Biology subjects

Baldwin, C.

Publications and source records attributed to Baldwin, C..

6 recordsLinked to original sources

bioRxiv2026

β-cell NCK1 is reduced in type 2 diabetes, leading to inefficient β-cell UPR and insulin secretion and revealing sex-specific adaptation during metabolic stress

Type 2 diabetes is characterized by failure of pancreatic {beta} cells to adapt insulin secretion to metabolic demand, due to impaired {beta}-cell function and/or reduced {beta}-cell mass. The unfolded protein response (UPR) is central to this adaptation by maintaining endoplasmic reticulum homeostasis and supporting insulin biosynthesis, secretion, proliferation, and survival. NCK1, is an adaptor protein that regulates diverse cellular processes, including insulin biosynthesis and UPR activation, positioning it at the crossroads of several processes essential for {beta}-cell function. Moreover its silencing is reported to enhance adaptive PERK signaling and {beta}-cell survival in vitro, suggesting that it could represent an important regulator of {beta}-cell adaptation. Here, we explored this potential role for NCK1 using {beta}-cell-specific knockout mice (NCK1{beta}KO) and human islets of both sexes. NCK1 expression was positively regulated by glucose yet reduced in islets from individuals living with type 2 diabetes. Loss of {beta}-cell NCK1 impaired insulin gene expression, insulin content, and glucose-stimulated insulin secretion in vitro, and disrupted UPR activation. In vivo, {beta}-cell NCK1 deletion led to sex-dependent adaptation to maintain glucose homeostasis. Under high-fat/high-sucrose diet, both NCK1{beta}KO male and female mice increased pancreatic insulin content, but only males showed improved insulin secretion associated with islet expansion and {beta}-cell proliferation. Females, in contrast, exhibited impaired insulin secretion despite preserved insulin stores, associated with increased numbers of small islets and altered PERK pathway activation. These findings identify NCK1 as a regulator of {beta}-cell insulin synthesis, secretion, and UPR signaling, and reveal sex-specific adaptive mechanisms to {beta}-cell stress. Reduced NCK1 in islets from people living type 2 diabetes may disrupt {beta}-cell adaptation to metabolic stress and contribute to diabetes.

physiology↗

bioRxiv2026

Ecological axes of skull diversification in a massive 1 vertebrate radiation

Eupercarian spiny-rayed fishes are one of the largest vertebrate radiations, rivaling mammals and occupying nearly every aquatic habitat. We present a densely sampled, time-calibrated phylogenomic framework for Eupercaria, supporting a revised classification, combined with the largest cranial phenomics dataset for fishes. Habitat and trophic ecology make independent, complementary contributions to skull shape. Most species cluster around a conserved generalized architecture, the Percomorph Pile, from which one clade of pufferfishes, anglerfishes, butterflyfishes, and surgeonfishes repeatedly invaded novel morphospace; exceptionally high rates on its deep branches indicate that rapid skull evolution arose early in this clade. Freshwater lineages converge on the ancestral condition, reflecting late arrival into systems occupied by older otophysans, whereas durophages show the greatest disparity and converge on derived forms. Cranial diversity was partitioned among subclades during the Cretaceous and later within them across the Cenozoic, showing that clade-level differences in evolutionary rates and ecological opportunity jointly shaped skull diversification.

evolutionary biology↗

bioRxiv2025

Glucagon-induced PGC-1α4/PPARγ promotes hepatic lipid storage and macrosteatosis in fasting and MASLD

The liver plays a central role in regulating the transition between fasting and feeding states, coordinating glycogen breakdown, gluconeogenesis, fatty acid catabolism, and lipid storage. Disruptions in this balance contribute to metabolic disorders, including Metabolic dysfunction Associated Steatotic Liver Disease (MASLD). Here, we identify a novel biological pathway downstream of glucagon that promotes the hepatic lipid accumulation associated with fasting. Using gain- and loss-of-function in vivo and in vitro models, we found that glucagon induces sustained expression of PGC-14, promoting lipid uptake and storage in hepatocytes by increasing PPAR{gamma} activity. Increased PPAR{gamma}/PGC-14 promotes hepatic Fsp27/Cidec expression, leading to lipid droplet expansion and triglyceride trapping in liver. Activity of the PPARGC1A alternative promoter and PGC-14 expression were higher in livers of patients with MASLD, and PGC-14 expression correlated with macrosteatosis. Consistently, persistent expression of hepatic PGC-14 in mice fed a western diet promoted macrosteatosis, exacerbated oxidative stress and altered hepatic lipid composition to resemble worsening Metabolic dysfunction Associated Steatohepatitis (MASH) in humans. Our findings demonstrate that glucagon-induced hepatic PGC-14/PPAR{gamma} activity facilitates efficient uptake and storage of lipids during fasting, but over-activation of this coordinated metabolic pathway leads to lipid accumulation and worsening of steatosis in MASLD.

physiology↗

bioRxiv2021

The critical role of natural history museums in advancing eDNA for biodiversity studies: a case study with Amazonian fishes

Ichthyological surveys have traditionally been conducted using whole-specimen, capture-based sampling with varied, but conventional fishing gear. Recently, environmental DNA (eDNA) metabarcoding has emerged as a complementary, and possible alternative, approach to whole-specimen methodologies. In the tropics, where much of the diversity remains undescribed, vast reaches continue unexplored, and anthropogenic activities are constant threats; there have been few eDNA attempts for ichthyological inventories. We tested the discriminatory power of eDNA using MiFish primers with existing public reference libraries and compared this with capture-based methods in two distinct ecosystems in the megadiverse Amazon basin. In our study, eDNA provided an accurate snapshot of the fishes at higher taxonomic levels and corroborated its effectiveness to detect specialized fish assemblages. Some flaws in fish metabarcoding studies are routine issues addressed in natural history museums. Thus, by expanding their archives to include eDNA and adopting a series of initiatives linking collection-based research, training and outreach, natural history museums can enable the effective use of eDNA to survey Earths hotspots of biodiversity before taxa go extinct. Our project surveying poorly explored rivers and using DNA vouchered archives to build metabarcoding libraries for Neotropical fishes can serve as a model of this protocol.

ecology↗

bioRxiv2021

Expression of a tetracycline-controlled transactivator (Tet-On/Off system) in beta cells reduces insulin expression and secretion in mice

Controllable genetic manipulation is an indispensable tool in research, greatly advancing our understanding of cell biology and physiology. However, in beta cells, transgene silencing, low inducibility, ectopic expression and off-targets effects on cell function and glucose homeostasis are a persistent challenge. In this study, we investigated whether an inducible, Tet-Off system with beta-cell specific MIP-itTA driven expression of TetO-CreJaw/J could circumvent previous issues of specificity, efficacy and toxicity. Following assessment of tissue-specific gene recombination; beta cell architecture; in vitro and in vivo glucose-stimulated insulin secretion (GSIS); and whole-body glucose homeostasis, we discovered that expression of any tetracycline-controlled transactivator (e.g. itTA, rtTA or tTA) in beta cells significantly reduced Insulin gene expression and decreased insulin content. This translated into lower pancreatic insulin levels and reduced insulin secretion in mice carrying a MIP-itTA transgene, independent of Cre-recombinase expression or doxycycline treatment. These results raise significant concern regarding the use of Tet-On or Tet-Off systems for genome editing in beta cells and emphasize the need to control for effects of transactivator expression. Our study echoes ongoing challenges faced by fundamental researchers focused on beta cells and highlights the need for consistent and careful control of experiments using these research tools.

physiology↗

bioRxiv2019

PGC-1α isoforms coordinate to balance hepatic metabolism and apoptosis in inflammatory environments

Liver is regularly exposed to changing metabolic and inflammatory environments. It must sense and adapt to metabolic need while balancing resources required to protect itself from insult. PGC-1 is a transcriptional coactivator that both coordinates metabolic adaptation to diverse stimuli and protects against inflammation. However, it is not known how PGC-1 integrates extracellular signals to balance metabolic and anti-inflammatory outcomes. PGC-1 exists as multiple, alternatively spliced variants expressed from different promoters. Primary mouse hepatocytes were used to evaluate the role(s) of different PGC-1 proteins in regulating hepatic metabolism and inflammatory signaling downstream of TNF. PGC-11 and PGC-14 were expressed in hepatocytes and expression analysis uncovered shared and isoform-specific roles for these variants linked to metabolism and inflammation. PGC-11 primarily impacted gene programs of nutrient and mitochondrial metabolism, while TNF signaling revealed that PGC-14 influenced several pathways related to innate immunity and cell death. Gain- and loss-of-function models illustrated that PGC-14 uniquely enhanced expression of anti-apoptotic gene programs and attenuated hepatocyte apoptosis in response to TNF or LPS. This was in contrast to PGC-11, which reduced the expression of a wide inflammatory gene network, but did not prevent liver cell death in response to the cytokine. We conclude that PGC-1 variants have distinct, yet complimentary roles in hepatic responses to metabolism and inflammation and identify PGC-14 as an important mitigator of apoptosis.

molecular biology↗