Quantitative mass spectrometry (MS)-based proteomics has become a streamlined technology with a wide range of usage. Many emerging applications, such as single-cell proteomics, spatial proteomics of tissue sections and the profiling of low-abundant posttranslational modifications, require the analysis of minimal sample amounts and are thus constrained by the sensitivity of the workflow. Here, we p...

Identifying the genes that regulate the accurate spatiotemporal diversity of neural progenitor cells (NPCs) helps to understand the mechanisms of human neocortex expansion. In primate brains, an additional intermediate progenitor layer, the outer subventricular zone (oSVZ), facilitates the expansion of the neocortex. Here, we identify an uncharacterized gene, KIAA0408, and show that its expression...

Mechanical loading drives structural and functional improvements in muscle and tendon, protecting against injury at their interface - the myotendinous junction (MTJ) - and within the tendon matrix. However, the early cellular and molecular events that initiate these adaptations in humans remain poorly understood. To investigate this, we applied single nucleus RNA sequencing and in situ hybridizati...

The reconstruction of human evolutionary history has undergone repeated advances, each made possible by methodological innovations. In recent decades, genetic and genomic data played a central role in the reconstruction of major evolutionary events such as the out-of-Africa migration, and genetic simulations of human evolutionary history have come to play a major role in testing more specific hypo...

The budding yeast Saccharomyces cerevisiae plays an integral role in the bioeconomy as a powerful host for industrial bio-manufacturing, driving the production of diverse bio-based products. Achieving optimal product yields requires precise fine-tuning of the expression levels of multiple pathway genes, which often relies on cloning-intensive methods. Here, we present PULSE, an in vivo promoter en...

Background and aims: Paneth cell niche promotes the function of intestinal stem cells (ISCs) during reduced food intake, but how ISC activity can be boosted when availability of resources is simultaneously reduced remains unknown. Methods: Mice were subjected to dietary restriction (DR) and ad libitum (AL) dietary regime. FACS-sorted DR and AL Paneth cells and Lgr5+ stem cells were co-cultured, an...

Understanding how adult stem cells generate neurons is critical for advancing regenerative medicine. However, few in vivo models enable studying how stem cell fates are specified as neurons in an adult body. The planarian Schmidtea mediterranea provides a powerful system for investigating these mechanisms, owing to its abundant adult pluripotent stem cells, termed neoblasts, and its capacity to re...

The human brain unfolds its functional architecture over multiple timescales during childhood and adolescence, yet we know little about how these developmental trajectories vary between individuals. Slow brain signals at different frequencies are thought to support distinct functional processes, but their contribution to shaping large-scale cortical organization across development remains unclear....

Electrical stimulation (ES) is used to treat neuropsychiatric disorders and investigate brain dynamics, yet its effects on human cortical microcircuits remain poorly understood. Cortical organoids provide a unique platform to investigate these mechanisms in isolation from subcortical and long-range cortical inputs. Here we illustrate how cortical organoids respond to ES, identifying the response p...

Background: Long-term persistent symbiotic associations may result in co-speciation and can be inferred if species trees of hosts and symbionts are congruent in topology and divergence times. Co-speciation has been seen to occur relatively frequently in obligate associations, but is less common in parasitic or facultative ones, mainly due to the difference in horizontal transmission rates. The lon...

Variants in GBA1 cause Gaucher disease (GD), a lysosomal storage disorder, and represent the most common genetic risk factor for Parkinson\'s disease (PD). While some GBA1 variants are associated with both GD and PD, several coding mutations, including E326K, specifically confer risk for developing PD. It is established that GD-linked variants in beta-glucocerebrosidase (GCase), the enzyme encoded...

Basement membranes (BM) are thin, nanoporous sheets of specialized extracellular matrix (ECM) that line epithelial tissues. They are dynamic structures that serve multiple key functions, as evidenced by numerous diseases, including cancer progression, that are associated with their alterations. Our understanding of the BM and its communication with adjoining epithelial cells remains highly fragmen...

Recapitulating the liver periportal area in vitro remains a major challenge due to its complex cellular composition and the coordinated development of both ductal and endothelial networks. Most existing bile duct organoid models fail to reproduce tubular extension and multicellular organization. Here, we present an approach that leverages biofunctionalized ECM micro-rods to scaffold the coordinate...

Alzheimer\'s disease (AD), particularly its sporadic form (SAD, 95% AD patients), is strongly associated with the apolipoprotein E4 ApoE4 genotype and characterized by oxidative stress, iron dysregulation, and increased susceptibility to ferroptosis. Lithium, a well-established neuroprotective agent, has shown potential to mitigate several pathological mechanisms in AD, including ferroptosis. This...

The circadian clock orchestrates adipocyte development and lipid remodeling, with its disruption leading to the development of obesity and insulin resistance. Here we demonstrate that the flavonoid compound naringenin displays clock modulatory activity via ROR that suppresses adipocyte lipid storage while promoting browning. In adipogenic progenitors, naringenin activates ROR with induction of clo...

PXDesign achieves nanomolar binder hit rates of 20-73% across five of six diverse protein targets, surpassing prior methods such as AlphaProteo. This experimental success rate is enabled by advances in both binder generation and filtering. We develop both a diffusion-based generative model (PXDesign-d) and a hallucination-based approach (PXDesign-h), each showing strong in silico performance that ...

Animal models can provide valuable insights into the mechanisms underlying stress-related disorders. Yet, significant translational challenges persist, as laboratory behavioral assays are often reductionistic, with limited attention to ethologically relevant behavioral diversity. Recent advances in high-throughput pose-estimation tools and computational ethology methods are addressing this limitat...

Maintaining neuronal inputs and outputs within the physiological range relies on the ability of neurons to update their responsiveness to inputs dependent on changing activity levels. Termed homeostatic plasticity, the mechanisms that neurons employ to control their responsiveness are varied, and proposed to include structural changes to a key neuronal structure, the axon initial segment (AIS). As...

Inference of interspecific gene flow using genomic data is important to reliable reconstruction of species phylogenies and to our understanding of the speciation process. Gene flow is harder to detect if it involves sister lineages than nonsisters; for example, most heuristic methods based on data summaries are unable to infer gene flow between sisters. Likelihood-based methods can identify introg...

Heterozygous mutations in the Glucocerebrosidase gene (GBA1), encoding the lysosomal hydrolase Beta-glucocerebrosidase (GCase), are a genetic risk factor for Parkinsons disease (PD). To explore the pathophysiological consequences of these mutations, we have used fibroblasts and dopaminergic neurons generated from induced pluripotent stem cells (iPSCs) derived from patients with GBA1-related PD. GC...