Isothiocyanates have been the focus of scientific research for over fifty years. Interest in these phytochemicals intensified following the discovery of sulforaphane, an isothiocyanate found in broccoli. Early studies on sulforaphane laid the groundwork for exploring numerous other isothiocyanates, which have since been recognized as potent inducers of mammalian cytoprotective responses via the KEAP1/NRF2 pathway, alongside modulation of additional key signaling pathways. In addition to these advances in understanding the molecular regulation of this pathway and its vital role in defending against electrophilic and oxidative stress, there has been increasing interest in translating these findings into strategies to enhance human health and treat disease. This review highlights preclinical studies demonstrating the beneficial effects of isothiocyanates in activating NRF2 across various pathological conditions, including cancer, cardiovascular diseases, diabetes, liver and kidney disorders, and neurological diseases. It also discusses intervention studies related to their safety, pharmacokinetic profiles, and clinical trials.

Cytochrome P450 enzymes (CYPs) are central to metabolism and stress adaptation. In Caenorhabditis elegans, the CYP-13 family performs diverse and conserved functions beyond xenobiotic detoxification. cyp-13 links lifespan regulation to the APP ortholog apl-1 and the heterochronic factor lin-14, integrating with DAF-16/FOXO, HSF-1, and DAF-12 pathways. In apoptosis, cyp-13 contributes to the degradosome complex with CPS-6/EndoG and WAH-1, facilitating DNA degradation. Several isoforms are inducible by aflatoxin B1 and PCB1254, underscoring roles in toxicant metabolism. Notably, cyp-13A12 regulates behavioral responses to reoxygenation via the EGL-9-HIF-1-PUFA-eicosanoid pathway, paralleling mammalian ischemia-reperfusion responses. Epigenetic regulation adds another layer, as BRCA1/BARD1 homologs brc-1 and brd-1 repress distinct subsets of cyp-13A genes through H2A ubiquitylation. Collectively, CYP-13 emerges as a multifunctional hub linking developmental, apoptotic, metabolic, stress, and chromatin-level processes, with clear parallels to human CYPs, highlighting its translational relevance to aging, cancer, and toxicology.

ABSTRACT Background The Himalayas emerged from a semi‐aquatic landscape into the tallest mountain system on Earth, driving major environmental changes. Yet, how mammalian communities responded to this transition remains poorly understood. Addressing this gap is critical for understanding the resilience of mammalian assemblages under ongoing environmental changes. Aim We summarize the history of the Himalayas, highlighting key landscape and environmental transformations, and use mammals to exemplify the Himalayas' role in community assembly. Findings Our review highlights that initial uplift due to the northward movement of the Indian Plate towards the Eurasian Plate resulted in a shallow sea and surrounding semi‐aquatic environments, supporting earliest ancestors of modern cetaceans. As uplift progressed, it served as a biological corridor between two plates, facilitating mammalian dispersal in both directions, with subsequent radiations. Continued uplift gave rise to differential climate zones, establishing diverse mammalian communities across elevational gradients. With further increase, it transitioned into a significant biogeographic barrier, driving desertification to the north, intensifying monsoon systems in the south, and shaping river systems and valleys, all impacting the biogeographic complexity of the region. During Quaternary glaciations, river valleys acted as climatic refugia, enabling the persistence of many mammalian lineages. Throughout, precipitation remained higher in the Eastern Himalayas than in the west, leading to additional longitudinal variation in mammalian assemblages. Today, Himalayan mammals span multiple biogeographic realms, with strongest mammalian community similarities to Southeast Asia. Future Direction Much of the material presented reflects evidence from the fossil record, spatial mapping, and recent but sparse genomic work on megafauna, which alone cannot fully explain mammalian responses to changes in the Himalayas. Modern genomic studies and broader sampling, mainly of highly diverse but underrepresented small taxa (rodents, bats, and shrews) are needed to update species origins, diversification, and community assembly to advance knowledge on Himalayan biodiversity dynamics.

Assessing systemic effects of Bothrops jararaca venom in the lungs in a mouse model by label-free proteomics using DDA and DIA.

Dynamic reorganization of the transcription machinery within nuclear membrane-less compartments is an emergent feature of mammalian stress response, associated with critical cellular decisions. However, mechanisms governing the subcellular formation of these stress-induced condensates and their role in transcription regulation remain poorly understood. Here, we find that heat shock factor 1 (HSF1), transcriptional mediator of protein and cellular homeostasis, forms condensates during various adverse conditions, but these assemblies exhibit context-dependent divergent transcriptional outcomes. During heat shock, HSF1 orchestrates the coordinated assembly of transcription hubs via canonical activation, including post-translational modifications (PTMs), trimerization, and DNA binding. While HSF1's disordered regions restrict condensate formation in unstressed situations, they promote stress-induced condensate maturation to transcriptionally active states. Strikingly, HSF1 condensates that form during other environmental and chemotherapeutic stresses stall at distinct stages of hub formation, assemble independent of PTMs, and exhibit reduced sub-condensate dynamics. These aspects culminate in attenuated genomic occupancy and transcriptional output at HSF1-associated loci, consistent with functional impairment of HSF1 and the transcription machinery via sequestration. Our work suggests that stress-induced transcription factor condensates drive conserved responses during physiological perturbations, but can be inactivated during pathological insults, rationalizing HSF1 and transcriptional dysfunction across degenerative diseases and toxic exposures.

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory condition characterized by increasing mortality and morbidity. Current animal models have certain limitations in elucidating the pathophysiology and underlying mechanisms of COPD, which hinder effective treatments. There is an urgent need to identify an informative model that can dissect the COPD mechanisms and screen therapeutic drugs. The Drosophila melanogaster is regarded as an ideal in vivo model for studying COPD due to its ability to present representative pathological hallmarks within a short time frame, its visualized tracheal morphology, and well-established genetic tools. In this study, we explore the feasibility of using Drosophila as a novel invertebrate model for investigating COPD. We summarize the conserved features between flies and mammals in response to airway inflammation, including airway structures, pathophysiological changes, immune responses, molecular mechanisms, and modeling approaches. Additionally, we outline potential translational applications, including high-throughput identification, drug discovery, and a prioritized preclinical platform. We also propose integrating insights from Drosophila with mammalian models and clinical COPD endotypes.

Myocardial injuries lead to cardiomyocyte loss and heart failure. Endogenous glucocorticoids, via the glucocorticoid receptor (GR), limit cardiomyocyte regeneration. Here we show that glucocorticoids suppress mammalian (murine) cardiomyocyte proliferative response to regenerative growth factors and cytokines. GR activation in neonatal cardiomyocytes upregulated MAPK-ERK inhibitors ERRFI1 and DUSP1. Using neuregulin 1 as a model, we demonstrated that glucocorticoids inhibit growth-factor-induced ERK activation, nuclear translocation and transcriptional output. Errfi1 and Dusp1 knockdown restored growth-factor-induced proliferation of glucocorticoid-exposed cardiomyocytes. Cardiac expression of DUSP1 and ERRFI1 increased postnatally, coinciding with regenerative capacity decline. In juvenile and adult cardiomyocytes, regenerative growth factors failed to induce the MAPK-ERK pathway and proliferation; however, DUSP1 inhibition restored these responses. GR antagonism enhanced growth-factor-induced cardiomyocyte protection, proliferation and cardiac function after adult myocardial injury. These findings reveal the emergence of a postnatal systemic brake on cardiomyocyte proliferative response to growth factors and support GR inhibition as a strategy to enhance growth-factor-based regenerative therapies.

Special issue: Mammalian adaptations and responses to high elevation in the face of climate change

Mammalian response to FSC forest certification in production plantations

Glucocorticoid-producing cells of the adrenal cortex (i.e. zona fasciculata, zF) constitute the critical effectors of the hypothalamic-pituitary-adrenal axis, mediating the mammalian stress response. With glucocorticoids being essential for life, zF dysfunction perturbs multiple organs that participate in optimizing cardiometabolic fitness. The zF forms a dynamic and heterogenous cell population endowed with the capacity to remodel through the engagement of both proliferative and differentiation programs that enable the adrenal to adapt and respond to diverse stressors. However, the mechanisms that sustain such differential responsiveness remain poorly understood. In this study, we resolve the transcriptome of the steroidogenic lineage by scRNA-seq using Sf1-Crehigh; RosamT/mG reporter mice. We identify HHEX, a homeodomain protein, as the most enriched transcription factor in glucocorticoid-producing cells. We utilize genetic mouse models to demonstrate that Hhex deletion causes glucocorticoid deficiency in male animals. Molecularly, we demonstrate that HHEX is an androgen receptor (AR) target gene, shaping the sexual dimorphism of the adrenal gland by repressing the female transcriptional program at puberty, while also maintaining zF cholesterol ester content by protecting lipid droplets from androgen-induced-lipophagy. Moreover, our study reveals that, in both sexes, HHEX is crucial for maintaining the identity of the innermost adrenocortical cell subpopulation. Specifically, loss of HHEX impairs the expression of Abcb1b (P-glycoprotein/MDR1), an efflux pump regulating steroid export and cellular levels of xenobiotics. Together, these data demonstrate that HHEX serves as a multi-functional regulator of post-natal adrenal maturation that is potentiated by androgens.

Trait-based ecological indices for evaluating mammalian species responses to habitat fragmentation

The Golgi stress response is a homeostatic mechanism that augments Golgi function when Golgi function becomes insufficient (Golgi stress). Glycosylation of the core proteins of proteoglycans is one of the important functions of the Golgi. If the production of core proteins is increased and the amount of glycosylation enzymes for proteoglycans becomes insufficient (PG-type Golgi stress), the proteoglycan pathway of the Golgi stress response is activated, resulting in the transcriptional induction of glycosylation enzymes, including NDST2, HS6ST1 and GLCE. The transcriptional induction of these glycosylation enzymes is regulated by the enhancer element, PGSE-A; however, transcription factors that induce transcription from PGSE-A have not yet been identified. We herein identified KLF2 and KLF4 as transcription factors that directly bind to PGSE-A, and found that overexpression of KLF2 and KLF4 augments transcriptional induction from PGSE-A during PG-type Golgi stress, whereas their dominant negative mutants suppress the transcriptional induction. Moreover, expression of KLF2 and KLF4 was up-regulated in response to PG-type Golgi stress. Transcriptional induction of human KLF4 gene is regulated by PGSE-A, while that of human KLF2 gene is mainly controlled by a novel enhancer called PGSE-C. These results suggest that KLF2 and KLF4 are important regulators of the proteoglycan pathway of the mammalian Golgi stress response.Key words: Golgi stress, proteoglycan, ER stress, organelle zone, organelle autoregulation, KLF2, KLF4, xyloside.

ABSTRACTUrbanization and human population growth have significantly increased the presence of anthropogenic materials in natural environments, prompting growing interest in how wildlife may be adapting to these changes. One such behavioral response is the incorporation of anthropogenic materials into animal nests, a phenomenon that has raised concerns due to its potential harmful effects, such as entanglement or ingestion. While this behavior has been documented widely in birds, it remains underreported in other taxa, partly due to the difficulty of locating nests. In this study, we describe multiple instances of anthropogenic materials (including plastic) being incorporated into the hibernation nests of European hedgehogs, Erinaceus europaeus. Four nests were dissected, of which two nests contained anthropogenic materials, including a plastic bag, foil and expanded polystyrene. These findings suggest that hedgehogs may opportunistically use available anthropogenic materials in nest construction, potentially as a response to urban environments. Our findings help broaden the understanding of mammalian responses to urbanization and emphasize the need to investigate whether the incorporation of these materials is likely to be harmful or adaptive to hedgehogs and for mammals generally.

Abstract Description The general paradigm of mammalian antiviral response involves the detection of viral pathogen-associated molecular patterns (PAMPs) by host Pattern Recognition Receptors (PRRs), which activate Interferon Regulatory Factors (especially IRF3 and IRF7). These IRFs trigger Interferon (IFN) transcription which induces a battery of antiviral genes, collectively called Interferon Stimulated Genes (ISGs). Type-I IFN expression, primarily driven by IRF3, is critical to mounting an antiviral response. However, tight regulation of the IFN-β response is essential within cells, as unchecked IFN-β expression can lead to immune pathologies. One mechanism of negative regulation of the IFN-β response is the degradation of IRF3. Our study aims to explore IRF3’s role in IFN induction and how its degradation modulates the IFN-β response to maintain immune homeostasis. We found that IRF3 undergoes proteasomal and autophagic degradation, partially dependent on IFN. Additionally, we investigated the role of ubiquitination on IRF3 stability and function, discovering that K33-linked ubiquitination stabilizes IRF3 but inhibits its transcriptional activity by preventing its nuclear translocation. Using a genome-wide CRISPR knockout screen and a proteomics screen, we identified cellular factors that regulate IRF3 stability in mammalian systems. Overall, this study reveals new fundamental knowledge about mammalian antiviral immunity and will facilitate the development of novel antiviral strategies. Funding Sources Supported by Prime Minister’s Research Fellowship (PMRF); INFOSYS Young Investigator Award for Research. Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)

ABSTRACTVenomous snakes owe their evolutionary success in part to the effectiveness of their strike. The success of a strike depends on reaching the prey quickly before it startles and has the chance to escape. Here, we present the first ever large-scale experiment comparing strike performance across 36 venomous snake species from three families (31 Viperidae, 4 Elapidae and 1 Colubridae). We used two high-speed video cameras (1000 frames s−1) to capture strikes at a ballistics gel prey and tracked the strike trajectory in three dimensions. The 3D coordinates were used to measure strike kinematics and performance. Kinematic performance was compared within Viperidae across predation style, diel activity pattern, diet, habitat type, temperature and first jaw contact with prey. Kinematic variables (peak velocity, peak acceleration, gape angle, start distance, contact angle, head size) varied by the part of the jaw that first contacts the prey. Start distance to prey also varied by peak acceleration, jaw gape angle and contact angle with prey. Vipers typically reached higher peak velocities than elapids; however, some elapids such as Acanthophis rugosus reached equally high velocities. Peak velocities were found to be higher in ambush predators and in snakes that prey on mammalian prey. Prey was often reached within 100 ms, which falls within the mammalian startle response. Behavioural differences across the three families were also observed: Viperidae performed a smooth strike that was often followed by fang repositioning; Elapidae reached their prey quickly, bit and repeatedly squeezed prey with their jaws; and Colubridae used their rear-positioned fangs by alternate jaw movement to damage the prey's surface.

Pre-N and C-terminal extension regions of Arabidopsis HSP90.7 regulate the chaperone activity and ER stress response

Hypoxic ventilatory decline (HVD) is part of the mammalian ventilatory response to hypoxia and is characterized by a decline in ventilation that begins after 3-5 min of sustained, moderate hypoxia. Exercise is a powerful ventilatory stimulus that increases ventilation and chemosensor sensitivity. The extent to which these opposing ventilatory stimuli interact is not fully characterized. We compared the ventilatory response to moderate exercise during two conditions: during pre-established HVD and shortly after the onset of hypoxia but before the establishment of HVD. Eleven (n = 6 males) young, healthy participants completed three testing visits. Day 1 was a maximal exercise test and days 2 and 3 were randomized experimental visits separated by > 48 h. Each experimental visit began with a 5 min normoxic baseline followed by 15 min of rest and 15 min of exercise at 30% of peak power. The experimental visits differed in that, during the "sustained hypoxia" protocol (oxyhemoglobin saturation ∼80%), hypoxia began at the start of rest, whereas in the "acute hypoxia" protocol, hypoxia began 1 min before exercise. At the onset of exercise, ventilation was significantly lower in the sustained hypoxia protocol (-5.1 L·min-1), suggesting a persistent blunting of ventilation. At end exercise, ventilation was not different between protocols (51.2 ± 11.6 vs. 50.5 ± 7.3 L·min-1, for sustained and acute hypoxia, respectively). The percent decline in ventilation (HVD) was greater during the sustained hypoxia (-23 ± 13 vs. -14 ± 9%, P = 0.04). We conclude that HVD persists when acute exercise is imposed on sustained isocapnic hypoxia.NEW & NOTEWORTHY Imposing moderate-intensity exercise on acute, sustained isocapnic hypoxia in close temporal proximity showed evidence of hypoxic ventilatory decline in the first 15 min of exercise. The percent decline in ventilation during exercise was smaller than the hypoxic ventilatory decline at rest, indicating a blunting of the ventilatory decline when occurring together with exercise. Duration of pre-exercise hypoxic exposure should be considered when interpreting hypoxic exercise ventilation.

Antibody responses to the influenza virus hemagglutinin (HA) stem, a major target for broadly protective vaccine development, have been extensively characterized in humans. However, they remain largely elusive in other natural influenza hosts, including pigs, which are considered intermediate hosts for the emergence of pandemic strains. By leveraging single-cell variable, diversity, and joining (VDJ) sequencing, this study identified 25 porcine antibodies to the HA stem, including two cross-group bnAbs, 14-8 and 15-1, from vaccinated specific-pathogen-free pigs and unvaccinated domestic pigs. Cryogenic electron microscopy analysis showed that 14-8 targeted the well-characterized central stem epitope, whereas 15-1 bound to a linear epitope spanning the HA1/HA2 junction. Additionally, while some porcine and human bnAbs targeted the central stem epitope via convergent molecular signatures, our results revealed a pig-specific recurring binding motif. Overall, our findings provide important insights into the commonalities and uniqueness of antibody responses between different species, which have significant implications for vaccine development for nonhuman animals.

Animal venoms comprise many toxins that work in concert to break apart the robust homeostatic systems of prey organisms. Conversely, prey organisms actively antagonize each step of envenoming, which displays a complex kinetics involving important changes at molecular, cell, tissue, and organism levels. In this study we explored the mammalian host response to envenoming using proteomics/N-terminomics and phosphoproteomics approaches to evaluate the in vivo effects of Bothrops jararaca venom in the mouse kidney after injection in the thigh muscle (1.6 mg/kg), mimicking a snakebite, and the impact of anti-Bothrops antivenom injected 1 h later (1.6 mg/kg; i.v. tail). For proteomics/N-terminomics, proteins were TMT-labeled, to allow for specific (tryptic) and semi-specific searches of MS/MS spectra to assess both global proteome and degradome. We quantified >7000 proteins, and prominent changes were observed in the kidney tissue, where protein differential abundance was identified after 3, 6, and 24 h, including markers of acute-phase response and injury. Likewise, the N-terminomic analysis revealed a significant impact of venom progressing from 3 h to 24 h, resulting in dysregulated proteolysis and indicating the activation of host proteases. The protease fingerprint matched legumain and cathepsin profiles. Venom toxins also promoted alteration in the dynamics of phosphorylation, with the activation of kinases. Under the conditions tested, antivenom administration (i) did not reduce the number of differentially abundant proteins and inflammation markers, (ii) partially attenuated the generation of proteolytic products in envenomed animals, and (iii) directly perturbed the phosphorylation signaling in control animals. Taken together, our findings underscore for the first time the mouse renal response to a protease-rich venom, revealed by the dynamic alteration in protein abundance, protease targets, and phosphorylation events, providing new facets of snake venom and antivenom systemic effects, which are important for the development of new therapies.

The paleoenvironments and ecosystems of northern China during the Miocene (ca. 23-5.3Ma) are complex topics, especially concerning the uplift of the Tibetan Plateau on the surrounding areas and the ecological adaptations of mammals as a consequence. Our data integrated stable carbon and oxygen isotope analysis, cenograms, and hypsodonty of herbivorous mammals. The results reveal open, arid, savanna-like habitats in the Junggar Basin during the late early Miocene (ca. 20.4-15.9Ma). These habitats subsequently spread to northern China by the late Miocene (ca. 11.6-5.3Ma), driving mammalian adaptation. Large herbivores, particularly proboscideans and rhinocerotids, exhibited strong adaptations to these new open environments, while smaller taxa maintained a preference for more closed, forested habitats. Additionally, during global climate changes, biodiversity declined, indicating increased ecological pressure. Despite these changes, faunal diets in the Junggar Basin remained consistent. Our findings contribute to understanding mid-Miocene paleoecology in northern China and the adaptive strategies of mammals in response to environmental changes.