Molecular Adaptations Research Articles

Comparative transcriptomic and proteomic signature of lung alveolar macrophages reveals the integrin CD11b as a regulatory hub during pneumococcal pneumonia infection.

Streptococcus pneumoniae is one of the main causes of community-acquired infections in the lung alveoli in children and the elderly. Alveolar macrophages (AM) patrol alveoli in homeostasis and under infectious conditions. However, the molecular adaptations of AM upon infections with Streptococcus pneumoniae are incompletely resolved. We used a comparative transcriptomic and proteomic approach to provide novel insights into the cellular mechanism that changes the molecular signature of AM during lung infections. Using a tandem mass spectrometry approach to murine cell-sorted AM, we revealed significant proteomic changes upon lung infection with Streptococcus pneumoniae. AM showed a strong neutrophil-associated proteomic signature, such as expression of CD11b, MPO, neutrophil gelatinases, and elastases, which was associated with phagocytosis of recruited neutrophils. Transcriptomic analysis indicated intrinsic expression of CD11b by AM. Moreover, comparative transcriptomic and proteomic profiling identified CD11b as the central molecular hub in AM, which influenced neutrophil recruitment, activation, and migration. In conclusion, our study provides novel insights into the intrinsic molecular adaptations of AM upon lung infection with Streptococcus pneumoniae and reveals profound alterations critical for effective antimicrobial immunity.

Sex differences in muscle protein expression and DNA methylation in response to exercise training

BackgroundExercise training elicits changes in muscle physiology, epigenomics, transcriptomics, and proteomics, with males and females exhibiting differing physiological responses to exercise training. However, the molecular mechanisms contributing to the differing adaptations between the sexes are poorly understood.MethodsWe performed a meta-analysis for sex differences in skeletal muscle DNA methylation following an endurance training intervention (Gene SMART cohort and E-MTAB-11282 cohort). We investigated for sex differences in the skeletal muscle proteome following an endurance training intervention (Gene SMART cohort). Lastly, we investigated whether the methylome and proteome are associated with baseline cardiorespiratory fitness (maximal oxygen consumption; VO2max) in a sex-specific manner.ResultsHere, we investigated for the first time, DNA methylome and proteome sex differences in response to exercise training in human skeletal muscle (n = 78; 50 males, 28 females). We identified 92 DNA methylation sites (CpGs) associated with exercise training; however, no CpGs changed in a sex-dependent manner. In contrast, we identified 189 proteins that are differentially expressed between the sexes following training, with 82 proteins differentially expressed between the sexes at baseline. Proteins showing the most robust sex-specific response to exercise include SIRT3, MRPL41, and MBP. Irrespective of sex, cardiorespiratory fitness was associated with robust methylome changes (19,257 CpGs) and no proteomic changes. We did not observe sex differences in the association between cardiorespiratory fitness and the DNA methylome. Integrative multi-omic analysis identified sex-specific mitochondrial metabolism pathways associated with exercise responses. Lastly, exercise training and cardiorespiratory fitness shifted the DNA methylomes to be more similar between the sexes.ConclusionsWe identified sex differences in protein expression changes, but not DNA methylation changes, following an endurance exercise training intervention; whereas we identified no sex differences in the DNA methylome or proteome response to lifelong training. Given the delicate interaction between sex and training as well as the limitations of the current study, more studies are required to elucidate whether there is a sex-specific training effect on the DNA methylome. We found that genes involved in mitochondrial metabolism pathways are differentially modulated between the sexes following endurance exercise training. These results shed light on sex differences in molecular adaptations to exercise training in skeletal muscle.

Abstract A002: Targeting hypoxia inducible factor (HIF)-2α with AB521, a novel and potent small molecule HIF-2α inhibitor, for the treatment of clear cell renal cell carcinoma

Abstract Cells in the solid tumor microenvironment are frequently exposed to hypoxic or pseudohypoxic conditions, necessitating molecular adaptations such as induction of transcriptional programs for survival. HIF-2α is a transcriptional regulator of hypoxia-induced genes that is regulated post-translationally in an oxygen-dependent manner via hydroxylation by prolyl hydroxylase enzymes - a modification required for recognition by pVHL for subsequent degradation. Therefore, under hypoxic conditions or in the case of pVHL inactivation (pseudohypoxia), HIF-2α is stabilized and translocates to the nucleus where it forms a heterodimer with ARNT to initiate transcription of its target genes. HIF-2α has been shown to be an oncogenic driver in clear cell renal cell carcinoma (ccRCC) where VHL mutations occur frequently, resulting in a pseudohypoxic state and stable HIF-2α expression. There is both preclinical and clinical evidence in ccRCC demonstrating that inhibiting HIF-2α is a valid therapeutic approach in blocking tumor progression. AB521 is a clinical-stage novel and potent small-molecule HIF-2α inhibitor. In vitro, AB521 effectively inhibits transcription of pro-tumorigenic HIF-2α target genes in multiple human cell types relevant to the tumor microenvironment, including cancer cells, primary endothelial cells, and pro-tumorigenic M2-polarized macrophages. AB521 also blocks HIF-2α-mediated gene transcription in vivo, as detected using both intratumoral and peripheral markers, an activity that is accompanied by a marked reduction in tumor burden in two VHL-mutant ccRCC xenograft models. Supporting a potential combinatorial treatment approach for HIF-2α inhibition in ccRCC, AB521 combines favorably with standard-of-care tyrosine kinase inhibitor cabozantinib in mouse models, further enhancing tumor efficacy in VHL-mutant ccRCC compared to either single agent alone. In healthy human volunteers, AB521 exhibits favorable pharmacokinetic (PK) and pharmacodynamic (PD) properties including a half-life of 18-24 hours, supportive of once-daily dosing, dose-dependent reductions in serum erythropoietin (EPO) following a single dose of 10 to 100 mg, and sustained EPO reduction after multiple daily dosing. In summary, AB521 is a potent and selective HIF-2α inhibitor that has been thoroughly characterized in a suite of in vitro assays, reduces tumor burden in ccRCC xenografts both as a single agent and in combination with cabozantinib, and exhibits favorable PK/PD properties in human healthy volunteers. Phase I clinical evaluation of AB521 in subjects with ccRCC and other solid tumors has been initiated and is currently ongoing (NCT05536141). Citation Format: Dana Piovesan, Soonweng Cho, Kenneth V. Lawson, Kai H. Liao, Paul G. Foster, Tzuling Cheng, Matthew J. Walters, Kelsey E. Sivick Gauthier. Targeting hypoxia inducible factor (HIF)-2α with AB521, a novel and potent small molecule HIF-2α inhibitor, for the treatment of clear cell renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr A002.

Diving on damage—the muscle transcriptome of parasitic infested harbor porpoises (Phocoena phocoena) hints at oxidative stress but not hypoxia

The only native cetacean in German waters, the harbor porpoise (Phocoena phocoena), is impacted by numerous pathological lesions in the respiratory tract mainly caused by parasites or bacteria. Although harbor porpoises have been observed to not use their complete lung volume, it has not been studied whether this insufficiency leads to lower oxygen uptake, impaired diving ability, and, ultimately, reduced foraging success. This project aims to analyze whether harbor porpoises developed novel molecular adaptations to compensate impairments in oxygen supply, thus remaining viable and competitive despite the high parasitic load. Here, initial comparative transcriptome RNA sequencing (NextSeq 2000, Illumina) was performed on muscles of harbor porpoises with a respiratory tract considered as healthy and of harbor porpoises that suffered from more severe lesions and parasitic infestations in the respiratory tract. Our findings suggest an elevated response to oxidative stress in the muscles of parasitic infested harbor porpoises compared with that of healthy animals. Higher antioxidant and antiapoptotic gene expression in the muscles of non-healthy harbor porpoises might function as a compensatory effect to enhanced reactive oxygen species production and accumulation in the muscles. Simultaneously enhanced selective proteasomal degradation and myogenesis suggest a tightly controlled, finely tuned switch of the intrinsic muscle response to stress. Lipid metabolism pathways and rate-limiting transcripts involved in glycolysis were upregulated and may uphold muscle energy supply for tissue function and energy-consuming regenerative and biosynthetic processes. These preliminary results hint at a defined response of the muscle to oxidative stress that may be caused by lung tissue with more severe pathological lesions and may indicate a possible adaptation in cetaceans.

NOX2 deficiency exacerbates diet-induced obesity and impairs molecular training adaptations in skeletal muscle

The production of reactive oxygen species (ROS) by NADPH oxidase (NOX) 2 has been linked to both insulin resistance and exercise training adaptations in skeletal muscle. This study explores the previously unexamined role of NOX2 in the interplay between diet-induced insulin resistance and exercise training (ET). Using a mouse model that harbors a point mutation in the essential NOX2 regulatory subunit, p47phox (Ncf1*), we investigated the impact of this mutation on various metabolic adaptations. Wild-type (WT) and Ncf1* mice were assigned to three groups: chow diet, 60% energy fat diet (HFD), and HFD with access to running wheels (HFD + E). After a 16-week intervention, a comprehensive phenotypic assessment was performed, including body composition, glucose tolerance, energy intake, muscle insulin signaling, redox-related proteins, and mitochondrial adaptations. The results revealed that NOX2 deficiency exacerbated the impact of HFD on body weight, body composition, and glucose intolerance. Moreover, in Ncf1* mice, ET did not improve glucose tolerance or increase muscle cross-sectional area. ET normalized body fat independently of genotype. The lack of NOX2 activity during ET reduced several metabolic adaptations in skeletal muscle, including insulin signaling and expression of Hexokinase II and oxidative phosphorylation complexes. In conclusion, these findings suggest that NOX2 mediates key beneficial effects of exercise training in the context of diet-induced obesity.

Plant-insect interaction in underutilized horticultural crops for sustainable production

Plants and insects have been living together for more than 350 million years. In co-evolution, both have evolved strategies to avoid each other’s defense systems. This evolutionary arms race between plants and insects has resulted in the development of an elegant defense system in plants that can recognise the non-self-molecules or signals from damaged cells, much like animals. It activates the plant’s immune response against the herbivores. Differences in genotypes of plant characters may affect insect-plant herbivore interactions, and variations in genotype traits are responsible for modifying the bottom-up effects. Recent evidence shows that the simultaneous occurrence of abiotic and biotic stress can positively affect plant performance by reducing the susceptibility to biotic stress, a positive sign for pest management. Plant responses to these stresses are multifaceted and involve copious antibiosis, physiological, antixenotic, molecular, molecular and cellular adaptations. Plants with antibiosis characteristics such as flavonoids, phenols, tannins, alkaloids, etc., may cause reduced insect survival, prolonged development time, decreased size and reduced new generation fitness. Quality and quantity of constitutive secondary metabolites production is species as well as cultivar specific and can be expressed as the signature of a particular plant or species and leads to the phenomenon of host-plant resistance. Hence, such plant resistance mechanisms have been effectively and widely used for managing insect pests in fields of underutilized crops. Natural defences are mediated through plant characteristics that affect insect biology, such as mechanical protection on the surface of the plants (e.g., hairs, trichomes, thorns, spines and thicker leaves) that either kill or retard the development of the herbivores. These phenomena of host plant resistance to insects can be exploited for the development of resistance crop cultivars which readily produce the inducible response upon mild infestation and can perform as one of the integrated pest management for sustainable crop production.

The resilience of the aquatic Isoëtes cangae to terrestrial environment: Insights into molecular and ecophysiological adaptations

The Isoëtes genus comprises a basal lineage of vascular plants with a wide distribution, including aquatic and terrestrial species, which can be attributed to environmental changes throughout its evolutionary history. The underwater quillwort, Isöetes cangae, is endemic to Lake Amendoim in the northern Amazon rainforest region of Brazil. To aid conservation strategies, we investigated the molecular and physiological changes associated with water column reduction and tolerance to terrestrial environments. Remarkably, this aquatic species has demonstrated a tolerance for periods without a water column during ex situ cultivation. Short-term experimental conditions (24 h) revealed upregulation of stress-related genes, while biochemical, morphological, and physiological parameters remained unchanged. In contrast, long-term terrestrial conditions (3–6 months) induced changes in the physiology and morphology of I. cangae, including an increase in antioxidant capacity, photoprotective mechanisms, and the preservation of reproductive structures. The Crassulacean Acid Metabolism was present in both aquatic and terrestrial conditions. Mature and immature spores were able to produce plants even after 12 months of desiccation, with desiccated spores generating more progeny than submerged spores.

ECR Spotlight – Jennifer Steffen

ECR Spotlight is a series of interviews with early-career authors from a selection of papers published in Journal of Experimental Biology and aims to promote not only the diversity of early-career researchers (ECRs) working in experimental biology during our centenary year but also the huge variety of animals and physiological systems that are essential for the ‘comparative’ approach. Jennifer Steffen is an author on ‘ Combined effects of salinity and intermittent hypoxia on mitochondrial capacity and reactive oxygen species efflux in the Pacific oyster, Crassostrea gigas’, published in JEB. Jennifer is a PhD candidate in the lab of Prof. Dr Inna Sokolova at the Institute of Biological Sciences, University of Rostock, Germany, investigating biochemical and molecular physiological adaptations to environmental changes with a special emphasis on mitochondrial functions.

Adaptive evolution of the enigmatic Takakia now facing climate change in Tibet

The most extreme environments are the most vulnerable to transformation under a rapidly changing climate. These ecosystems harbor some of the most specialized species, which will likely suffer the highest extinction rates. We document the steepest temperature increase (2010-2021) on record at altitudes of above 4,000 m, triggering a decline of the relictual and highly adapted moss Takakia lepidozioides. Its de-novo-sequenced genome with 27,467 protein-coding genes includes distinct adaptations to abiotic stresses and comprises the largest number of fast-evolving genes under positive selection. The uplift of the study site in the last 65 million years has resulted in life-threatening UV-B radiation and drastically reduced temperatures, and we detected several of the molecular adaptations of Takakia to these environmental changes. Surprisingly, specific morphological features likely occurred earlier than 165 mya in much warmer environments. Following nearly 400 million years of evolution and resilience, this species is now facing extinction.

Lower plants are emerging gene sources for agriculture and insect control proteins.

The non-seed lower plants (e.g., charophyte algae, bryophytes, and ferns) have multiple human uses, but their contributions to agriculture and research have lagged seed plants. While sharing broadly conserved biology with seed plants and the major crops, lower plants sometimes possess alternative molecular and physiological adaptations. These adaptations may guide crop improvements. One such area is the presence of multiple classes of insecticidal proteins found in lower plant genomes which are either absent or widely diverged in seed plants. There are documented uses of lower plants, and ferns for example have been used in human diets. Among the occasional identifiable toxins or antinutritive components present in lower plants, none include these insecticidal proteins. Apart from these discrete risk factors which can be addressed in the safety assessment, there should be no general safety concern about sourcing genes from lower plant species.

The Yeast Protein Kinase Sch9 Functions as a Central Nutrient-Responsive Hub That Calibrates Metabolic and Stress-Related Responses.

Yeast cells are equipped with different nutrient signaling pathways that enable them to sense the availability of various nutrients and adjust metabolism and growth accordingly. These pathways are part of an intricate network since most of them are cross-regulated and subject to feedback regulation at different levels. In yeast, a central role is played by Sch9, a protein kinase that functions as a proximal effector of the conserved growth-regulatory TORC1 complex to mediate information on the availability of free amino acids. However, recent studies established that Sch9 is more than a TORC1-effector as its activity is tuned by several other kinases. This allows Sch9 to function as an integrator that aligns different input signals to achieve accuracy in metabolic responses and stress-related molecular adaptations. In this review, we highlight the latest findings on the structure and regulation of Sch9, as well as its role as a nutrient-responsive hub that impacts on growth and longevity of yeast cells. Given that most key players impinging on Sch9 are well-conserved, we also discuss how studies on Sch9 can be instrumental to further elucidate mechanisms underpinning healthy aging in mammalians.

Resistance training diminishes mitochondrial adaptations to subsequent endurance training in healthy untrained men.

We investigated the effects of performing a period of resistance training (RT) on the performance and molecular adaptations to a subsequent period of endurance training (ET). Twenty-five young adults were divided into an RT+ET group (n=13), which underwent 7weeks of RT followed by 7weeks of ET, and an ET-only group (n=12), which performed 7weeks of ET. Body composition, endurance performance and muscle biopsies were collected before RT (T1, baseline for RT+ET), before ET (T2, after RT for RT+ET and baseline for ET) and after ET (T3). Immunohistochemistry was performed to determine fibre cross-sectional area (fCSA), myonuclear content, myonuclear domain size, satellite cell number and mitochondrial content. Western blots were used to quantify markers of mitochondrial remodelling. Citrate synthase activity and markers of ribosome content were also investigated. RT improved body composition and strength, increased vastus lateralis thickness, mixed and type II fCSA, myonuclear number, markers of ribosome content, and satellite cell content (P<0.050). In response to ET, both groups similarly decreased body fat percentage (P<0.0001) and improved endurance performance (e.g. , and speed at which the onset of blood lactate accumulation occurred, P<0.0001). Levels of mitochondrial complexes I-IV in the ET-only group increased 32-66%, while those in the RT+ET group increased 1-11% (time, P<0.050). Additionally, mixed fibre relative mitochondrial content increased 15% in the ET-only group but decreased 13% in the RT+ET group (interaction, P=0.043). In conclusion, RT performed prior to ET had no additional benefits to ET adaptations. Moreover, prior RT seemed to impair mitochondrial adaptations to ET. KEY POINTS: Resistance training is largely underappreciated as a method to improve endurance performance, despite reports showing it may improve mitochondrial function. Although several concurrent training studies are available, in this study we investigated the effects of performing a period of resistance training on the performance and molecular adaptations to subsequent endurance training. Prior resistance training did not improve endurance performance and impaired most mitochondrial adaptations to subsequent endurance training, but this effect may have been a result of detraining from resistance training.

Heart Disease and Microgravity: The Dawn of a New Medical Era?: A Narrative Review.

After a decline in interest in space missions following the cessation of the Apollo missions, there has been a recent resurgence. Activities on the International Space Station have raised awareness of a positive resumption of space travel to more challenging destinations such as Mars and a possible adaptation of human life on the Moon. The biological and physiological studies conducted on these stations in low Earth orbit are crucial in familiarizing humanity with the potential problems that can arise during long journeys. Cosmic rays and microgravity are the 2 main negative phenomena in space flights. Microgravity in the interplanetary environment plays a special role in altering normal organic processes. These studies are compared to studies conducted on Earth with laboratory technologies that mimic the space environment. To date, the molecular and physiological adaptations of the human body to this unnatural environment are very poor. The aim of this review is therefore to provide an overview of the most important findings on the molecular and physiological anomalies that develop during microgravity in short and long space flights.

Transcriptomic profiling of reward and sensory brain areas in perinatal fentanyl exposed juvenile mice.

Use of the synthetic opioid fentanyl increased ~300% in the last decade, including among women of reproductive ages. Adverse neonatal outcomes and long-term behavioral disruptions are associated with perinatal opioid exposure. Our previous work demonstrated that perinatal fentanyl exposed mice displayed enhanced negative affect and somatosensory circuit and behavioral disruptions during adolescence. However, little is known about molecular adaptations across brain regions that underlie these outcomes. We performed RNA sequencing across three reward and two sensory brain areas to study transcriptional programs in perinatal fentanyl exposed juvenile mice. Pregnant dams received 10 μg/ml fentanyl in the drinking water from embryonic day 0 (E0) through gestational periods until weaning at postnatal day 21 (P21). RNA was extracted from nucleus accumbens (NAc), prelimbic cortex (PrL), ventral tegmental area (VTA), somatosensory cortex (S1) and ventrobasal thalamus (VBT) from perinatal fentanyl exposed mice of both sexes at P35. RNA sequencing was performed, followed by analysis of differentially expressed genes (DEGs) and gene co-expression networks. Transcriptome analysis revealed DEGs and gene modules significantly associated with exposure to perinatal fentanyl in a sex-wise manner. The VTA had the most DEGs, while robust gene enrichment occurred in NAc. Genes enriched in mitochondrial respiration were pronounced in NAc and VTA of perinatal fentanyl exposed males, extracellular matrix (ECM) and neuronal migration enrichment were pronounced in NAc and VTA of perinatal fentanyl exposed males, while genes associated with vesicular cycling and synaptic signaling were markedly altered in NAc of perinatal fentanyl exposed female mice. In sensory areas from perinatal fentanyl exposed females, we found alterations in mitochondrial respiration, synaptic and ciliary organization processes. Our findings demonstrate distinct transcriptomes across reward and sensory brain regions, with some showing discordance between sexes. These transcriptome adaptations may underlie structural, functional, and behavioral changes observed in perinatal fentanyl exposed mice.

Genomic screening of 16 UK native bat species through conservationist networks uncovers coronaviruses with zoonotic potential

There has been limited characterisation of bat-borne coronaviruses in Europe. Here, we screened for coronaviruses in 48 faecal samples from 16 of the 17 bat species breeding in the UK, collected through a bat rehabilitation and conservationist network. We recovered nine complete genomes, including two novel coronavirus species, across six bat species: four alphacoronaviruses, a MERS-related betacoronavirus, and four closely related sarbecoviruses. We demonstrate that at least one of these sarbecoviruses can bind and use the human ACE2 receptor for infecting human cells, albeit suboptimally. Additionally, the spike proteins of these sarbecoviruses possess an R-A-K-Q motif, which lies only one nucleotide mutation away from a furin cleavage site (FCS) that enhances infectivity in other coronaviruses, including SARS-CoV-2. However, mutating this motif to an FCS does not enable spike cleavage. Overall, while UK sarbecoviruses would require further molecular adaptations to infect humans, their zoonotic risk warrants closer surveillance.

Differentially expressed transcripts of Tetracapsuloides bryosalmonae (Cnidaria) between carrier and dead-end hosts involved in key biological processes: novel insights from a coupled approach of FACS and RNA sequencing

Tetracapsuloides bryosalmonae is a malacosporean endoparasite that infects a wide range of salmonids and causes proliferative kidney disease (PKD). Brown trout serves as a carrier host whereas rainbow trout represents a dead-end host. We thus asked if the parasite adapts to the different hosts by changing molecular mechanisms. We used fluorescent activated cell sorting (FACS) to isolate parasites from the kidney of brown trout and rainbow trout following experimental infection with T. bryosalmonae. The sorted parasite cells were then subjected to RNA sequencing. By this approach, we identified 1120 parasite transcripts that were expressed differentially in parasites derived from brown trout and rainbow trout. We found elevated levels of transcripts related to cytoskeleton organisation, cell polarity, peptidyl-serine phosphorylation in parasites sorted from brown trout. In contrast, transcripts related to translation, ribonucleoprotein complex biogenesis and subunit organisation, non-membrane bounded organelle assembly, regulation of protein catabolic process and protein refolding were upregulated in rainbow trout-derived parasites. These findings show distinct molecular adaptations of parasites, which may underlie their distinct outcomes in the two hosts. Moreover, the identification of these differentially expressed transcripts may enable the identification of novel drug targets that may be exploited as treatment against T. bryosalmonae. We here also describe for the first time how FACS based isolation of T. bryosalmonae cells from infected kidney of fish fosters research and allows to define differentially expressed parasite transcripts in carrier and dead-end fish hosts.

Understanding physiological and molecular adaptations of three diverse halophytic grasses under saline and sodic stresses

Physiological and biochemical analyses of three halophytes were conducted to explore their tolerance and phytoremediation potential. The halophytes Urochondra setulosa, Sporobolus marginatus and Leptochloa fusca were categorised based on gas exchange attributes, antioxidant system, biomass production under soil salinity (ECe 30-50 dS/m) and sodicity (pH 9.5-10). L. fusca and S. marginatus produced slightly higher biomass under the sodic condition of pH 9.5, while in U. setulosa, it increased under salinity stress. Under sodic conditions, L. fusca showed less reduction in potassium content and maintained a higher K+/Na+ ratio in their leaf tissues. A maximum decrease in net photosynthesis was observed in L. fusca (28.55%) at ECe ~ 50 dS m-1 while minimum in S. marginatus (13.73%) at pH ~ 10.0. Comparatively, U. setulosa showed higher stomatal conductance and transpiration rate than L. fusca and S. marginatus. At the highest pH and salinity, the antioxidant activities of enzymes APX, SOD, GR and POX increased in all three halophytes. Quantitative expression of MnSOD, NHX1 and FuSOS1 genes in all three halophytes increased with salt stresses. Based on these indicators, these halophytes were categorised as salt-tolerant or alkaline-stress-tolerant.

Implications of a temperature-dependent heat capacity for temperature-gated ion channels

Temperature influences dynamics and state-equilibrium distributions in all molecular processes, and only a relatively narrow range of temperatures is compatible with life-organisms must avoid temperature extremes that can cause physical damage or metabolic disruption. Animals evolved a set of sensory ion channels, many of them in the family of transient receptor potential cation channels that detect biologically relevant changes in temperature with remarkable sensitivity. Depending on the specific ion channel, heating or cooling elicits conformational changes in the channel to enable the flow of cations into sensory neurons, giving rise to electrical signaling and sensory perception. The molecular mechanisms responsible for the heightened temperature-sensitivity in these ion channels, as well as the molecular adaptations that make each channel specifically heat- or cold-activated, are largely unknown. It has been hypothesized that a heat capacity difference (ΔCp) between two conformational states of these biological thermosensors can drive their temperature-sensitivity, but no experimental measurements of ΔCp have been achieved for these channel proteins. Contrary to the general assumption that the ΔCp is constant, measurements from soluble proteins indicate that the ΔCp is likely to be a function of temperature. By investigating the theoretical consequences for a linearly temperature-dependent ΔCp on the open-closed equilibrium of an ion channel, we uncover a range of possible channel behaviors that are consistent with experimental measurements of channel activity and that extend beyond what had been generally assumed to be possible for a simple two-state model, challenging long-held assumptions about ion channel gating models at equilibrium.

Effects of high-resistance wheel running on hallmarks of endurance and resistance training adaptations in mice.

Exercise effectively promotes and preserves cardiorespiratory, neuromuscular, metabolic, and cognitive functions throughout life. The molecular mechanisms underlying the beneficial adaptations to exercise training are, however, still poorly understood. To improve the mechanistic study of specific exercise training adaptations, standardized, physiological, and well-characterized training interventions are required. Therefore, we performed a comprehensive interrogation of systemic changes and muscle-specific cellular and molecular adaptations to voluntary low-resistance wheel running (Run) and progressive high-resistance wheel running (RR) in young male mice. Following 10 weeks of training, both groups showed similar improvements in body composition and peak oxygen uptake (V̇O2peak ), as well as elevated mitochondrial proteins and capillarization markers in the M. plantaris. Run mice clearly outperformed RR mice in a forced treadmill running capacity test, while RR mice displayed increased grip strength as well as superior mass gains in the M. soleus, associated with distinct proteomic changes specifying the two paradigms. Thus, even though both training modalities induce overlapping adaptations, Run interventions preferably improve submaximal running performance, while progressive RR is a valid model to study training-induced gains in grip strength and plantar flexor hypertrophy.

Large-scale phylogenomics of aquatic bacteria reveal molecular mechanisms for adaptation to salinity.

The crossing of environmental barriers poses major adaptive challenges. Rareness of freshwater-marine transitions separates the bacterial communities, but how these are related to brackish counterparts remains elusive, as do the molecular adaptations facilitating cross-biome transitions. We conducted large-scale phylogenomic analysis of freshwater, brackish, and marine quality-filtered metagenome-assembled genomes (11,248). Average nucleotide identity analyses showed that bacterial species rarely existed in multiple biomes. In contrast, distinct brackish basins cohosted numerous species, but their intraspecific population structures displayed clear signs of geographic separation. We further identified the most recent cross-biome transitions, which were rare, ancient, and most commonly directed toward the brackish biome. Transitions were accompanied by systematic changes in amino acid composition and isoelectric point distributions of inferred proteomes, which evolved over millions of years, as well as convergent gains or losses of specific gene functions. Therefore, adaptive challenges entailing proteome reorganization and specific changes in gene content constrains the cross-biome transitions, resulting in species-level separation between aquatic biomes.