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Purified human globin injected into rats forms aggregates which are identifiable by their characteristic appearance in thin sections in the electron microscope and by their positive autoradiographs when the globin is tritiated before injection. Globin is taken up by endothelial cells of glomerular capillaries and is transported across the cell within the limits of a surrounding membrane. Globin is rarely seen to pass through fenestrations. Globin is also taken into the stalk region where it is seen usually within the sponge fibers and only occasionally within stalk cells. Globin is seen in all stages of passage through the basement membranes and sponge fibers, which are not deformed by its passage. On the basis of the findings presented here and by others, it is postulated that the basement membrane and sponge fibers consist of a thixotrophic gel. After traversing the basement membrane, the globin passes between foot processes of the epithelial cells. The slit membranes are deformed by this passage and thus appear to be distinctive structures. The globin is next found free in Bowman's space; the earliest aggregates are seen there within 1 minute after injection. Globin taken up in the stalk region is slowly discharged and very little is found there 6 hours postinjection.

The multidrug resistance‐associated protein (MRP) ABCC4 facilitates substrate transport across the cytoplasmic membrane, crucial for normal physiology and mediating multidrug resistance in tumor cells. Despite intensive studies on MRPs, ABCC4's transport mechanism remains incompletely understood. In this study, we unveiled an inward‐open conformation with an ATP bound to degenerate NBD1. Additionally, we captured the structure with both ATP and substrate co‐bound in the inward‐open state. Our findings uncover the asymmetric ATP binding in ABCC4 and provide insights into substrate binding and transport mechanisms. ATP binding to NBD1 is parallel to substrate binding to ABCC4, and is a prerequisite for ATP‐bound NBD2‐induced global conformational changes. Our findings shed new light on targeting ABCC4 in combination with anticancer therapy. [ABSTRACT FROM AUTHOR]

ObjectiveDespite great advances in obesity therapeutics in recent years, there is still a need to identify additional therapeutic targets for the treatment of this disease. We previously discovered a signature of genes, including Chloride intracellular channel 1 (Clic1), whose expression was associated with drug-induced weight gain, and in these studies, we assess the effect of Clic1 inhibition on food intake and body weight in mice.MethodsWe studied the impact of Clic1 inhibition in mouse models of binge-eating, diet-induced obese mice and genetic models of obesity (Magel2 KO mice).ResultsClic1 knockout (KO) mice ate significantly less and had a lower body weight than WT littermates when either fed chow or high fat diet. Furthermore, pharmacological inhibition of Clic1 in diet-induced obese mice resulted in suppression of food intake and promoted highly efficacious weight loss. Clic1 inhibition also reduced food intake in binge-eating models and hyperphagic Magel2 KO mice. We observed that chronic obesity resulted in a significant change in subcellular localization of Clic1 with an increased ratio of Clic1 in the membrane in the obese state. These observations provide a novel therapeutic strategy to block Clic1 translocation as a potential mechanism to reduce food intake and lower body weight.ConclusionsThese studies attribute a novel role of Clic1 as a driver of food intake and overconsumption. In summary, we have identified hypothalamic expression of Clic1 plays a key role in food intake, providing a novel therapeutic target to treat overconsumption that is the root cause of modern obesity.

Intrinsically disordered regions (IDRs) within human proteins play critical roles in cellular information processing, including signaling, transcription, stress response, DNA repair, genome organization, and RNA processing. Here, we summarize current challenges in the field and propose cutting-edge approaches to address them in physiology and disease processes, with a focus on cancer. Intrinsically disordered regions (IDRs) within human proteins play critical roles in cellular information processing, including signaling, transcription, stress response, DNA repair, genome organization, and RNA processing. Here, we summarize current challenges in the field and propose cutting-edge approaches to address them in normal physiology and disease, with a focus on cancer. [ABSTRACT FROM AUTHOR]

The ruminants' productive capacity was enhanced by the addition of protein sources high in non-hydrolyzed protein to the Rumen because of its palatability, availability in large quantities, balanced amino acid composition, and rapid decomposition in the Rumen; the various commonly used soybean meal is one of the protein sources in ruminant feed and the most widely used in nutrition. However, its high cost led to the search for alternatives to it at a lower cost; one of these additives is corn gluten meal, which is a by-product of the manufacturing because corn gluten gain has a protein content of 60–65% crude protein, it eliminates the need to supplement traditional feed with protein sources, lowering the cost of feed. Urea is one of the most essential nitrogenous additives that are used to improve the nutritional value and benefit from coarse feed, and because it has a value almost equal to the concentrates for ruminants, as urea decomposes in the Rumen at high speed to ammonia, which is used to produce amino acids and microbial protein by microbiology, and those substances are utilized protein substances by the animal. [ABSTRACT FROM AUTHOR]

Background: Protein S-nitrosylation (SNO) plays a key role in transferring nitric oxide-mediated signals in both animals and plants and has emerged as an important mechanism for regulating protein functions and cell signaling of all main classes of protein. It is involved in several biological processes including immune response, protein stability, transcription regulation, post translational regulation, DNA damage repair, redox regulation, and is an emerging paradigm of redox signaling for protection against oxidative stress. The development of robust computational tools to predict protein SNO sites would contribute to further interpretation of the pathological and physiological mechanisms of SNO. Results: Using an intermediate fusion-based stacked generalization approach, we integrated embeddings from supervised embedding layer and contextualized protein language model (ProtT5) and developed a tool called pLMSNOSite (protein language model-based SNO site predictor). On an independent test set of experimentally identified SNO sites, pLMSNOSite achieved values of 0.340, 0.735 and 0.773 for MCC, sensitivity and specificity respectively. These results show that pLMSNOSite performs better than the compared approaches for the prediction of S-nitrosylation sites. Conclusion: Together, the experimental results suggest that pLMSNOSite achieves significant improvement in the prediction performance of S-nitrosylation sites and represents a robust computational approach for predicting protein S-nitrosylation sites. pLMSNOSite could be a useful resource for further elucidation of SNO and is publicly available at https://github.com/KCLabMTU/pLMSNOSite. [ABSTRACT FROM AUTHOR]

Nitric oxide releasing compound sodium nitroprusside (SNP) is regarded as novel chemical to beat the daunting challenges of postharvest losses in cut flowers. In the recent years, it has yielded propitious results as postharvest vase preservative for cut flowers. Our study explicates the efficacy of SNP in mitigating postharvest senescence in Consolida ajacis (L.) Schur cut spikes. The freshly excised C. ajacis spikes were subjected to different SNP treatments viz , 20 μM, 40 μM, 60 μM and 80 μM. The control spikes were held in distilled water. The spikes held in test solutions showed a marked improvement in vase life and flower quality. Our results indicate a profound surge in sugars, phenols and soluble proteins in SNP-treated spikes over control. Moreover, the SNP treatments improved membrane stability as signposted by decreased lipoxygenase activity (LOX). The SNP treatments also upregulated different antioxidant enzymes viz , ascorbate peroxidase (APX), catalase (CAT) and superoxide dismutase (SOD). The current study recommends 40 μM SNP as optimum concentration for preserving floral quality and extending display period of C. ajacis spikes. Together, these findings reveal that SNP at proper dosage can efficiently alleviate deteriorative postharvest changes by modulating physiological and biochemical mechanisms underlying senescence. Nitric oxide is regarded as novel chemical to beat the daunting challenges of postharvest losses in cut flowers. Flower quality and vase life are crucial postharvest attributes key to marketability and customer satisfaction of cut flowers. Our study explicates the efficacy of nitric oxide in mitigating postharvest senescence in Consolida ajacis (L.) Schur cut spikes. [ABSTRACT FROM AUTHOR]

The keynote speaker was Lasker Laureate Professor Kazutoshi Mori, speaking on the unfolded protein response, and there were sessions on: glycation in obesity, diabetes, and diabetic complications; glycation in food; glycation through the life course - from maternal bonding to aging; glycation in plants - physiology, function, and food security; glycation in the COVID-19 response; glycation analytics and chemistry; glycation in kidney disease, cancer, and mental health; glycation-related imaging, diagnostic algorithms, and therapeutics; and methods and models in glycation research. 10.3390/ijms21113942 23 Rabbani N., Xue M., Thornalley P.J. Dicarbonyl stress, protein glycation and the unfolded protein response. Glyoxalase expression in malignancy, anti-proliferative effects of methylglyoxal, glyoxalase I inhibitor diesters and S -D-lactoylglutathione, and methylglyoxal-modified protein binding and endocytosis by the advanced glycation endproduct receptor. On 20-24 September 2021, leading researchers in the field of glycation met online at the 14th International Symposium on the Maillard Reaction (IMARS-14), hosted by the authors of this introductory editorial, who are from Doha, Qatar. [Extracted from the article]

Aims In cardiomyocytes, acute disturbances to intracellular pH (pHi) are promptly corrected by a system of finely tuned sarcolemmal acid–base transporters. However, these fluxes become thermodynamically re-balanced in acidic environments, which inadvertently causes their set-point pHi to fall outside the physiological range. It is unclear whether an adaptive mechanism exists to correct this thermodynamic challenge, and return pHi to normal. Methods and results Following left ventricle cryo-damage, a diffuse pattern of low extracellular pH (pHe) was detected by acid-sensing pHLIP. Despite this, pHi measured in the beating heart (13C NMR) was normal. Myocytes had adapted to their acidic environment by reducing Cl−/ HCO 3 − exchange (CBE)-dependent acid-loading and increasing Na+/H+ exchange (NHE1)-dependent acid-extrusion, as measured by fluorescence (cSNARF1). The outcome of this adaptation on pHi is revealed as a cytoplasmic alkalinization when cells are superfused at physiological pHe. Conversely, mice given oral bicarbonate (to improve systemic buffering) had reduced myocardial NHE1 expression, consistent with a needs-dependent expression of pHi-regulatory transporters. The response to sustained acidity could be replicated in vitro using neonatal ventricular myocytes incubated at low pHe for 48 h. The adaptive increase in NHE1 and decrease in CBE activities was linked to Slc9a1 (NHE1) up-regulation and Slc4a2 (AE2) down-regulation. This response was triggered by intracellular H+ ions because it persisted in the absence of CO2/ HCO 3 − and became ablated when acidic incubation media had lower chloride, a solution manoeuvre that reduces the extent of pHi-decrease. Pharmacological inhibition of FAK-family non-receptor kinases, previously characterized as pH-sensors, ablated this pHi autoregulation. In support of a pHi-sensing role, FAK protein Pyk2 (auto)phosphorylation was reduced within minutes of exposure to acidity, ahead of adaptive changes to pHi control. Conclusions Cardiomyocytes fine-tune the expression of pHi-regulators so that pHi is at least 7.0. This autoregulatory feedback mechanism defines physiological pHi and protects it during pHe vulnerabilities. [ABSTRACT FROM AUTHOR]

[Display omitted] • J-domain proteins (JDPs) confer multifunctionality to Hsp70. • Modular domain organization of JDPs enables for functional diversifications. • JDPs fulfill fundamental functions in central protein quality control (PQC) pathways. • JDPs exert overlapping but also specialized PQC activities. • JDPs couple protein damage to chaperone gene expression. The Hsp70 chaperone system is a central component of cellular protein quality control (PQC) by acting in a multitude of protein folding processes ranging from the folding of newly synthesized proteins to the disassembly and refolding of protein aggregates. This multifunctionality of Hsp70 is governed by J-domain proteins (JDPs), which act as indispensable co-chaperones that target specific substrates to Hsp70. The number of distinct JDPs present in a species always outnumbers Hsp70, documenting JDP function in functional diversification of Hsp70. In this review, we describe the physiological roles of JDPs in the Saccharomyces cerevisiae PQC system, with a focus on the abundant JDP generalists, Zuo1, Ydj1 and Sis1, which function in fundamental cellular processes. Ribosome-bound Zuo1 cooperates with the Hsp70 chaperones Ssb1/2 in folding and assembly of nascent polypeptides. Ydj1 and Sis1 cooperate with the Hsp70 members Ssa1 to Ssa4 to exert overlapping functions in protein folding and targeting of newly synthesized proteins to organelles including mitochondria and facilitating the degradation of aberrant proteins by E3 ligases. Furthermore, they act in protein disaggregation reactions, though Ydj1 and Sis1 differ in their modes of Hsp70 cooperation and substrate specificities. This results in functional specialization as seen in prion propagation and the underlying dominant role of Sis1 in targeting Hsp70 for shearing of prion amyloid fibrils. [ABSTRACT FROM AUTHOR]

ObjectiveIdentify determinants of plasma adropin concentrations, a secreted peptide translated from the Energy Homeostasis Associated (ENHO) gene linked to metabolic control and vascular function.MethodsAssociations between plasma adropin concentrations, demographics (sex, age, BMI) and circulating biomarkers of lipid and glucose metabolism were assessed in plasma obtained after an overnight fast in humans. The regulation of adropin expression was then assessed in silico, in cultured human cells, and in animal models.ResultsIn humans, plasma adropin concentrations are inversely related to atherogenic LDL-cholesterol (LDL-C) levels in men (n = 349), but not in women (n = 401). Analysis of hepatic Enho expression in male mice suggests control by the biological clock. Expression is rhythmic, peaking during maximal food consumption in the dark correlating with transcriptional activation by RORα/γ. The nadir in the light phase coincides with the rest phase and repression by Rev-erb. Plasma adropin concentrations in nonhuman primates (rhesus monkeys) also exhibit peaks coinciding with feeding times (07:00 h, 15:00 h). The ROR inverse agonists SR1001 and the 7-oxygenated sterols 7-β-hydroxysterol and 7-ketocholesterol, or the Rev-erb agonist SR9009, suppress ENHO expression in cultured human HepG2 cells. Consumption of high-cholesterol diets suppress expression of the adropin transcript in mouse liver. However, adropin over expression does not prevent hypercholesterolemia resulting from a high cholesterol diet and/or LDL receptor mutations.ConclusionsIn humans, associations between plasma adropin concentrations and LDL-C suggest a link with hepatic lipid metabolism. Mouse studies suggest that the relationship between adropin and cholesterol metabolism is unidirectional, and predominantly involves suppression of adropin expression by cholesterol and 7-oxygenated sterols. Sensing of fatty acids, cholesterol and oxysterols by the RORα/γ ligand-binding domain suggests a plausible functional link between adropin expression and cellular lipid metabolism. Furthermore, the nuclear receptors RORα/γ and Rev-erb may couple adropin synthesis with circadian rhythms in carbohydrate and lipid metabolism.

Serine/arginine-rich (SR) proteins are a type of splicing factor. They play significant roles in constitutive and alternative pre-mRNA splicing, and are involved in post-splicing activities, such as mRNA nuclear export, nonsense-mediated mRNA decay, mRNA translation, and miRNA biogenesis. In plants, SR proteins function under a complex regulatory network by protein–protein and RNA–protein interactions between SR proteins, other splicing factors, other proteins, or even RNAs. The regulatory networks of SR proteins are complex—they are regulated by the SR proteins themselves, they are phosphorylated and dephosphorylated through interactions with kinase, and they participate in signal transduction pathways, whereby signaling cascades can link the splicing machinery to the exterior environment. In a complex network, SR proteins are involved in plant growth and development, signal transduction, responses to abiotic and biotic stresses, and metabolism. Here, I review the current status of research on plant SR proteins, construct a model of SR proteins function, and ask many questions about SR proteins in plants. [ABSTRACT FROM AUTHOR]

N6‐Methyladenosine (m6A) is the most common internal RNA modification in the consensus sequence of 5′‐RRACH‐3′. The methyl mark is added by writer proteins (METTL3/METTL14 metyltransferase complex) and removed by eraser proteins (m6A demethylases; FTO and ALKBH5). Recognition of this methyl mark by m6A reader proteins leads to changes in RNA metabolism. How the writer and eraser proteins determine their targets is not well‐understood, despite the importance of this information in understanding the regulatory mechanisms and physiological roles of m6A. However, approaches for targeted manipulation of the methylation state at specific sites are being developed. In this review, I summarize the recent findings on the mechanisms of target identification of m6A regulatory proteins, as well as recent approaches for targeted m6A modifications. [ABSTRACT FROM AUTHOR]

The study aimed to evaluate the effects of different stages of lactation (0 to > 300 d) and pregnancy (0 to > 180 d) on serum amyloid A (SAA), C-reactive protein (CRP), glucose, total cholesterol (TCho), and triglyceride (TG) concentrations in dairy cows of different breeds. Thus, 40 healthy multiparous cows (10 Holstein, 10 Simmental, 10 Brown, and 10 Modicana) were randomly selected, and blood samples were collected once every 60 d for 1 year. Overall, SAA and CRP serum concentrations progressively increased and became more variable along the lactation, peaking at > 240–300 d, and then decreased in the last period (> 300 d). Along pregnancy, SAA and CRP initially increased, with the highest concentrations at > 60–120 d, and then decreased until the last phase of pregnancy (> 180 d). However, lactation and gestation phases did not significantly affect SAA and CRP when all the cows were analyzed together. A significant and positive correlation was observed between SAA and CRP both along lactation (r=0.89 ; p<0.0001) and pregnancy (r=0.91 ; p<0.0001). Breeds only showed differences in CRP levels along gestation (p=0.0102), due to a peak registered at 0–60 d in Holstein cows. In pregnant cows, glucose was positively correlated with SAA (r=0.43 ; p=0.0017) and CRP (r=0.42 ; p=0.0019). Hence, these significant and positive relationships reflect the physiological adaptations of the dairy cows along both gestational and lactational dynamics, suggesting that these proteins may also be involved in non-pathological processes. In this perspective, this study established that the obtained response markedly varies among healthy individuals along lactation and gestation and thus that the physiological range of acute-phase proteins (APPs) is wide; this makes it difficult to use these proteins as a marker of different physiological reproductive and productive periods. [ABSTRACT FROM AUTHOR]

Calcium- and integrin-binding protein 2 (CIB2) is a small EF-hand protein capable of binding Mg2+ and Ca2+ ions. While its biological function remains largely unclear, an increasing number of studies have shown that CIB2 is an essential component of the mechano-transduction machinery that operates in cochlear hair cells. Mutations in the gene encoding CIB2 have been associated with non-syndromic deafness. In addition to playing an important role in the physiology of hearing, CIB2 has been implicated in a multitude of very different processes, ranging from integrin signaling in platelets and skeletal muscle to autophagy, suggesting extensive functional plasticity. In this review, we summarize the current understanding of biochemical and biophysical properties of CIB2 and the biological roles that have been proposed for the protein in a variety of processes. We also highlight the many molecular aspects that remain unclarified and deserve further investigation. [ABSTRACT FROM AUTHOR]

Background: Cancer, a metabolic disorder with multifactorial input, is the most complex human disease to study and find a cure. Over several decades, massive research effort leads to a better understanding molecular biology of cancer and its progression. Plants and animals both were explored for novel anti-tumor agents, and enzyme-based drugs have shown significant results. These animals evolved with an enzyme with promiscuous nature capable of catalyzing multiple biochemical reactions. Enzymes are an integral part of animal physiology and are reported excellent sources of the drug. Objectives: The study aimed to isolate, purify and characterize the protein component from Aporrectodea longa for anti-cancer potential. Materials and Methods: A. longa species earthworms were collected and processed for the extraction of total protein content. The anti-tumor protein component was purified via salt precipitation, charge-based purification, and sizebased purification. SDS-PAGE was used to investigate molecular weight information. The anti-tumor activity was evaluated using different cell lines, including MCF 7, Hep G2, and HT 29 with Cisplatin, 5-fluorouracil, and tamoxifen as a standard anti-cancer drug. Results: The isolated and purified protein fraction had shown proteolytic activity against casein and fibrinogen. Protein fraction represents a serine protease and average molecular weight of nearly 42kDa. The result shows protein component possesses excellent antitumor activity analyzed by MTT assay. Conclusion: Anti-tumor activity of isolated and purified protein fraction from A. longa may serve as a potential candidate for anti-cancer therapy. However, molecular studies are required to explore the precise mechanism of action of candidate protein. [ABSTRACT FROM AUTHOR]

Robust adhesion to wet, salt-encrusted, corroded and slimy surfaces has been an essential adaptation in the life histories of sessile marine organisms for hundreds of millions of years, but it remains a major impasse for technology. Mussel adhesion has served as one of many model systems providing a fundamental understanding of what is required for attachment to wet surfaces. Most polymer engineers have focused on the use of 3,4-dihydroxyphenyl-l-alanine (Dopa), a peculiar but abundant catecholic amino acid in mussel adhesive proteins. The premise of this Review is that although Dopa does have the potential for diverse cohesive and adhesive interactions, these will be difficult to achieve in synthetic homologs without a deeper knowledge of mussel biology; that is, how, at different length and time scales, mussels regulate the reactivity of their adhesive proteins. To deposit adhesive proteins onto target surfaces, the mussel foot creates an insulated reaction chamber with extreme reaction conditions such as low pH, low ionic strength and high reducing poise. These conditions enable adhesive proteins to undergo controlled fluid-fluid phase separation, surface adsorption and spreading, microstructure formation and, finally, solidification.

Cardiovascular disease (CVD) and stroke affect over 92 million Americans and account for nearly 1 out of 3 deaths in the US. The use of animal models in cardiovascular research has led to considerable advances in treatment and in our understanding of the pathophysiology of many CVDs. Still, animals may not fully recapitulate human disease states; species differences have long been postulated to be one of the main reasons for a failure of translation between animals and humans in drug discovery and development. Indeed, it has become increasingly clear over the past few decades that to answer certain biomedical questions, like the physiological mechanisms that go awry in many human CVDs, animal tissues may not always be the best option to use. While human cardiac tissue has long been used for laboratory research, published findings often contradict each other, leading to difficulties in interpretation. Current difficulties in utilizing human cardiac tissue include differences in acquisition time, varying tissue procurement protocols, and the struggle to define a human "control" sample. With the tremendous emphasis on translational research that continues to grow, research studies using human tissues are becoming more common. This mini review will discuss advantages, disadvantages, and considerations of using human cardiac tissue in the study of CVDs, paying specific attention to the study of phosphoproteins. [ABSTRACT FROM AUTHOR]

Background: Targeting glutamine metabolism is previously indicated as a potential and attractive strategy for gastric cancer (GC) therapy. However, the underlying mechanisms responsible for the modification of glutamine metabolism in GC cells have not been fully elucidated. Accordingly, the current study sought to investigate the physiological mechanisms of RUNX3-mediated circDYRK1A in glutamine metabolism of GC.Methods: Firstly, GC tissues and adjacent normal tissues were obtained from 50 GC patients to determine circDYRK1A expression in GC tissues. Next, the binding affinity among RUNX3, circDYRK1A, miR-889-3p, and FBXO4 was detected to clarify the mechanistic basis. Moreover, GC cells were subjected to ectopic expression and knockdown manipulations of circDYRK1A, miR-889-3p, and/or FBXO4 to assay GC cell malignant phenotypes, levels of glutamine, glutamic acid, and α-KG in cell supernatant and glutamine metabolism-related proteins (GLS and GDH). Finally, nude mice were xenografted with GC cells to explore the in vivo effects of circDYRK1A on the tumorigenicity and apoptosis.Results: circDYRK1A was found to be poorly expressed in GC tissues. RUNX3 was validated to bind to the circDYRK1A promoter, and circDYRK1A functioned as a miR-889-3p sponge to up-regulate FBXO4 expression. Moreover, RUNX3-upregulated circDYRK1A reduced levels of glutamine, glutamic acid, and α-KG, and protein levels of GLS and GDH, and further diminished malignant phenotypes in vitro. Furthermore, in vivo experimentation substantiated that circDYRK1A inhibited the tumorigenicity and augmented the apoptosis in GC.Conclusion: In conclusion, these findings highlighted the significance and mechanism of RUNX3-mediated circDYRK1A in suppressing glutamine metabolism in GC via the miR-889-3p/FBXO4 axis. [ABSTRACT FROM AUTHOR]

Objective: Existing burn resuscitation protocols exhibit a large variability in treatment efficacy. Hence, they must be further optimized based on comprehensive knowledge of burn pathophysiology. A physics-based mathematical model that can replicate physiological responses in diverse burn patients can serve as an attractive basis to perform non-clinical testing of burn resuscitation protocols and to expand knowledge on burn pathophysiology. We intend to develop, optimize, validate, and analyze a mathematical model to replicate physiological responses in burn patients. Methods: Using clinical datasets collected from 233 burn patients receiving burn resuscitation, we developed and validated a mathematical model applicable to computer-aided in-human burn resuscitation trial and knowledge expansion. Using the validated mathematical model, we examined possible physiological mechanisms responsible for the cohort-dependent differences in burn pathophysiology between younger versus older patients, female versus male patients, and patients with versus without inhalational injury. Results: We demonstrated that the mathematical model can replicate physiological responses in burn patients associated with wide demographic characteristics and injury severity, and that an increased inflammatory response to injury may be a key contributing factor in increasing the mortality risk of older patients and patients with inhalation injury via an increase in the fluid retention. Conclusion: We developed and validated a physiologically plausible mathematical model of volume kinetic and kidney function after burn injury and resuscitation suited to in-human application. Significance: The mathematical model may provide an attractive platform to conduct non-clinical testing of burn resuscitation protocols and test new hypotheses on burn pathophysiology. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) and stroke affect over 92 million Americans and account for nearly 1 out of 3 deaths in the US. The use of animal models in cardiovascular research has led to considerable advances in treatment and in our understanding of the pathophysiology of many CVDs. Still, animals may not fully recapitulate human disease states; species differences have long been postulated to be one of the main reasons for a failure of translation between animals and humans in drug discovery and development. Indeed, it has become increasingly clear over the past few decades that to answer certain biomedical questions, like the physiological mechanisms that go awry in many human CVDs, animal tissues may not always be the best option to use. While human cardiac tissue has long been used for laboratory research, published findings often contradict each other, leading to difficulties in interpretation. Current difficulties in utilizing human cardiac tissue include differences in acquisition time, varying tissue procurement protocols, and the struggle to define a human “control” sample. With the tremendous emphasis on translational research that continues to grow, research studies using human tissues are becoming more common. This mini review will discuss advantages, disadvantages, and considerations of using human cardiac tissue in the study of CVDs, paying specific attention to the study of phosphoproteins.

The excretion of nitrogenous waste products in the form of ammonia (NH3) and ammonium (NH4 (+)) is a fundamental process in aquatic organisms. For mytilid bivalves, little is known about the mechanisms and sites of excretion. This study investigated the localization and the mechanisms of ammonia excretion in mytilid mussels. An Rh protein was found to be abundantly expressed in the apical cell membrane of the plicate organ, which was previously described as a solely respiratory organ. The Rh protein was also expressed in the gill, although at significantly lower concentrations, but was not detectable in mussel kidney. Furthermore, NH3/NH4 (+) was not enriched in the urine, suggesting that kidneys are not involved in active NH3/NH4 (+) excretion. Exposure to elevated seawater pH of 8.5 transiently reduced NH3/NH4 (+) excretion rates, but they returned to control values following 24 h acclimation. These mussels had increased abundance of V-type H(+)-ATPase in the apical membranes of plicate organ cells; however, NH3/NH4 (+) excretion rates were not affected by the V-type H(+)-ATPase specific inhibitor concanamycin A (100 nmol l(-1)). In contrast, inhibition of ciliary beating with dopamine and increased seawater viscosity significantly reduced NH3 excretion rates under control pH (8.0). These results suggest that NH3/NH4 (+) excretion in mytilid mussels takes place by passive NH3 diffusion across respiratory epithelia via the Rh protein, facilitated by the water current produced for filter feeding, which prevents accumulation of NH3 in the boundary layer. This mechanism would be energy efficient for sessile organisms, as they already generate water currents for filter feeding.

The article presents a study that explores structures of neurokinin 1 receptor in complex with Gq and Gs proteins reveal substance P binding mode and unique activation features. It mentions that structures provide important structural insights into ligand and G protein promiscuity, the lack of basal signaling, and agonist- and antagonist-induced conformations in the neurokinin receptor family.

Secretory proteins are an essential component of interorgan communication networks that regulate animal physiology. Current approaches for identifying secretory proteins from specific cell and tissue types are largely limited to in vitro or ex vivo models which often fail to recapitulate in vivo biology. As such, there is mounting interest in developing in vivo analytical tools that can provide accurate information on the origin, identity, and spatiotemporal dynamics of secretory proteins. Here, we describe iSLET (in situ Secretory protein Labeling via ER-anchored TurboID) which selectively labels proteins that transit through the classical secretory pathway via catalytic actions of Sec61b-TurboID, a proximity labeling enzyme anchored in the ER lumen. To validate iSLET in a whole-body system, we express iSLET in the mouse liver and demonstrate efficient labeling of liver secretory proteins which could be tracked and identified within circulating blood plasma. Furthermore, proteomic analysis of the labeled liver secretome enriched from liver iSLET mouse plasma is highly consistent with previous reports of liver secretory protein profiles. Taken together, iSLET is a versatile and powerful tool for studying spatiotemporal dynamics of secretory proteins, a valuable class of biomarkers and therapeutic targets. The in vivo identification of proteins secreted from a specific cell type or tissue remains challenging. Here, the authors develop a proximity labeling-based method to selectively label secreted proteins and combine it with proteomics to identify liver secretory proteins in mouse plasma. [ABSTRACT FROM AUTHOR]