level exposure risks. We will conduct metagenomic profiling on pooled DNA extracts from human stool samples (hospital and community-level) and from household environments. Bayesian statistical models will quantify relationships between AMR gene abundance in the environment and in human stool, and invasive bacteria identified among clinical patients, accounting for geography and seasonality. A cost-utility analysis will determine under what circumstances the use of pooled metagenomic data to inform empirical antibiotic policies would represent an efficient use of resources.
Ethics and dissemination
The proposed surveillance protocol is developed in partnership with local communities and local and international researchers and has received ethical approval in Kenya and Burkina Faso. It will assess whether intermittent, pooled-sample metagenomics provides a viable, low-cost and practical approach for population-level AMR surveillance in settings that—like many in rural sSA—lack systematic microbiological diagnostics and where sewage systems for wastewater-based surveillance are absent. By providing an alternative to routine microbiological-based surveillance where this proves challenging to implement, this approach may help improve treatment outcomes, contribute to equity and public health. Findings will be disseminated through peer-reviewed publications and academic conferences and will contribute to the recently proposed WHO AMR surveillance strategy, which combines survey-based approaches with routine AMR surveillance
Abundant hydrocarbons in a buried galactic nucleus with signs of carbonaceous grain and polycyclic aromatic hydrocarbon processing
Get PDFHydrocarbons play a key role in shaping the chemistry of the interstellar medium, but their enrichment and relation with carbonaceous grains and polycyclic aromatic hydrocarbons still lack clear observational constraints. Here we report on JWST NIRSpec + MIRI/MRS infrared observations (~3–28 μm) of the local ultra-luminous infrared galaxy (ULIRG) IRAS 07251−0248, which revealed the extragalactic detection of small gas-phase hydrocarbons, such as benzene (C6H6), triacetylene (C6H2), diacetylene (C4H2), acetylene (C2H2), methane (CH4) and methyl radical (CH3), as well as deep amorphous C–H absorptions in the solid phase. The unexpectedly high abundance of these molecules indicates an extremely rich hydrocarbon chemistry not explained by high-temperature gas-phase chemistry, ice desorption or oxygen depletion. Instead, the most plausible explanation is the erosion and fragmentation of carbonaceous grains and polycyclic aromatic hydrocarbons. This scenario is supported by the correlation between the abundance of one of their main fragmentation products, C2H2, and the cosmic-ray ionization rate for a sample of local ULIRGs. These hydrocarbons are outflowing at ~160 km s−1, which may represent a potential formation pathway for hydrogenated amorphous grains. Our results indicate that IRAS 07251−0248 might not be unique but represents an extreme example of the commonly rich hydrocarbon chemistry prevalent in deeply obscured galactic nuclei
Physiology-guided personalized mechanical ventilation to prevent ventilator-induced lung injury
Get PDFMechanical ventilation is essential for managing acute respiratory failure, yet it carries a significant risk of ventilator-induced lung injury (VILI). Lung-protective ventilation, most notably through the use of low tidal volumes, has improved outcomes in acute respiratory distress syndrome (ARDS), but these conventional strategies do not fully account for the profound heterogeneity of the injured lung or the variability in patient-specific physiology. Although tidal volumes of 4–8 ml/kg predicted body weight (PBW) provide a general reference for limiting strain, truly protective ventilation requires individualization based on regional aeration, compliance, and recruitability. Variability in these parameters leads to uneven distributions of stress and strain, while dynamic changes in respiratory drive, inspiratory effort, and cardiopulmonary interactions further complicate uniform ventilatory management. The mechanisms underlying VILI: barotrauma, volutrauma, atelectrauma, and biotrauma extend beyond the lung parenchyma and contribute to ventilator-associated diaphragm dysfunction and secondary organ injury. Bedside physiological tools, including esophageal manometry, electrical impedance tomography, and lung ultrasound, allow real-time evaluation of lung stress, regional ventilation, recruitability, and patient effort. When incorporated into clinical decision-making, these modalities facilitate individualized adjustments aimed at avoiding overdistension and collapse, limiting injurious pressures and volumes, and maintaining adequate gas exchange and hemodynamic stability. Advances in technology, such as closed-loop ventilation systems, adaptive control algorithms, and computational modeling, offer additional opportunities to refine personalized strategies and anticipate harmful mechanical patterns. Collectively, physiology-guided, personalized mechanical ventilation shifts practice from protocol-driven approaches to patient-centered care, with the overarching goal of mitigating VILI and improving outcomes in critically ill patients
Astrocyte Enrichment of 3D Cortical Constructs Enhances Brain Repair
Get PDFRegenerative medicine offers a promising approach to treat brain injuries, yet challenges persist in promoting neuronal survival and integration. Recent studies demonstrate that human cells implanted into rodent brains can exhibit plasticity, integrate into neural circuits and alleviate functional deficits. However, integration is often poor, with inadequate vascularization, and insufficient support cells such as astrocytes. Astrocytes play a crucial role in neuronal development and recovery by releasing growth factors, facilitating synaptogenesis, and promoting blood vessel formation. This study investigated human neuronal progenitor cells cultured alone or cultured with mouse astrocytes and formed into 3D constructs using microfluidics. Co‐cultures exhibited enhanced neuronal maturation, viability, and density. Following implantation into mouse brains, co‐cultures reduced lesion size, increased axonal growth, and improved astrocyte coupling to blood vessels within the graft. Additionally, we show that NPCs and co‐cultures increased astrocyte size in implants. Deconvolved high‐resolution microscopy identified synapses and optogenetics showed functional connections between the host and implants. These findings underscore the essential role of astrocytes in enhancing neuronal tissue integration and advancing brain injury treatments
Defining the molecular mechanisms of control of the TMEM16A channel by GPCR receptors
No full textBackground: The scope of this project is to study the mechanisms underlying the regulation of the vascular transmembrane protein TMEM16A, a Ca2+-gated Cl- (CaCC) channel. The physiological and pharmacological stimuli studied include: (i) activation of G protein-coupled receptors (GPCRs) by physiological agonists, (ii) changes in the histological properties of the vessel wall, and (iii) intracellular pathways and possible binding partners that the channel may share with other ion channel types.Vascular tone is regulated by a network of ion channels, GPCRs, and extracellular matrix (ECM) remodelling pathways. The TMEM16A channel constitutes a key depolarising mechanism in vascular smooth muscle cells (VSMCs). The channel opens in response to inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ release during GqPCR activation. Whether G-protein βγ subunits may modulate TMEM16A activity is unestablished and is, therefore, investigated in this thesis.Because the channel is also sensitive to stretch, consequent alterations in vessel compliance may affect channel activity. Therefore, the role of matrix metalloproteinases (MMPs) in the control of vessel tone and TMEM16A signalling is further investigated in this thesis.A range of intracellular pathways have also been studied. Firstly, the mechanisms by which the lysosomal Niemann–Pick C1 (NPC1) protein affects TMEM16A function were investigated. In addition, this study examined whether TMEM16A channel activity is regulated by potential binding partners such as the K+ voltage-gated channel subfamily E member 1 (KCNE1) and the leucine-rich repeat and Ig domain-containing (LINGO) proteins.Methods and results: TMEM16A channels expressed in human embryonic kidney 293T (HEK293T) cells mediated outwardly rectifying currents, with properties closely resembling those of CaCC currents observed in VSMCs. Co-expression of TMEM16A with the a1 adrenoreceptor (a1R) resulted in CaCC currents in response to phenylephrine. TMEM16A currents were not altered by the inhibition of GPCR bg subunits with gallein, or the addition of bg subunits in the pipette solution. When a1R was stimulated with phenylephrine, gallein reduced TMEM16A currents in a range of physiological membrane potentials (Vm). TMEM16A currents measured in cells co-transfected with the b2 adrenoreceptor (b2R) were not affected by gallein, implying that the channel is specifically activated by bg subunits released by GqPCR, but not GsPCR. Treatment of isolated rat aortic rings with gallein did not alter the aortic response to phenylephrine possibly because of opposing effects of gallein on TMEM16A and K+ channels.Inhibition of Niemann Pick C1 protein (NPC1) altered phospholipase C (PLC) expression and phosphatidylinositol 4,5-bisphosphate (PIP2) signalling. Furthermore, whole-cell patch clamp experiments revealed that KCNE1 had minor effects on TMEM16A currents, while LINGO 2 selectively increased TMEM16A currents at positive Vm. Finally, pharmacological targeting of elastogenesis pathways was examined using established modulators. Inhibition of MMP12 with MMP408 directly inhibited TMEM16A currents, indicating an off-target interaction that could influence vascular signalling. Although MMP408 did not acutely alter contractility in mouse aortic rings, its chronic impact on vascular compliance needs further study, particularly in the context of ECM remodelling and ion channel regulation.Conclusion: This study identifies several regulatory pathways for the vascular TMEM16A channel. These findings present potential signalling mechanisms that could be targeted for therapeutic intervention. Such strategies may be relevant for treating diseases associated with altered vascular tone, including hypertension and stroke
Defining recurrent urinary tract infection and reinfection risk: electronic health record study
Get PDFBackground There is limited evidence to support the current standard recurrent urinary tract infection (rUTI) definition of ≥2 UTIs within 6 months or ≥3 within 12 months. Information about reinfection risk after meeting criteria for rUTI may aid decisions on the value of prophylactic approaches.
Aim To estimate the risk of subsequent UTI associated with different rUTI definitions.
Design & setting Electronic health record study using Infections in Oxfordshire Research Database (IORD, 2008-2019) and the Clinical Practice Research Datalink (CPRD, 2009-2019).
Method We identified community-acquired UTIs, separated by 28 days, in non-pregnant women aged 16+years. We created candidate rUTI definitions varying the time window from 3-9 months, and the number of UTIs required to meet the definition from 2-3 episodes. For each definition, we calculated Kaplan-Meier risk estimates of subsequent UTIs within 6 and 12 months after meeting rUTI criteria.
Results Of eligible women with at least one UTI, 18% (15,617/84,809) in IORD and 20% (334,487/1,703,088) in CPRD experienced ≥1 rUTI (current definition). The risk of at least two subsequent UTIs within 12 months after meeting the current rUTI definition rose from 17% (IORD) and 16% (CPRD) to 33% (IORD) and 32% (CPRD) under a rUTI definition of ≥3 UTIs within 6 months. Risk of subsequent UTI also increased with age.
Conclusion Risk estimates of subsequent UTIs after a rUTI vary according to the definition of rUTI adopted. Estimates provided here could support shared decision making around UTI prophylaxis and stratification of populations included in future rUTI research
Development of bifunctional small molecules to induce acetylation by CBP/p300
No full textLysine acetylation is a common, reversible, highly dynamic post-translational modification which occurs at thousands of sites in the human proteome. Lysine acetyltransferases (KATs) catalyse the transfer of an acetyl group onto lysine, while lysine deacetylases (KDACs) catalyse the removal of the modification.Heat shock protein 90 (Hsp90ɑ and Hsp90β) are ATP-dependent molecular chaperones that maintain active conformations of client proteins. Previous studies involving the knockdown or chemical inhibition of KDACs (particularly HDAC6) have shown hyper-acetylation on Hsp90ɑ attenuates chaperone function, while Hsp90ɑ K/Q mutants (acetyl-lysine mimetic) have unique interaction profiles with co-chaperones and client proteins. Induced proximity between an effector enzyme and a target protein with a bifunctional molecule promotes post-translational modification on the target. This concept is the basis of target protein degradation and has recently been shown to be applicable to lysine acetylation.The aim of this thesis was to develop a bifunctional molecule, termed Acetylation Directing Chimera (AcDC), that recruits the acetyl transferases CBP/p300 towards Hsp90 and induces an increase in lysine acetylation on that specific target protein. Starting with the CBP/p300 bromodomain inhibitor, inobrodib, and Hsp90 N-terminal domain inhibitor, BIIB021, we designed and synthesised AcDCs comprising varied linkers (AcDC-1–4). We demonstrated specific AcDC-induced proximity with recombinant proteins in an AlphaScreen based assay and validated a co-operative binding model with isothermal calorimetry (ITC). NanoBRET based assays demonstrated target engagement and induced proximity with full-length proteins in a cellular system. Co-immunoprecipitation of endogenous Hsp90 from showed AcDC-2 forms a stable complex with CBP (but not necessarily p300). We studied whether this induced proximity results in a significant change in lysine acetylation on Hsp90, and determined the observed phenotypic effects were predominantly driven by inhibition of the proteins’ binding domains
Association between 24-hour systolic blood pressure time in target range and mortality
Get PDFBackground: Time in target range (TTR) reflects the proportion of time blood pressure (BP) remains within a defined range, integrating BP variability and control. We examined associations of systolic BP (SBP) TTR during ambulatory BP monitoring (ABPM) with cardiovascular (CV) and all-cause mortality. Methods: Patients from the Spanish ABPM Registry who were receiving antihypertensive medications or who had sustained or masked hypertension without treatment, defined by office BP ≥140/90 mmHg and 24-hour BP ≥130/80 mmHg. TTR was estimated by linear interpolation between consecutive SBP recordings obtained from ABPM and expressed as the proportion of time SBP remained within 120-134 mmHg during daytime and 110-119 mmHg during nighttime, from which 24-hour TTR was derived. Associations with mortality were assessed by Cox regression adjusted for demographic and clinical variables. Results: A total of 48,687 patients (46% women) were analyzed. Over a median follow-up of 9.7 years, 6,502 deaths occurred, including 2,185 CV deaths. Higher 24- hour TTR was associated with lower all-cause mortality (HR 0.83 per 1-SD increment; 95% CI 0.80-0.85). Similarly, higher 24-hour TTR was associated with lower CV mortality (HR 0.80 per 1-SD increment; 95% CI 0.76-0.84). Both associations remained significant after adjusting for mean 24-hour SBP and SBP variability. Conclusions: Higher 24-hour SBP TTR derived from ABPM was independently associated with lower all-cause and CV mortality
Integrating the Microbiome Into Infection Ecology and Evolution in Wild Animals
Get PDFParasites are a ubiquitous force in nature threatening wildlife populations and ecosystems. Interactions between hosts and their parasites are impacted by host‐associated microbiomes, which are essential for host development, physiology and immunity. We synthesise current understanding of the ecological interactions between host microbiomes and parasites, ranging from competitive to facilitative, and explore their potential evolutionary consequences for parasite virulence and transmission in the wild. We highlight recent mechanistic insights that support integrating a microbiome perspective into wildlife parasitology, with examples across diverse animal taxa including amphibians, bats, insects and corals, particularly within the context of climate change. Adopting such a holistic approach can open new avenues whereby host microbial shifts can be used to predict and mitigate infectious diseases in wild populations. Finally, we propose a conceptual framework to guide future research on microbiome‐parasite–host interactions, aiming to better reflect natural ecological complexities and advance both fundamental understanding and conservation applications