Mammalian Response Research Articles

Mediation of mammalian olfactory response by presence of odor-evoked potassium current.

It is well understood that odorants interact with specialized G-protein coupled receptors embedded in the ciliary membrane of olfactory sensory neurons (OSN) which initiates a voltage-generating intracellular cascade of signal transduction events that can be recorded at the epithelial level as an electroolfactogram (EOG). While the depolarizing excitatory pathway in vertebrates involving cyclic adenosine monophosphate (cAMP)-induced Na+/Ca2+ influx and calcium-induced Cl- efflux is well established, there is evidence of potassium-associated inhibitory currents that correspond with cellular activation. While several Ca2+-dependent feedback mechanisms contribute to cellular deactivation which have been commonly attributed to these inhibitory currents, the frequently observed positive ionic conductance prior to excitatory depolarization have led many to suggest an additional earlier inhibitory mechanism at the receptor level that may be independent of downstream calcium influx. Due to conflicting conclusions, the role and mechanism behind Ca2+-independent inhibitory currents in olfactory cells is not fully understood. We investigated the functional and temporal involvement of potassium channels in odor transduction by comparing electroolfactogram (EOG) recordings in rat olfactory epithelia following ion channel inhibition and targeted activation of downstream components with or without potassium-blocking. Several K+-channel blocking agents (4-Aminopyridine, charybdotoxin, & iberiotoxin) demonstrated a diminished pre-action potential positive current that corresponded with reduced excitatory response to odor stimulation that was recovered when blockers were removed. We further assessed EOG responses in the absence of odor or with odor response enhancing zinc nanoparticles. Chemically eliciting membrane excitation in the absence of odor stimulation with a phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX), in combination with K+-channel inhibition, further indicated potassium channel activation precedes excitatory events and is independent of cAMP-induced calcium influx. These results support previous findings of odor-activated inhibitory potassium currents that may play a functional role in subsequent G-protein activity.

Adult auditory brain responses to nestling begging calls in seasonal songbirds: an fMRI study in non-parenting male and female starlings (Sturnus vulgaris).

The present study aims to investigate whether begging calls elicit specific auditory responses in non-parenting birds, whether these responses are influenced by the hormonal status of the bird, and whether they reflect biparental care for offspring in the European starling (Sturnus vulgaris). An fMRI experiment was conducted to expose non-parenting male and female European starlings to recordings of conspecific nestling begging calls during both artificially induced breeding and non-breeding seasons. This response was compared with their reaction to conspecific individual warbling song motifs and artificial pure tones, serving as social species-specific and artificial control stimuli, respectively. Our findings reveal that begging calls evoke a response in non-parenting male and female starlings, with significantly higher responsiveness observed in the right Field L and the Caudomedial Nidopallium (NCM), regardless of season or sex. Moreover, a significant seasonal variation in auditory brain responses was elicited in both sexes exclusively by begging calls, not by the applied control stimuli, within a ventral midsagittal region of NCM. This heightened response to begging calls, even in non-parenting birds, in the right primary auditory system (Field L), and the photoperiod induced hormonal neuromodulation of auditory responses to offspring's begging calls in the secondary auditory system (NCM), bears resemblance to mammalian responses to hunger calls. This suggests a convergent evolution aimed at facilitating swift adult responses to such calls crucial for offspring survival.

RNA Surveillance Factor SMG5 Is Essential for Mouse Embryonic Stem Cell Differentiation.

Nonsense-mediated mRNA decay (NMD) is a highly conserved post-transcriptional gene expression regulatory mechanism in eukaryotic cells. NMD eliminates aberrant mRNAs with premature termination codons to surveil transcriptome integrity. Furthermore, NMD fine-tunes gene expression by destabilizing RNAs with specific NMD features. Thus, by controlling the quality and quantity of the transcriptome, NMD plays a vital role in mammalian development, stress response, and tumorigenesis. Deficiencies of NMD factors result in early embryonic lethality, while the underlying mechanisms are poorly understood. SMG5 is a key NMD factor. In this study, we generated an Smg5 conditional knockout mouse model and found that Smg5-null results in early embryonic lethality before E13.5. Furthermore, we produced multiple lines of Smg5 knockout mouse embryonic stem cells (mESCs) and found that the deletion of Smg5 in mESCs does not compromise cell viability. Smg5-null delays differentiation of mESCs. Mechanistically, our study reveals that the c-MYC protein, but not c-Myc mRNA, is upregulated in SMG5-deficient mESCs. The overproduction of c-MYC protein could be caused by enhanced protein synthesis upon SMG5 loss. Furthermore, SMG5-null results in dysregulation of alternative splicing on multiple stem cell differentiation regulators. Overall, our findings underscore the importance of SMG5-NMD in regulating mESC cell-state transition.

In-depth transcriptome profiling of Cherry Valley duck lungs exposed to chronic heat stress.

Amidst rising global temperatures, chronic heat stress (CHS) is increasingly problematic for the poultry industry. While mammalian CHS responses are well-studied, avian-specific research is lacking. This study uses in-depth transcriptome sequencing to evaluate the pulmonary response of Cherry Valley ducks to CHS at ambient temperatures of 20°C and a heat-stressed 29°C. We detailed the CHS-induced gene expression changes, encompassing mRNAs, lncRNAs, and miRNAs. Through protein-protein interaction network analysis, we identified central genes involved in the heat stress response-TLR7, IGF1, MAP3K1, CIITA, LCP2, PRKCB, and PLCB2. Subsequent functional enrichment analysis of the differentially expressed genes and RNA targets revealed significant engagement in immune responses and regulatory processes. KEGG pathway analysis underscored crucial immune pathways, specifically those related to intestinal IgA production and Toll-like receptor signaling, as well as Salmonella infection and calcium signaling pathways. Importantly, we determined six miRNAs-miR-146, miR-217, miR-29a-3p, miR-10926, miR-146b-5p, and miR-17-1-3p-as potential key regulators within the ceRNA network. These findings enhance our comprehension of the physiological adaptation of ducks to CHS and may provide a foundation for developing strategies to improve duck production under thermal stress.

Impacts of anthropogenic habitat modification on mammalian diversity in the Mau Forest Complex, Kenya

Habitat destruction is a major driver of biodiversity loss, especially in the tropics. We investigated changes in the diversity and occupancy of forest-dwelling mammals in response to habitat loss, alteration, and degradation at the Mau Forest Complex (MFC), southwestern Kenya. Using a systematic camera trapping grid, we estimated patterns of mammalian diversity, occupancy of small carnivores, and detection rates of functional mammalian groups across three habitat types (primary forests, secondary forests, and cultivated habitats). Between March 2019 and October 2021, 246 camera traps were deployed across 181 locations representing 5509 sampling days, resulting in 47,345 images of 52 mammalian species in nine mammalian orders. Alpha diversity differed among treatments, with primary forests having the highest diversity, and cultivated habitats the lowest, though results were not statistically significant. Beta diversity differed significantly among treatments, indicating differences in community composition as well as species richness. Overall occupancy for small carnivores was highest in primary forests and lowest in cultivated habitats, with some species specializing in primary forests while others were able to occupy more degraded habitats. Among functional groups, detection rates only differed significantly for large rodents, primates, and ungulates. Our results indicate that although functional groups and species may respond differently to habitat loss and alteration at the MFC, overall species diversity of specialist mammals was highest in the less-disturbed primary forests. Specialist, forest-dependent species are likely most affected by human activities, making them especially vulnerable to habitat loss at the MFC.

Transcriptional upregulation of the myo-inositol biosynthesis pathway is enhanced by NFAT5 in hyperosmotically stressed tilapia cells.

Euryhaline fish experience variable osmotic environments requiring physiological adjustments to tolerate elevated salinity. Mozambique tilapia (Oreochromis mossambicus) possess one of the highest salinity tolerance limits of any fish. In tilapia and other euryhaline fish species, the myo-inositol biosynthesis (MIB) pathway enzymes, myo-inositol phosphate synthase (MIPS) and inositol monophosphatase 1 (IMPA1.1), are among the most upregulated mRNAs and proteins indicating the high importance of this pathway for hyperosmotic (HO) stress tolerance. These abundance changes must be precluded by HO perception and signaling mechanism activation to regulate the expression of MIPS and IMPA1.1 genes. In previous work using a O. mossambicus cell line (OmB), a reoccurring osmosensitive enhancer element (OSRE1) in both MIPS and IMPA1.1 was shown to transcriptionally upregulate these enzymes in response to HO stress. The OSRE1 core consensus (5'-GGAAA-3') matches the core binding sequence of the predominant mammalian HO response transcription factor, nuclear factor of activated T-cells (NFAT5). HO-challenged OmB cells showed an increase in NFAT5 mRNA suggesting NFAT5 may contribute to MIB pathway regulation in euryhaline fish. Ectopic expression of wild-type NFAT5 induced an IMPA1.1 promoter-driven reporter by 5.1-fold (P < 0.01). Moreover, expression of dominant negative NFAT5 in HO media resulted in a 47% suppression of the reporter signal (P < 0.005). Furthermore, reductions of IMPA1.1 (37-49%) and MIPS (6-37%) mRNA abundance were observed in HO-challenged NFAT5 knockout cells relative to control cells. Collectively, these multiple lines of experimental evidence establish NFAT5 as a tilapia transcription factor contributing to HO-induced activation of the MIB pathway.NEW & NOTEWORTHY In our study, we use a multi-pronged synthetic biology approach to demonstrate that the fish homolog of the predominant mammalian osmotic stress transcription factor nuclear factor of activated T-cells (NFAT5) also contributes to the activation of hyperosmolality inducible genes in cells of extremely euryhaline fish. However, in addition to NFAT5 the presence of other strong osmotically inducible signaling mechanisms is required for full activation of osmoregulated tilapia genes.

Forest type modulates mammalian responses to megafires

Although considered an evolutionary force responsible for shaping ecosystems and biodiversity, fires’ natural cycle is being altered by human activities, increasing the odds of destructive megafire events. Here, we show that forest type modulates the responses of terrestrial mammals, from species to assemblage level, to a catastrophic megafire in the Brazilian Pantanal. We unraveled that mammalian richness was higher 1 year after fire passage compared to a pre-fire condition, which can be attributed to habitat modification caused by wildfires, attracting herbivores and open-area tolerant species. We observed changes in assemblage composition between burned/unburned sites, but no difference in mammalian richness or relative abundance. However, by partitioning the effects of burned area proportion per forest type (monospecific vs. polyspecific), we detected differential responses of mammals at several levels of organization, with pronounced declines in species richness and relative abundance in monospecific forests. Eighty-six percent of the species presented moderate to strong negative effects on their relative abundance, with an overall strong negative effect for the entire assemblage. Wildfires are predicted to be more frequent with climate and land use change, and if events analogous to Pantanal-2020 become recurrent, they might trigger regional beta diversity change, benefitting open-area tolerant species.

Poly (ADP-ribose) polymerase 1 promotes HuR/ELAVL1 cytoplasmic localization and inflammatory gene expression by regulating p38 MAPK activity

Post-transcriptional regulation of cytokine/chemokine mRNA turnover is critical for immune processes and contributes to the mammalian cellular response to diverse inflammatory stimuli. The ubiquitous RNA-binding protein human antigen R (HuR) is an integral regulator of inflammation-associated mRNA fate. HuR function is regulated by various post-translational modifications that alter its subcellular localization and ability to stabilize target mRNAs. Both poly (ADP-ribose) polymerase 1 (PARP1) and p38 mitogen-activated protein kinases (MAPKs) have been reported to regulate the biological function of HuR, but their specific regulatory and crosstalk mechanisms remain unclear. In this study, we show that PARP1 acts via p38 to synergistically promote cytoplasmic accumulation of HuR and stabilization of inflammation-associated mRNAs in cells under inflammatory conditions. Specifically, p38 binds to auto-poly ADP-ribosylated (PARylated) PARP1 resulting in the covalent PARylation of p38 by PARP1, thereby promoting the retention and activity of p38 in the nucleus. In addition, PARylation of HuR facilitates the phosphorylation of HuR at the serine 197 site mediated by p38, which then increases the translocation of HuR to the cytoplasm, ultimately stabilizing the inflammation-associated mRNA expression at the post-transcriptional level.

Mammalian community responses in relation to anthropogenic disturbances and resource gradients in the shade coffee forest ecosystem of Southwestern Ethiopia

Understanding the effects of variation in resource availability and habitat disturbance on the ecology of mammals is vital for successful conservation management. In this study, we examined how human disturbances, resource availability and elevation gradients influence mammal assemblages in both managed coffee forest and natural forest of the Belete-Gera National Forest Priority Area, southwestern Ethiopia. We surveyed mammals using motion-detecting infrared camera traps in 90 locations for a total of 4142 camera days. We measured distance from main roads and settlements as disturbance factors, and distance from water sources, key grazing sites, and forest edges and woody plant diversity as resource variables. We assessed the mammal assemblages in coffee forest and natural forests using generalized linear models. Further, we used linear modelling to compare the relationships of mammal detection rates by feeding guilds and body size to resource variables. In total, we recorded 8815 videos identifying 23 different mammal species. The mammal assemblages in coffee forests were negatively associated with increasing distances from key grazing sites, water sources, and elevation. In contrast, the association with increasing distance from the road and woody plant diversity was positive. In addition, herbivores and large (25–200 kg) and very large (≥200 kg) mammals, were all negatively associated with increasing distance from the natural forest edges. With the conversion of natural forest to coffee forest and the intensification of coffee forest management, sustainable management of key grazing sites, water sources, and diverse woody plant species will be essential to the conservation of mammals. In addition, to ensure mammal conservation, adjacent natural forests around coffee forests should also be protected.

TLR7 in channel catfish (Ictalurus punctatus) is expressed in the endolysosome and is stimulated by synthetic ssRNA analogs, imiquimod, and resiquimod.

Toll-like receptors (TLRs) are pivotal pattern recognition receptors (PRRs) and key mediators of innate immunity. Despite the significance of channel catfish (Ictalurus punctatus) in comparative immunology and aquaculture, its 20 TLR genes remain largely functionally uncharacterized. In this study, our aim was to determine the catfish TLR7 agonists, signaling potential, and cellular localization. Using a mammalian reporter system, we identified imiquimod and resiquimod, typical ssRNA analogs, as potent catfish TLR7 agonists. Notably, unlike grass carp TLR7, catfish TLR7 lacks the ability to respond to poly (I:C). Confocal microscopy revealed predominant catfish TLR7 expression in lysosomes, co-localizing with the endosomal chaperone protein, UNC93B1. Furthermore, imiquimod stimulation elicited robust IFNb transcription in peripheral blood leukocytes isolated from adult catfish. These findings underscore the conservation of TLR7 signaling in catfish, reminiscent of mammalian TLR7 responses. Our study sheds light on the functional aspects of catfish TLR7 and contributes to a better understanding of its role in immune defense mechanisms.

Central command activation during exercise is essential for the bradycardic response to diving

Mammalian diving response evokes complex cardiovascular adjustments, including bradycardia during sustained muscular activity. This is intriguing because voluntary exercise involves the activation of central command and skeletal muscle afferents, known to provoke tachycardia by reducing vagal outflow and increasing cardiac sympathetic activity. Nonetheless, it is currently unknown how diving-induced bradycardia can override the exercise tachycardia. Given this, we aimed to test the hypothesis that central and peripheral afferent mechanisms interact to modulate this physiological phenomenon. In three visits, 32 healthy subjects (15 women; 22±3 yr) were exposed to trigeminal nerve stimulation (i.e., facial cooling; TGS) to partially activate the diving reflex at rest (semi-recumbent position) and under three protocols: 1) during voluntary light (resting heart rate+20 beats.min−1) and moderate (resting heart rate+50 beats.min−1) steady-state cycling exercise; 2) during isolation of peripheral afferent reflexes via passive exercise (muscle mechanoreceptors) and cold pressor test (nociceptors; CPT), and; 3) during CPT with concurrent light exercise. The exercise intensities were assumed to provide different levels of central command activation, while both passive exercise and CPT were used to provide insights into the contribution of central command to diving bradycardia. TGS was performed for at least 90 seconds in all conditions. Beat-to-beat heart rate (HR, by electrocardiography) and blood pressure (finger photoplethysmography) were continuously measured, and surface electromyography was used to ensure the lack of volitional component during passive exercise. TGS elicited significant bradycardia at rest (Δ-12±0.9 beats·min−1; P&lt;0.001), and this response was increased during voluntary light exercise (Δ-15±1.2 beats·min−1; P=0.002), but unaffected during voluntary moderate exercise when compared to rest (Δ-11±1.3 beats·min−1; P=0.536). In contrast, compared to rest, the HR response to TGS during passive exercise was significantly attenuated (Δ-13±1.2 beats·min−1 vs. Δ-9±1.7 beats·min−1; P=0.039), whereas CPT completely abolish the diving bradycardic response (Δ0±1.6 beats·min−1; P&lt;0.001). However, when the volitional component was restored during CPT with concurrent light exercise, TGS provoked a significant bradycardic response, when compared to CPT condition (Δ1±1.6 beats·min−1 vs. Δ-10±2.1 beats·min−1; P=0.004). Notably, our findings were not affected by sex. In conclusion, these findings suggest that 1) central command activation during cycling exercise is essential for the bradycardic response to diving; 2) isolated peripheral afferent reflexes exert inhibitory feedback to modulate diving-induced bradycardia, and; 3) central and peripheral afferent feedback are important mechanisms by which exercise modulates the dive response. CNPq 307764/2022-2; CAPES (001). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Diving into old age: exercise and aging affect cardiovascular control in a long-lived mammal, the Weddell seal

The central component of the mammalian dive response is bradycardia, which, in combination with other physiological mechanisms, conserves intrinsic oxygen stores and facilitates longer submersion. Several factors are hypothesized to affect diving heart rate ( fH) and its variability (HRV) through a shift in autonomic balance. This study aimed to elucidate how dive duration, aging, and exercise influence fH and HRV (calculated as root mean square of successive RR interval differences) of free-ranging Weddell seals ( Leptonychotes weddellii). We expected that mean dive fH and HRV would differ with dive duration, advancing age, and exercise intensity due to a shift in autonomic balance. We collected ECG data from free-ranging female Weddell seals in Erebus Bay, Antarctica (n=10 seals, n=120 dives, age range 9-25 years old). To increase the cost of transport, we affxed a “drag block” to three seals for a portion of their deployment period (n=30 dives). Linear mixed effects model selection identified the effects of dive behavior (duration and depth), seal age, and drag block presence on mean dive fH and HRV. As dive duration increased, mean dive fH decreased (F1,107=227.91, p&lt;0.0001) while HRV increased (F1,103=84.47, p&lt;0.0001), suggesting increased parasympathetic tone. HRV was reduced in older seals (F1,8=8.73, p=0.018), indicating attenuation of parasympathetic influence on bradycardia with advancing age. Consistent with this interpretation, HRV increased with dive duration more steeply in younger animals (age*duration: F1,103=10.31, p=0.002). When exercise effort was experimentally modified by attaching a drag block to free-ranging seals, both mean dive fH (F1,107=6.07, p=0.015) and HRV (F1,103=4.34, p=0.039) were affected; dive HRV was significantly higher when seals dove with a drag block. However, this result should be interpreted with caution until the effects of swimming effort on fH and HRV can be determined. There was a significant interaction between animal age and factors affecting cardiovascular control (age*drag: F1,107=5.16, p=0.028); mean dive fH increased with age when seals did not carry a drag block, but decreased with age when a drag block was present. Taken together, our results point to cardiovascular aging as a physiological element that could affect the foraging ability, fitness, and life history of a long-lived free-ranging mammal. Funding by the National Science Foundation (#0649609, #0440715, #2020706). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Lytic bacteriophages induce the secretion of antiviral and proinflammatory cytokines from human respiratory epithelial cells.

Phage therapy is a therapeutic approach to treat multidrug-resistant (MDR) infections that employs lytic bacteriophages (phages) to eliminate bacteria. Despite the abundant evidence for its success as an antimicrobial in Eastern Europe, there is scarce data regarding its effects on the human host. Here, we aimed to understand how lytic phages interact with cells of the airway epithelium, the tissue site that is colonized by bacterial biofilms in numerous chronic respiratory disorders. Using a panel of Pseudomonas aeruginosa phages and human airway epithelial cells (AECs) derived from a person with cystic fibrosis (CF), we determined that interactions between phages and epithelial cells depend on specific phage properties as well as physiochemical features of the microenvironment. Although poor at internalizing phages, the airway epithelium responds to phage exposure by changing its transcriptional profile and secreting antiviral and proinflammatory cytokines that correlate with specific phage families. Overall, our findings indicate that mammalian responses to phages are heterogenous and could potentially alter the way that respiratory local defenses aid in bacterial clearance during phage therapy. Thus, besides phage receptor specificity in a particular bacterial isolate, the criteria to select lytic phages for therapy should be expanded to include mammalian cell responses.

A neurofunctional signature of subjective disgust generalizes to oral distaste and socio-moral contexts.

While disgust originates in the hard-wired mammalian distaste response, the conscious experience of disgust in humans strongly depends on subjective appraisal and may even extend to socio-moral contexts. Here, in a series of studies, we combined functional magnetic resonance imaging with machine-learning-based predictive modelling to establish a comprehensive neurobiological model of subjective disgust. The developed neurofunctional signature accurately predicted momentary self-reported subjective disgust across discovery (n = 78) and pre-registered validation (n = 30) cohorts and generalized across core disgust (n = 34 and n = 26), gustatory distaste (n = 30) and socio-moral (unfair offers; n = 43) contexts. Disgust experience was encoded in distributed cortical and subcortical systems, and exhibited distinct and shared neural representations with subjective fear or negative affect in interoceptive-emotional awareness and conscious appraisal systems, while the signatures most accurately predicted the respective target experience. We provide an accurate functional magnetic resonance imaging signature for disgust with a high potential to resolve ongoing evolutionary debates.

A spatiotemporal atlas of mouse liver homeostasis and regeneration.

The mechanism by which mammalian liver cell responses are coordinated during tissue homeostasis and perturbation is poorly understood, representing a major obstacle in our understanding of many diseases. This knowledge gap is caused by the difficulty involved with studying multiple cell types in different states and locations, particularly when these are transient. We have combined Stereo-seq (spatiotemporal enhanced resolution omics-sequencing) with single-cell transcriptomic profiling of 473,290 cells to generate a high-definition spatiotemporal atlas of mouse liver homeostasis and regeneration at the whole-lobe scale. Our integrative study dissects in detail the molecular gradients controlling liver cell function, systematically defining how gene networks are dynamically modulated through intercellular communication to promote regeneration. Among other important regulators, we identified the transcriptional cofactor TBL1XR1 as a rheostat linking inflammation to Wnt/β-catenin signaling for facilitating hepatocyte proliferation. Our data and analytical pipelines lay the foundation for future high-definition tissue-scale atlases of organ physiology and malfunction.

What can the common fruit fly teach us about stroke?: lessons learned from the hypoxic tolerant Drosophila melanogaster.

Stroke, resulting in hypoxia and glucose deprivation, is a leading cause of death and disability worldwide. Presently, there are no treatments that reduce neuronal damage and preserve function aside from tissue plasminogen activator administration and rehabilitation therapy. Interestingly, Drosophila melanogaster, the common fruit fly, demonstrates robust hypoxic tolerance, characterized by minimal effects on survival and motor function following systemic hypoxia. Due to its organized brain, conserved neurotransmitter systems, and genetic similarity to humans and other mammals, uncovering the mechanisms of Drosophila's tolerance could be a promising approach for the development of new therapeutics. Interestingly, a key facet of hypoxic tolerance in Drosophila is organism-wide metabolic suppression, a response involving multiple genes and pathways. Specifically, studies have demonstrated that pathways associated with oxidative stress, insulin, hypoxia-inducible factors, NFκB, Wnt, Hippo, and Notch, all potentially contribute to Drosophila hypoxic tolerance. While manipulating the oxidative stress response and insulin signaling pathway has similar outcomes in Drosophila hypoxia and the mammalian middle cerebral artery occlusion (MCAO) model of ischemia, effects of Notch pathway manipulation differ between Drosophila and mammals. Additional research is warranted to further explore how other pathways implicated in hypoxic tolerance in Drosophila, such as NFκB, and Hippo, may be utilized to benefit mammalian response to ischemia. Together, these studies demonstrate that exploration of the hypoxic response in Drosophila may lead to new avenues of research for stroke treatment in humans.

Sodium-glucose cotransporter 2 inhibitors influence skeletal muscle pathology in patients with heart failure and reduced ejection fraction.

Patients with heart failure and reduced ejection fraction (HFrEF) exhibit skeletal muscle pathology, which contributes to symptoms and decreased quality of life. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve clinical outcomes in HFrEF but their mechanism of action remains poorly understood. We aimed, therefore, to determine whether SGLT2i influence skeletal muscle pathology in patients with HFrEF. Muscle biopsies from 28 male patients with HFrEF (New York Heart association class I-III) treated with SGLT2i (>12 months) or without SGLT2i were compared. Comprehensive analyses of muscle structure (immunohistochemistry), transcriptome (RNA sequencing), and metabolome (liquid chromatography-mass spectrometry) were performed, and serum inflammatory profiling (ELISA). Experiments in mice (n = 16) treated with SGLT2i were also performed. Myofiber atrophy was ~20% less in patients taking SGLT2i (p = 0.07). Transcriptomics and follow-up measures identified a unique signature in patients taking SGLT2i related to beneficial effects on atrophy, metabolism, and inflammation. Metabolomics identified influenced tryptophan metabolism in patients taking SGLT2i: kynurenic acid was 24% higher and kynurenine was 32% lower (p < 0.001). Serum profiling identified that SGLT2i treatment was associated with lower (p < 0.05) pro-inflammatory cytokines by 26-64% alongside downstream muscle interleukin (IL)-6-JAK/STAT3 signalling (p = 008 and 0.09). Serum IL-6 and muscle kynurenine were correlated (R = 0.65; p < 0.05). Muscle pathology was lower in mice treated with SGLT2i indicative of a conserved mammalian response to treatment. Treatment with SGLT2i influenced skeletal muscle pathology in patients with HFrEF and was associated with anti-atrophic, anti-inflammatory, and pro-metabolic effects. These changes may be regulated via IL-6-kynurenine signalling. Together, clinical improvements following SGLT2i treatment in patients with HFrEF may be partly explained by their positive effects on skeletal muscle pathology.

I did not scream. i could not; i was terrified. i just followed them...i blocked my mind. then they all raped me: A narrative inquiry on the onset of tonic immobility among women rape victims in Nigeria.

Tonic immobility (TI) is a common uncontrollable autonomic mammalian response to an extremely fearful situation. It is one of the most immediate devastating consequences of rape and remains poorly understood. While controversies over its definition persist among researchers, this also reflects on the care for and support to victims. The study aimed to explore and describe the onset of TI and the meaning attached to the experience among women raped victims in Nigeria. The study design was the qualitative narrative inquiry approach. Criterion and purposive sampling were conducted across four post-rape care facilities in Lagos, Nigeria, to recruit 13 participants. In-depth face-to-face interviews were conducted using a semi-structured interview guide to generate data that were thematically analysed. The findings of the study revealed five themes relating to the onset of TI as follows: the first two focused on the experience of TI: (1) the onset of TI prior to rape due to perceived imminent danger, (2) the onset of TI as a self-protection mechanism from further harm) while the last three relate to the meaning-making of the experience of TI (3) self-loathing as a meaning attached to TI, (4) suicidal ideations as a meaning attached to TI, and (5) divine intervention as a meaning attached to TI. Conclusion: The findings underscore the experiences and meanings that participants attach to TI following rape. There is a strong likelihood that tonic-immobility is not an uncommon experience amongst rape victims, but that in the absence of research, specialized care on the condition, and its associated consequences will haunt many women, affecting their psychological well-being and their entire quality of life. Describing the phenomenon as it is experienced by the participants is critical because understanding the condition is the first step toward effective appropriate management.

Mammalian integrated stress responses in stressed organelles and their functions.

The integrated stress response (ISR) triggered in response to various cellular stress enables mammalian cells to effectively cope with diverse stressful conditions while maintaining their normal functions. Four kinases (PERK, PKR, GCN2, and HRI) of ISR regulate ISR signaling and intracellular protein translation via mediating the phosphorylation of eukaryotic translation initiation factor 2 α (eIF2α) at Ser51. Early ISR creates an opportunity for cells to repair themselves and restore homeostasis. This effect, however, is reversed in the late stages of ISR. Currently, some studies have shown the non-negligible impact of ISR on diseases such as ischemic diseases, cognitive impairment, metabolic syndrome, cancer, vanishing white matter, etc. Hence, artificial regulation of ISR and its signaling with ISR modulators becomes a promising therapeutic strategy for relieving disease symptoms and improving clinical outcomes. Here, we provide an overview of the essential mechanisms of ISR and describe the ISR-related pathways in organelles including mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes. Meanwhile, the regulatory effects of ISR modulators and their potential application in various diseases are also enumerated.

Full T-cell activation and function in teleosts require collaboration of first and co-stimulatory signals.

Mammalian T-cell responses require synergism between the first signal and co-stimulatory signal. However, whether and how dual signaling regulates the T-cell response in early vertebrates remains unknown. In the present study, we discovered that the Nile tilapia ( Oreochromis niloticus) encodes key components of the LAT signalosome, namely, LAT, ITK, GRB2, VAV1, SLP-76, GADS, and PLC-γ1. These components are evolutionarily conserved, and CD3ε mAb-induced T-cell activation markedly increased their expression. Additionally, at least ITK, GRB2, and VAV1 were found to interact with LAT for signalosome formation. Downstream of the first signal, the NF-κB, MAPK/ERK, and PI3K-AKT pathways were activated upon CD3ε mAb stimulation. Furthermore, treatment of lymphocytes with CD28 mAbs triggered the AKT-mTORC1 pathway downstream of the co-stimulatory signal. Combined CD3ε and CD28 mAb stimulation enhanced ERK1/2 and S6 phosphorylation and elevated NFAT1, c-Fos, IL-2, CD122, and CD44 expression, thereby signifying T-cell activation. Moreover, rather than relying on the first or co-stimulatory signal alone, both signals were required for T-cell proliferation. Full T-cell activation was accompanied by marked apoptosis and cytotoxic responses. These findings suggest that tilapia relies on dual signaling to maintain an optimal T-cell response, providing a novel perspective for understanding the evolution of the adaptive immune system.