While aging is the greatest risk factor for the development of neurodegenerative disease, the role of aging in these diseases is poorly understood. Our previous work has shown that targeting aging pathways can be neuroprotective in animal models of neurodegenerative disease. Based on these findings, we believe that by gaining insight into the aging process that knowledge can be applied to identify…
Likely the strongest predictor of visual feedback is self-motion. In mice, the coupling between movement and visual feedback is learned with first visual experience of the world, and brief perturbations of the coupling result in strong visuomotor mismatch responses in visual cortex that possibly reflect prediction errors. In humans, predictive coding has primarily been studied using oddball…
Women represent about 80% of patients with autoimmune diseases. This may partly result from sex-based differences in T cell receptor (TCR) selection during thymocyte development, potentially influenced by hormones and the lower expression of the Autoimmune Regulator (AIRE) transcription factor in females. To investigate this, we analyzed sex-specific differences in TCR generation and selection. We…
Viral infection begins with attachment to host surface structures such as receptors, pili, or porins. While prior research has focused on structural compatibility and recognition, the role of host physiology, particularly metabolic state, on viral commitment to infection remains underexplored. Here, we measured the adsorption rates ( η ) of five Escherichia coli phages representing various life…
Active vision requires coordinated attentional processing across both foveal and peripheral receptive fields (RFs), yet the underlying neural dynamics and computational mechanisms remain poorly understood. Previous research has predominantly focused on attention in the visual periphery, leaving the role of foveal processing in naturalistic tasks largely unexplored. Here, we recorded neural…
We have previously shown that the slender form of Trypanosoma (T.) brucei is able to infect teneral tsetse flies, develop to the first fly form, which is the procyclic form, and complete the life cycle in the insect vector (Schuster et al., 2021). Further, analysis of the transmission index (TI; defined as the number of salivary gland infections relative to the number of midgut infections)…
The bacterium Listeria monocytogenes can grow in the cytoplasm of infected human cells, but there it relies on specific biosynthetic pathways for intracellular nutrient supply. We previously found that the glycine cleavage system (GCS) is needed for intracellular growth. The GCS decarboxylates glycine for generation of 1C-tetrahydrofolates (1C-THF), folate-dependent one-carbon donors needed for…
When indicating a preference between two options, decision makers are thought to compare and accumulate evidence in an attention-guided process. Little is known about this process’s neural substrates or how visual attention affects the representations of accumulated evidence. We conducted a simultaneous eye-tracking and fMRI experiment in which human subjects gradually learnt about the value of…
Neonatal bacterial meningitis is a leading cause of infant morbidity and mortality, yet the molecular and cellular basis of the leptomeningeal response to infection remains poorly defined. Here, we study a mouse model of neonatal Escherichia coli meningitis, combining conditional gene knockouts, leptomeningeal single-nucleus RNA sequencing, and endothelial cell culture to explore the role of…
When confronted by predators, animals make innate decisions with rapid reaction times—a trait shaped by natural selection to maximize survival. However, rapid reactions are effective only when grounded in accurate judgments and appropriate choices, which often require cognitive control. To address how such choices are shaped, we developed a behavioral paradigm to investigate how threat intensity,…
Polyphenisms–where alternative phenotypes develop from a single genome in response to environmental cues–are not only widespread in nature, but also occur at multiple levels of biological organization, from cells to individuals to societies. Polyphenism is thought to promote phenotypic diversification through the gain, loss, and re-evolution of alternative phenotypes. After the origin of a…
The mitochondrial DNA (mtDNA) can trigger immune responses and directly entrap pathogens, but it is not known to encode active immune factors. The immune system is traditionally thought to be exclusively nuclear-encoded. Here, we report the identification of a host defense peptide (HDP) encoded in the human mitochondrial genome that presumably derives from the primordial proto-mitochondrial…
Mice, like humans, enhance tactile perception through repeated sampling of spatially segregated sensory inputs. In the whisker system, individual whisker identity is preserved along the whisker-brainstem-thalamus-cortex pathway, culminating in distinct cortical domains: barrels and septa. Using simultaneous in vivo recordings from barrel and septal domains, we identify a progressive divergence in…
AMPA receptors (AMPARs) mediate most of the fast excitatory synaptic transmission in the mammalian brain. Their efficacy in responding to presynaptic glutamate release depends on their kinetics, which are determined by AMPARs and their auxiliary subunit composition. α/β-Hydrolase domain-containing 6 (ABHD6) is an AMPAR auxiliary subunit that has been shown to negatively regulate the surface…
Monkeys generalize many visual categorization rules, such as animate versus inanimate, but fail on culturally defined ones, placing their behavior closer to networks trained on images alone than to humans.
This study explores the use of polarized second-harmonic generation (pSHG) to investigate myosin conformation in the relaxed state, differentiating between the actin-available, disordered (ON) state and the energy-conserving, ordered (OFF) state. By shifting the ON/OFF equilibrium using both physical and chemical manipulations, we demonstrate the sensitivity of pSHG in quantifying the ON/OFF ratio…
The Drosophila larva is extensively used as a model organism in neuroethological studies where precise behavioral tracking enables the statistical analysis of individual and population-level behavioral metrics that can inform mathematical models of larval behavior. Here, we propose a hierarchical model architecture comprising three layers to facilitate modular model construction, closed-loop…
Chimerism happens rarely among most mammals, but is common in marmosets and tamarins, a result of fraternal twin or triplet birth patterns in which in utero connected circulatory systems (through which stem cells transit) lead to persistent blood chimerism (12–80%) throughout life. The presence of Y-chromosome DNA sequences in organs of female marmosets has long suggested that chimerism might also…
G-protein-coupled receptor 30 (GPR30) is a bicarbonate receptor that plays a vital role in cellular responses to extracellular pH and ion homeostasis. Despite its significance, the mechanisms by which GPR30 interacts with bicarbonate ions remain elusive. There is no consensus on a drug that targets GPR30, and difficulties in pharmacological analyses have limited biological and drug discovery…
Parkinson’s disease (PD) is commonly associated with the loss of dopaminergic neurons in the substantia nigra , but many other cell types are affected even before neuron loss occurs. Recent studies have linked oligodendrocytes to early stages of PD, though their precise role is still unclear. PINK1 is mutated in familial PD, and through unbiased single-cell sequencing of the entire brain of…
During zygotic genome activation in Drosophila , broad domains of Polycomb-modified chromatin are rapidly established across the genome. Here, we investigate the spatial and temporal dynamics by which Polycomb group (PcG) histone modifications, H3K27me3 and H2Aub, emerge during early embryogenesis. Using ChIP-seq and live imaging of CRISPR-engineered GFP-tagged PcG components, we show that…
The transcription factor CHOP helps cells switch from an emergency stress response to a chronic one, where cells survive but lose some of the functions that define their identity.
Although the causal association between aging and osteoarthritis (OA) has been documented, our understanding of the underlying mechanism remains incomplete. To define the regulatory molecules governing chondrocyte aging, we performed transcriptomic analysis of young and old human chondrocytes from healthy donors. The data predicted that GATA-binding protein 4 (GATA4) may play a key role in…
During sleep, our brain undergoes highly synchronized activity, orchestrated by distinct neural rhythms. Little is known about the associated brain activation during these sleep rhythms, and even less about their functional implications. In this study, we investigated the brain-wide activation underlying human sleep rhythms by employing simultaneous electroencephalography and functional magnetic…
Vector-borne, protist parasites have evolved complex developmental programs to adapt to very distinct host environments. How these important pathogens transition between insect and mammalian stages is only poorly understood. Here, we investigated stage differentiation in Leishmania donovani , a trypanosomatid parasite with constitutive gene transcription, offering a model to study…
Toxin-antidote elements (TAs) are selfish DNA sequences that bias their transmission to the next generation. TAs typically consist of two linked genes: a toxin and an antidote. The toxin kills progeny that do not inherit the TA, while the antidote counteracts the toxin in progeny that inherit the TA. We previously discovered two TAs in Caenorhabditis elegans that follow the canonical TA model of…
Huntington’s disease (HD) is an inherited neurodegenerative disorder characterised by progressive cognitive and motor decline driven by basal ganglia (BG) atrophy. Clinical trials of novel disease-modifying therapies are ongoing, creating a need for sensitive non-invasive imaging biomarkers. Soma and Neurite Density Imaging (SANDI) is a multi-shell diffusion MRI model that estimates intracellular…
Dendritic spine dysfunction may contribute to the etiology and symptom expression of neuropsychiatric disorders. The intimate relationship between spine morphology and function suggests that decoding disease-related abnormalities from spine morphology can aid in developing synapse-targeted interventions. Here, we describe a population analysis of dendritic spine nanostructure applied to the…
Bordetella pertussis , the etiologic agent of whooping cough, remains a serious public health concern despite widespread vaccination. Improved therapeutics and vaccines are urgently needed. Host recognition of bacterial peptidoglycan (PGN), including B. pertussis extracellular PGN fragment tracheal cytotoxin (TCT) shapes the immune response to infection. Peptidoglycan recognition proteins…
Urbanization is a major global driver of biodiversity change, with species responses to urban settings ranging from avoidance to exploitation. To better understand these responses, we conducted a global analysis of urban relative affinity inferred from occurrence data across more than 30,000 animal and plant species. Our synthesis showed a consistent pattern across taxa and biogeographic regions:…
The formation of condensates by the Linker for the Activation of T-cells (LAT) is a key signal gating and amplification step in the T-cell receptor signaling pathway. LAT condensation is challenging to study in-vivo and is therefore often investigated using reconstitution experiments. While these experiments recapitulate key aspects of LAT condensation, they also exhibit some puzzling features.…
Nuclear pore complexes (NPCs) are key gateways to the nucleus and major organizers of genome architecture. Despite their importance, it is still not fully understood how NPCs are formed and degraded. Tools to track specific NPCs over time or under stress could unlock critical insights into these questions. Here, we demonstrate that a brief pulse of expression of a previously developed nanobody…
Mutations in the MECP2 gene cause the severe neurological disorder Rett syndrome. A cluster of frameshift-causing C-terminal deletions (CTDs) removes ~100 amino acids and accounts for approximately 10% of RTT-causing mutations. Their pathogenicity is unexpected because this C-terminal domain is dispensable in mice. Analysis of pathogenic and benign human MECP2 variants reveals that some…
Background: Endometrial cancer (EC) is a common gynecological malignancy with increasing incidence. While several serum biomarkers have been studied for EC, their combined prognostic value remains unclear. This study aimed to evaluate the prognostic significance of preoperative serum CA125, CA19-9, CA72-4, CEA, and AFP levels in EC patients and develop a risk score for predicting survival…
Tailoring malaria control interventions to regional transmission dynamics and behavioural characteristics can optimise them in resource-limited settings.
Suicidal thoughts and behaviors (STB) are among the leading causes of death worldwide. Although previous research has consistently documented elevated risk-taking in individuals with STB and identified mood disturbances as central features of suicidality, the precise cognitive and affective computational mechanisms underlying this increased risky behavior remain poorly understood. Here, 83…
Effective emotional processing, crucial for adaptive behavior, is mediated by the medial prefrontal cortex (mPFC) via connections to the basolateral amygdala (BLA), and nucleus accumbens (NAc), traditionally considered functionally similar in modulating reward and aversion responses. However, the functional specialization of the mPFC→BLA and mPFC→NAc pathways in representing affective states…
Translation failure, in which promising animal study results cannot be reproduced in human trials, is a challenge in biomedical research. Metrics for replication success are widely used to evaluate reproducibility, that is the extent to which the results of a study agree with those of replication studies. The relevance of these metrics in assessing animal-to-human translation success (or failure)…
Parkinson’s disease (PD) is a multisystemic disorder that manifests through motor and non-motor symptoms. Motor dysfunction results from the degeneration of dopamine-producing neurons in the substantia nigra pars compacta. Increasing evidence suggests that synapse dysfunction precedes neuronal loss by years. Still, early synaptic alterations in PD remain poorly understood. Here, we integrate…
Adult stem cells are thought to drive the regenerative potential of the endometrium and contribute to the pathogenesis of endometriosis; however, their identity and defining features remain to be characterized. Here, we used in vivo and in vitro approaches to demonstrate that cells with high aldehyde dehydrogenase 1 activity (ALDH HI cells) were long-lived progenitors in the endometrium with a…
Why does the same oncogenic mutation drive tumor formation in some tissues but not in others? While cancer driver mutations are well documented, their tissue-specific effects remain largely attributed to genetic factors, leaving the biophysical aspects underexplored. Here, we demonstrate that mechanical interactions between newly transformed and wild-type cells are critical in determining survival…
Urination, a vital and conserved process of emptying urine from the urinary bladder in mammals, requires precise coordination between the bladder and external urethral sphincter (EUS) that is tightly controlled by a complex neural network. However, the specific subpopulation of neurons that accounts for such coordination remains unidentified, limiting the development of target-specific therapies…
Virus entry is thought to involve binding a unique receptor for cell attachment and cytosolic entry. For SARS-CoV-2 underlying the COVID-19 pandemic, angiotensin-converting enzyme 2 (ACE2) is widely considered the receptor for cell-surface attachment and subsequent cell entry. Using advanced light microscopy to resolve individual virions and receptors, we found instead that heparan sulfate (HS),…
Hypoxic stress triggers transcriptional signaling mainly through hypoxia-inducible transcription factors (HIFs), which bind hypoxia response elements (HREs) in gene regulatory regions. However, only a small proportion (~1%) of known HREs are occupied by HIFs during hypoxia, suggesting the involvement of additional hypoxia-responsive factors. To address this gap, we utilized MNase-defined cistrome…
The rise of antibiotic resistance has renewed interest in bacteriophages as therapeutic alternatives. However, coevolution of phage and bacteria will naturally give rise to phage-resistant pathogens, complicating phage therapy efforts. A critical bottleneck in the production of phage therapeutics is the discovery of virulent phages against resistant pathogens. Conventional methods for discovery…
Hyperalignment aligns individual brain activity and functional connectivity patterns to a common, high-dimensional model space, resolving idiosyncrasies in functional–anatomical correspondence and revealing shared information encoded in fine-grained spatial patterns. Given that the brain undergoes significant developmental and functional changes over the lifespan, certain features in brain…
Nutrient limitation is a characteristic feature of poorly perfused tumors. In contrast to well-perfused tissues, nutrient deficits in tumors impose metabolic constraints on cancer cells. The metabolic constraints created by the tumor microenvironment can lead to vulnerabilities in cancers. Identifying the metabolic constraints of the tumor microenvironment and the vulnerabilities that arise in…
