Preliminary investigation into long-term stress by isolated captivity-related changes of reproduction hormones in Cynomolgus monkey.

BACKGROUND: Stress profoundly affects physical and emotional well-being, extending its physiological influence to the female menstrual cycle, impeding the hypothalamus-pituitary-gonadal (HPG) axis, and affecting fertility by suppressing sex-stimulating hormones. METHODS: In this study, we meticulously analyzed menstrual cycles and corresponding hormonal fluctuations in three female Cynomolgus monkeys. RESULTS: The preliminary findings indicated lower-than-normal levels of cortisol, follicle-stimulating hormone (FSH), and estradiol. Anovulatory bleeding occurred in one monkey, which could be linked to stress. In contrast to cortisol, alkaline phosphatase (ALP), which is correlated to cortisol levels, was consistently elevated in menstruating monkeys, suggesting its potential as a stress indicator. The non-menstruating group exhibited stress-related weight loss, emphasizing the observed ALP trends. CONCLUSIONS: Non-menstruating monkeys may experience more stress than menstruating monkeys. The implications of this study extend beyond the confines of primate studies and offer a valuable method for enhancing the welfare of female Cynomolgus monkeys.

Resilient anatomy and local plasticity of naive and stress haematopoiesis.

The bone marrow adjusts blood cell production to meet physiological demands in response to insults. The spatial organization of normal and stress responses are unknown owing to the lack of methods to visualize most steps of blood production. Here we develop strategies to image multipotent haematopoiesis, erythropoiesis and lymphopoiesis in mice. We combine these with imaging of myelopoiesis1 to define the anatomy of normal and stress haematopoiesis. In the steady state, across the skeleton, single stem cells and multipotent progenitors distribute through the marrow enriched near megakaryocytes. Lineage-committed progenitors are recruited to blood vessels, where they contribute to lineage-specific microanatomical structures composed of progenitors and immature cells, which function as the production sites for each major blood lineage. This overall anatomy is resilient to insults, as it was maintained after haemorrhage, systemic bacterial infection and granulocyte colony-stimulating factor (G-CSF) treatment, and during ageing. Production sites enable haematopoietic plasticity as they differentially and selectively modulate their numbers and output in response to insults. We found that stress responses are variable across the skeleton: the tibia and the sternum respond in opposite ways to G-CSF, and the skull does not increase erythropoiesis after haemorrhage. Our studies enable in situ analyses of haematopoiesis, define the anatomy of normal and stress responses, identify discrete microanatomical production sites that confer plasticity to haematopoiesis, and uncover unprecedented heterogeneity of stress responses across the skeleton.

Increased patient body mass index is associated with increased surgeon physiologic stress during total hip arthroplasty.

INTRODUCTION: While increased body mass index (BMI) in patients undergoing total hip arthroplasty (THA) increases surgical complexity, there is a paucity of objective studies assessing the impact of patient BMI on the cardiovascular stress experienced by surgeons during THA. The aim of this study was to assess the impact of patient BMI on surgeon cardiovascular strain during THA. METHODS: We prospectively evaluated three fellowship-trained arthroplasty surgeons performing a total of 115 THAs. A smart-vest worn by the surgeons recorded mean heart rate, stress index (correlate of sympathetic activation), respiratory rate, minute ventilation, and energy expenditure throughout the procedures. Patient demographics as well as perioperative data including surgical approach, surgery duration, number of assistants, and the timing of the surgery during the day were collected. Linear regression was utilized to assess the impact of patient characteristics and perioperative data on cardiorespiratory metrics. RESULTS: Average surgeon heart rate, energy expenditure, and stress index during surgery were 98.50 beats/min, 309.49 cal/h, and 14.10, respectively. Higher patient BMI was significantly associated with increased hourly energy expenditure (P = 0.027), mean heart rate (P = 0.037), and stress index (P = 0.027) independent of surgical approach. Respiratory rate and minute ventilation were not associated with patient BMI. The number of assistants and time of surgery during the day did not impact cardiorespiratory strain on the surgeon. CONCLUSION: The physiologic burden on surgeons during primary THA significantly increases as patient BMI increases. This study suggests that healthcare systems should consider adjusting reimbursement models to account for increased surgeon workload due to obesity. Further surgeons should adopt strategies in operative planning and case scheduling to handle this added physical strain. LEVEL OF EVIDENCE: III.

Insight on thermal stress response of demosponge Chondrosia reniformis (Nardo, 1847).

Global warming has led to an increase in extreme weather and climate phenomena, including floods and heatwaves. Marine heatwaves have frightening consequences for coastal benthic communities around the world. Each species exhibits a natural range of thermal tolerance and responds to temperature variations through behavioral, physiological, biochemical, and molecular adjustments. Physiological stress leading to disease and mass mortality appears when tolerance thresholds are exceeded. Sessile species are therefore particularly affected by these phenomena. Among these sessile species, marine sponges are important members of coral reef ecosystems. To better understand the sponge thermal stress response, we tested the response of demosponge Chondrosia reniformis (Nardo, 1847) to three different temperatures (8 °C, 24 °C and 30 °C) during two exposure periods of time (4 and 14 h). Histological studies of whole parts of the sponge, biochemical analyses (Defense enzymes) and gene expression levels of some target genes were undertaken in this study. The exposure to cold temperature (8 °C) resulted in inhibition of antioxidant enzymes and less modification in the gene expression level of the heat shock proteins (HSPs). These latter were strongly upregulated after exposure to a temperature of 24 °C for 4 h. However, exposure to 30 °C at both periods of time resulted in indication of HSP, antioxidant enzymes, the gene involved in the apoptosis process (Bcl-2: B-cell lymphoma 2), the gene involved in inflammation (TNF: Tumor Necrosis Factor), as well as the aquaporin gene, involved in H2O2 permeation. Moreover, the normal organization of the whole organism was disrupted by the extension and fusion of choanocyte chambers and alteration of the pinacoderm. Interestingly, exposure to sublethal temperatures may show that this sponge has an adaptation threshold temperature. These insights into the adaptation mechanisms of sponges contribute to better management and conservation of sponges and to the prediction of ecosystem trajectories with future climate change.

Mães em quarentena: maternidade em tempos de isolamento social decorrente da Covid-19 / Madres en cuarentena: la maternidad en tiempos de aislamiento social y Covid-19 / Mothers in quarantine: motherhood in times of social isolation due to Covid-19 pandemic

RESUMO Este estudo teve por objetivo analisar o impacto do isolamento social decorrente da pandemia de Covid-19 sobre a vida familiar, com ênfase na vivência da maternidade e na relação com os filhos. Participaram 20 mães de camadas sociais médias, de 29 a 45 anos, que mantinham atividades laborais a distância e estavam em isolamento social. Foram realizadas entrevistas individuais em profundidade por meio digital. O material coletado foi transcrito e submetido à análise de conteúdo temática. Os resultados mostraram que as mudanças impostas pela pandemia impactaram diretamente a vida familiar, explicitando as desigualdades de gênero na organização da rotina, distribuição de tarefas domésticas e cuidados parentais. Observou-se uma relação ambivalente das mães com a maternidade e com seus imperativos sociais, que reverberam no vínculo que estabelecem com seus filhos. A análise revela que a sobrecarga emocional e física contribui para exacerbar sentimentos de culpa e solidão vivenciados na relação com a maternidade, além de evidenciar conflitos no desempenho dos papéis de mãe, esposa e profissional. As entrevistadas demonstraram exaustão com as demandas domésticas e de cuidados com os filhos, além de conflitos relacionados ao descompasso entre expectativas e padrões sociais que regulam o exercício da maternidade e suas experiências pessoais como mães. As conclusões sugerem a presença de uma crise identitária relacionada aos ideais sociais vinculados às vivências da maternidade, o que convida a pensar na urgência de se olhar para o sofrimento materno, buscando compreender as dimensões subjetivas das transformações que perpassam essa experiência na vigência do isolamento social.

RESUMEN El objetivo de este estudio fue analizar los efectos del aislamiento social resultante de la pandemia de COVID-19 en la vida familiar, con énfasis en la experiencia de la maternidad y la relación con los niños. Participaron 20 madres de estratos sociales medios, de 29 a 45 años de edad, que mantenían actividades laborales a distancia y se encontraban en aislamiento social. Se realizaron entrevistas individuales exhaustivas por medios digitales. El material recopilado se transcribió y se sometió a un análisis de contenido temático. Los resultados mostraron que los cambios impuestos por la pandemia afectaban directamente a la vida familiar, lo que explicaba las desigualdades de género en la organización rutinaria, la distribución de las tareas domésticas y el cuidado de los niños. Se observó una relación ambivalente entre las madres y la maternidad y sus imperativos sociales, que reverberaban en el vínculo que establecen con sus hijos. El análisis revela que la sobrecarga emocional y física contribuye a exacerbar los sentimientos de culpa y soledad experimentados en la relación con la maternidad, además de mostrar conflictos en el desempeño de los papeles de madre, esposa y profesional. Las mujeres entrevistadas mostraron agotamiento con las demandas domésticas y el cuidado de sus hijos, además de conflictos relacionados con el desajuste entre las expectativas y las normas sociales que regulan el ejercicio de la maternidad y sus experiencias personales como madres. Las conclusiones sugieren la presencia de una crisis de identidad ligada a los ideales sociales vinculados a las experiencias de la maternidad, lo que invita a pensar en la urgencia de mirar el sufrimiento materno, tratando de comprender las dimensiones subjetivas de las transformaciones en tiempos de aislamiento social.

ABSTRACT This study aimed to analyze the impacts of the social isolation resulting from the COVID-19 pandemic on family life, with emphasis on the experience of motherhood and the relationship with children. Twenty mothers from the middle social strata, from 29 to 45 years old, who kept working activities at a distance and were in social isolation, participated. In-depth individual interviews were conducted by digital means. The collected material was transcribed and submitted to thematic content analysis. The results showed that the changes imposed by the pandemic directly impacted family life, highlighting gender inequalities in routine organization, distribution of household tasks and parental care. An ambivalent relationship was observed between mothers and maternity and their social imperatives, which reverberated in the bond they establish with their children. The analysis reveals that emotional and physical burden contributes to exacerbate feelings of guilt and loneliness experienced in the relationship with motherhood, in addition to showing conflicts in the performance of the roles of mother, wife and professional. The women interviewed showed exhaustion with domestic and child care demands, in addition to conflicts related to the mismatch between expectations and social standards that regulate the exercise of motherhood and their personal experiences as mothers. The conclusions suggest the presence of an identity crisis due to the social ideals linked to the experiences of motherhood, which invites us to think about the urgency of looking at maternal suffering, seeking to understand the subjective dimensions of the transformations that this experience goes through in the times of social isolation.

Physiological and metabolomic responses of the ethylene insensitive squash mutant etr2b to drought.

The squash gain-of-function mutant etr2b disrupts the ethylene-binding domain of ethylene receptor CpETR2B, conferring partial ethylene insensitivity, changes in flower and fruit development, and enhanced salt tolerance. In this paper, we found that etr2b also confers a growth advantage as well as a physiological and metabolomic response that make the mutant better adapted to drought. Mutant plants had a higher root and leaf biomass than WT under both well-watered and drought conditions, but the reduction in growth parameters in response to drought was similar in WT and etr2b. Water deficit reduced all gas-exchange parameters in both WT and etr2b, but under moderate drought the mutant increased photosynthesis rate in comparison with control conditions, and showed a higher leaf CO2 concentration, transpiration rate, and stomata conductance than WT. The response of etr2b to drought indicates that ethylene is a negative regulator of plant growth under both control and drought. Since etr2b increased ABA content in well-watered plant, but prevented the induction of ABA production in response to drought, it is likely that the etr2b response under drought is not mediated by ABA. A 1H NMR metabolomic analysis revealed that etr2b enhances the accumulation of osmolytes (soluble sugars and trigonelline), unsaturated and polyunsaturated fatty acids, and phenolic compounds under drought, concomitantly with a reduction of malic- and fumaric-acid. The role of CpETR2B and ethylene in the regulation of these drought-protective metabolites is discussed.

House sparrows prioritize skin repair over constitutive innate immunity during long-term chronic stress.

The reactive scope model was created to address two major unanswered questions in stress physiology: how and when does the adaptive acute stress response turn into harmful chronic stress? Previous studies suggest that immunoenhancement should occur in reactive homeostasis (acute stress) and immunosuppression should occur in homeostatic overload (chronic stress). We used this dichotomy of immune function to further elucidate the transition from acute to chronic stress by treating house sparrows (Passer domesticus) with different intensities of chronic stress and then monitoring their immune function. By varying the number of stressors given per day and the length of chronic stress bouts over a period of 6 months, we produced four treatment groups: high, medium, and low stress, and captivity-only. We tracked immunity through the bacterial killing assay and monitored healing of a 4 mm skin biopsy punch. We hypothesized that higher-stress birds would repair their skin more slowly and have lower bacterial killing capacity. The opposite was true-high-stress birds initially repaired their skin fastest. Additionally, all birds dramatically reduced bacterial killing capacity after the biopsy and increased food-derived uric acid, suggesting increased energy acquisition and a shift in immune resources to a more immediate concern (healing). Once healing finished, only the high-stress birds were unable to recover circulating immune function, suggesting that the combination of high stress and an immune challenge pushed these birds into homeostatic overload. Prioritizing healing over other immunological processes might be the best defense for a bird in its natural habitat.

The HAPSTR2 retrogene buffers stress signaling and resilience in mammals.

We recently identified HAPSTR1 (C16orf72) as a key component in a novel pathway which regulates the cellular response to molecular stressors, such as DNA damage, nutrient scarcity, and protein misfolding. Here, we identify a functional paralog to HAPSTR1: HAPSTR2. HAPSTR2 formed early in mammalian evolution, via genomic integration of a reverse transcribed HAPSTR1 transcript, and has since been preserved under purifying selection. HAPSTR2, expressed primarily in neural and germline tissues and a subset of cancers, retains established biochemical features of HAPSTR1 to achieve two functions. In normal physiology, HAPSTR2 directly interacts with HAPSTR1, markedly augmenting HAPSTR1 protein stability in a manner independent from HAPSTR1's canonical E3 ligase, HUWE1. Alternatively, in the context of HAPSTR1 loss, HAPSTR2 expression is sufficient to buffer stress signaling and resilience. Thus, we discover a mammalian retrogene which safeguards fitness.

Second Virtual International Symposium on Cellular and Organismal Stress Responses, September 8-9, 2022.

The Second International Symposium on Cellular and Organismal Stress Responses took place virtually on September 8-9, 2022. This meeting was supported by the Cell Stress Society International (CSSI) and organized by Patricija Van Oosten-Hawle and Andrew Truman (University of North Carolina at Charlotte, USA) and Mehdi Mollapour (SUNY Upstate Medical University, USA). The goal of this symposium was to continue the theme from the initial meeting in 2020 by providing a platform for established researchers, new investigators, postdoctoral fellows, and students to present and exchange ideas on various topics on cellular stress and chaperones. We will summarize the highlights of the meeting here and recognize those that received recognition from the CSSI.

MYB30 integrates light signals with antioxidant biosynthesis to regulate plant responses during postsubmergence recovery.

Submergence is an abiotic stress that limits agricultural production world-wide. Plants sense oxygen levels during submergence and postsubmergence reoxygenation and modulate their responses. Increasing evidence suggests that completely submerged plants are often exposed to low-light stress, owing to the depth and turbidity of the surrounding water; however, how light availability affects submergence tolerance remains largely unknown. Here, we showed that Arabidopsis thaliana MYB DOMAIN PROTEIN30 (MYB30) is an important transcription factor that integrates light signaling and postsubmergence stress responses. MYB DOMAIN PROTEIN30 protein abundance decreased upon submergence and accumulated during reoxygenation. Under submergence conditions, CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1), a central regulator of light signaling, caused the ubiquitination and degradation of MYB30. In response to desubmergence, however, light-induced MYB30 interacted with MYC2, a master transcription factor involved in jasmonate signaling, and activated the expression of the VITAMIN C DEFECTIVE1 (VTC1) and GLUTATHIONE SYNTHETASE1 (GSH1) gene families to enhance antioxidant biosynthesis. Consistent with this, the myb30 knockout mutant showed increased sensitivity to submergence, which was partially rescued by overexpression of VTC1 or GSH1. Thus, our findings uncover the mechanism by which the COP1-MYB30 module integrates light signals with cellular oxidative homeostasis to coordinate plant responses to postsubmergence stress.

Stress granules dynamics: benefits in cancer.

Stress granules (SGs) are stress-induced subcellular compartments, which carry out a particular function to cope with stress. These granules protect cells from stress-related damage and cell death through dynamic sequestration of numerous ribonucleoproteins (RNPs) and signaling proteins, thereby promoting cell survival under both physiological and pathological condition. During tumorigenesis, cancer cells are repeatedly exposed to diverse stress stimuli from the tumor microenvironment, and the dynamics of SGs is often modulated due to the alteration of gene expression patterns in cancer cells, leading to tumor progression as well as resistance to anticancer treatment. In this mini review, we provide a brief discussion about our current understanding of the fundamental roles of SGs during physiological stress and the effect of dysregulated SGs on cancer cell fitness and cancer therapy. [BMB Reports 2022; 55(12): 577-586].

Using Exogenous Melatonin, Glutathione, Proline, and Glycine Betaine Treatments to Combat Abiotic Stresses in Crops.

Abiotic stresses, such as drought, salinity, heat, cold, and heavy metals, are associated with global climate change and hamper plant growth and development, affecting crop yields and quality. However, the negative effects of abiotic stresses can be mitigated through exogenous treatments using small biomolecules. For example, the foliar application of melatonin provides the following: it protects the photosynthetic apparatus; it increases the antioxidant defenses, osmoprotectant, and soluble sugar levels; it prevents tissue damage and reduces electrolyte leakage; it improves reactive oxygen species (ROS) scavenging; and it increases biomass, maintains the redox and ion homeostasis, and improves gaseous exchange. Glutathione spray upregulates the glyoxalase system, reduces methylglyoxal (MG) toxicity and oxidative stress, decreases hydrogen peroxide and malondialdehyde accumulation, improves the defense mechanisms, tissue repairs, and nitrogen fixation, and upregulates the phytochelatins. The exogenous application of proline enhances growth and other physiological characteristics, upregulates osmoprotection, protects the integrity of the plasma lemma, reduces lipid peroxidation, increases photosynthetic pigments, phenolic acids, flavonoids, and amino acids, and enhances stress tolerance, carbon fixation, and leaf nitrogen content. The foliar application of glycine betaine improves growth, upregulates osmoprotection and osmoregulation, increases relative water content, net photosynthetic rate, and catalase activity, decreases photorespiration, ion leakage, and lipid peroxidation, protects the oxygen-evolving complex, and prevents chlorosis. Chemical priming has various important advantages over transgenic technology as it is typically more affordable for farmers and safe for plants, people, and animals, while being considered environmentally acceptable. Chemical priming helps to improve the quality and quantity of the yield. This review summarizes and discusses how exogenous melatonin, glutathione, proline, and glycine betaine can help crops combat abiotic stresses.

The Role of Plant Progesterone in Regulating Growth, Development, and Biotic/Abiotic Stress Responses.

Progesterone is a steroid hormone that performs important functions in mammals. However, studies on its physiological functions in plants have gradually increased in recent years. Therefore, this review summarizes the regulatory functions of progesterone on plant growth and development, as well as its response to stress. Moreover, the plant metabolic processes of progesterone are also discussed. Overall, progesterone is ubiquitous in plants and can regulate numerous plant physiological processes at low concentrations. Since progesterone shares similar characteristics with plant hormones, it is expected to become a candidate for plant hormone. However, most of the current research on progesterone in plants is limited to the physiological level, and more molecular level research is needed to clarify progesterone signaling pathways.

Automutilação em abutre real (Sarcoramphus papa) mantido em cativeiro / Automutilation in real vulture (Sarcoramphus papa) maintained in captivity / Automutilación en un buitre dorado (Sarcoramphus papa) mantenido en cautividad

O abutre real (Sarcoramphus papa) é um pássaro compacto de cor extraordinária, cabeça nua, possui carúnculas e papilas carnudas vermelhas e alaranjadas em torno do bico, a íris é branca com um anel orbital vermelho. Em cativeiro, o estresse é uma condição bastante observada, o que pode levar a automutilação, podendo evoluir para lesões graves na pele e músculos. O objetivo do presente relato é descrever os procedimentos adotados em um caso de automutilação em Sarcoramphus papa, mantido em cativeiro, e a importância do manejo adequado para essa espécie em cativeiro. Foi atendido em um Hospital Veterinário Universitário, um urubu-rei apresentando ferimento contaminado, com exposição óssea na asa direita. Após tratamento o animal foi encaminhado para uma reserva conservacionista para que fosse condicionada a voltar para seu habitat natural.(AU)

The real vulture is a compact bird of extraordinary color (in adult plumage). Its bare head, as the scientific name suggests, has caricatures and fleshy red papillae applied around the beak, and an iris of the eye is white with a red orbital ring. In captivity, stress is a widely observed condition, which can lead to self-mutilation, which can progress to severe skin and muscle injuries. The purpose of this report is to describe the procedures adopted in the case of automation in Sarcoramphus papa, kept in captivity and with an importance of the appropriate manual for this species in captivity. He was seen at a University Veterinary Hospital, a king vulture showed a contaminated wound, with bone exposure on the right. After treatment or animal was sent to a conservation reserve to be conditioned and return to its natural habitat.(AU)

buitre real (Sarcoramphus papa) es un ave compacta de extraordinario color, cabeza desnuda, tiene carúnculas y papilas rojas y anaranjadas alrededor del pico, el iris es blanco con un anillo orbital rojo. En cautiverio, el estrés es una condición ampliamente observada, que puede llevar a la automutilación, posiblemente evolucionando en lesiones graves de la piel y los músculos. El objetivo del presente informe es describir los procedimientos adoptados en un caso de automutilación en Sarcoramphus papa, mantenido en cautividad, y la importancia del manejo adecuado para esta especie en cautividad. Un buitre real que presentaba una lesión contaminada con exposición ósea en el ala derecha fue tratado en un Hospital Universitario Veterinario. Tras el tratamiento, el animal fue enviado a una reserva de conservación para que pudiera ser acondicionado para volver a su hábitat natural.(AU)

Integrated regulation of PKA by fast and slow neurotransmission in the nucleus accumbens controls plasticity and stress responses.

Cortical glutamate and midbrain dopamine neurotransmission converge to mediate striatum-dependent behaviors, while maladaptations in striatal circuitry contribute to mental disorders. However, the crosstalk between glutamate and dopamine signaling has not been entirely elucidated. Here we uncover a molecular mechanism by which glutamatergic and dopaminergic signaling integrate to regulate cAMP-dependent protein kinase (PKA) via phosphorylation of the PKA regulatory subunit, RIIß. Using a combination of biochemical, pharmacological, neurophysiological, and behavioral approaches, we find that glutamate-dependent reduction in cyclin-dependent kinase 5 (Cdk5)-dependent RIIß phosphorylation alters the PKA holoenzyme autoinhibitory state to increase PKA signaling in response to dopamine. Furthermore, we show that disruption of RIIß phosphorylation by Cdk5 enhances cortico-ventral striatal synaptic plasticity. In addition, we demonstrate that acute and chronic stress in rats inversely modulate RIIß phosphorylation and ventral striatal infusion of a small interfering peptide that selectively targets RIIß regulation by Cdk5 improves behavioral response to stress. We propose this new signaling mechanism integrating ventral striatal glutamate and dopamine neurotransmission is important to brain function, may contribute to neuropsychiatric conditions, and serves as a possible target for the development of novel therapeutics for stress-related disorders.

An integrated approach to understand fluid shear stress-driven and reactive oxygen species-mediated metastasis of colon adenocarcinoma through mRNA-miRNA-lncRNA-circRNA networks.

Development of colon adenocarcinoma (COAD) metastasis involves several mediators including fluid shear stress (FSS), intracellular ROS levels, and non-coding RNAs. In our present study, we identified and investigated the role of regulatory non-coding RNA molecules specifically involved in COAD metastasis and their association with FSS and ROS. Interactions between the mRNAs associated with FSS and ROS, the corresponding microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) in COAD metastasis were used to generate the mRNA-miRNA-lncRNA-circRNA network. Experimental validation of the identified RNA hubs using quantitative real-time PCR demonstrated a direct effect of the FSS on their expression levels in cancer cells. FSS resulted in the downregulation of HMGA1 and RAN, as well as the upregulation of HSP90AA1, PMAIP1 and BIRC5. Application of shear stress also led to downregulation of hsa-miR-26b-5p and hsa-miR-34a-5p levels in HCT116 cells. Further, functional enrichment and survival analysis of the significant miRNAs, as well as the OncoPrint and the survival analyses of the selected mRNAs were performed. Subsequently, their functional role was also corroborated with existing literature. Ten significant miRNA hubs were identified, out of which hsa-miR-17-5p and hsa-miR-20a-5p were found to interact with lncRNA (CCAT2) while hsa-miR-335 was found to interact with four circRNAs. Fifteen significant miRNAs were identified in 10 different modules suggesting their importance in FSS and ROS-mediated COAD metastasis. Finally, 10 miRNAs and 3 mRNAs associated with FSS and/or ROS were identified as significant overall survival markers; 33 mRNAs were also identified as metastasis-free survival markers whereas 15 mRNAs showed > 10% gene alterations in TCGA-COAD data and may serve as promising therapeutic biomarkers in the COAD metastasis.

USP40 deubiquitinates HINT1 and stabilizes p53 in podocyte damage.

Podocyte damage is a major pathological lesion leading to focal segmental glomerulosclerosis (FSGS). Podocytes damaged by cellular stress undergo hypertrophy to compensate for podocytopenia. It is known that cyclin-dependent kinase inhibitors induced by p53 ensure podocytes hypertrophy; however, its precise mechanism remains to be further investigated. In this study, we found that ubiquitin specific protease 40 (USP40) is a novel regulator of p53. Although USP40 knockout mice established in the present study revealed no abnormal kidney phenotype, intermediate filament Nestin was upregulated in the glomeruli, and was bound to and colocalized with USP40. We also found that USP40 deubiquitinated histidine triad nucleotide-binding protein 1 (HINT1), an inducer of p53. Gene knockdown experiments of USP40 in cultured podocytes revealed the reduction of HINT1 and p53 protein expression. Finally, in glomerular podocytes of mouse FSGS, upregulation of HINT1 occurred in advance of the proteinuria, which was followed by upregulation of USP40, p53 and Nestin. In conclusion, USP40 bound to Nestin deubiquitinates HINT1, and in consequence upregulates p53. These results provide additional insight into the pathological mechanism of podocyte hypertrophy in FSGS.

Energy metabolism response of Litopenaeus vannamei to combined stress of acute cold exposure and waterless duration: Implications for physiological regulation and waterless live transport.

Maintaining the homeostasis of energy metabolism is crucial for organism's stress tolerance and survival. Acute cold exposure (AC) and waterless duration (WD) represent the two predominate abiotic stressors during waterless live transport of Litopenaeus vannamei. Although previous reports have explored the physiological response of L. vannamei to combined stress AC + WD, the roles of energy metabolism response in regulation of stress tolerance remains unknown. The present study comparatively examined the variations of energy metabolism-related indicators in hemolymph (cortisol, hemocyanin, glucose and lactate), hepatopancreas and muscle tissues (levels of lactate and glycogen, activities of hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), lactate dehydrogenase (LDH), succinate dehydrogenase (SDH) and adenosine triphosphatase (ATPase), and ATP levels). Combined stress significantly disturbed the homeostasis of energy metabolism with the increase in levels of hemocyanin, glucose and lactate, and decrease in glycogen and ATP content (P < 0.05). In addition, the activities of HK, PFK, PK, and SDH initially elevated and then decreased with the prolongation of combined stress from 3h to 9h duration, while the activity of lactate dehydrogenase (LDH) remained gradual elevation and ATPase activity decreased in a duration time dependent manner throughout the experiment. These alterations revealed that exposure to combined stress could accelerate anaerobic metabolism at initial stage and inhibit aerobic metabolism in a duration time-dependent manner, following with the reduction of energy biosynthesis and the disturbance of energy metabolism equilibrium. On the other hand, the progressive impairment on hepatopancreas tissue was observed under combined stress. In summary, the deficiency of ATP supply and histopathological injures on hepatopancreas tissue might the underlying mechanisms inducing mortality of L. vannamei during live transport.

The mouse brain after foot shock in four dimensions: Temporal dynamics at a single-cell resolution.

Acute stress leads to sequential activation of functional brain networks. A biologically relevant question is exactly which (single) cells belonging to brain networks are changed in activity over time after acute stress across the entire brain. We developed a preprocessing and analytical pipeline to chart whole-brain immediate early genes' expression-as proxy for cellular activity-after a single stressful foot shock in four dimensions: that is, from functional networks up to three-dimensional (3D) single-cell resolution and over time. The pipeline is available as an R package. Most brain areas (96%) showed increased numbers of c-fos+ cells after foot shock, yet hypothalamic areas stood out as being most active and prompt in their activation, followed by amygdalar, prefrontal, hippocampal, and finally, thalamic areas. At the cellular level, c-fos+ density clearly shifted over time across subareas, as illustrated for the basolateral amygdala. Moreover, some brain areas showed increased numbers of c-fos+ cells, while others-like the dentate gyrus-dramatically increased c-fos intensity in just a subset of cells, reminiscent of engrams; importantly, this "strategy" changed after foot shock in half of the brain areas. One of the strengths of our approach is that single-cell data were simultaneously examined across all of the 90 brain areas and can be visualized in 3D in our interactive web portal.

Associations of three major physiological stress systems with suicidal ideation and suicide attempts in patients with a depressive and/or anxiety disorder.

BACKGROUND: People with depressive and/or anxiety disorders are at increased risk of suicidal ideation and suicide attempts, but biological correlates signaling such risk remain unclear. Independent and cumulative dysregulations in physiological stress systems, in particular the hypothalamic-pituitaryadrenal axis (HPA-axis), immune-inflammatory system, and autonomous nervous system (ANS), may contribute to this risk. However, findings have either been heterogeneous or absent thus far. METHODS: Associations between individual markers and cumulative indices of the HPA-axis (cortisol awakening response and evening cortisol), immune-inflammatory system (C-reactive protein, interleukin-6 (IL-6), and tumor necrosis factor-α), and the ANS (heart rate, respiratory sinus arrhythmia, and pre-ejection period) and the outcomes no suicide ideation with suicide attempt (SI-SA+), suicide ideation without suicide attempt (SI+SA-) and suicide ideation with suicide attempt (SI+SA+) were investigated in 1749 persons with depressive and/or anxiety disorders from the Netherlands Study of Depression and Anxiety (NESDA). RESULTS: High levels of CRP and IL-6 were associated with SI-SA+ and SI+SA+ respectively when compared to non-suicidal patients after adjusting for confounders and multiple testing. Also, cumulative immune-inflammatory dysregulations were positively associated with SI+SA+, suggesting a dose-response effect. No significant associations were found between HPA-axis or ANS indicators and suicide-outcomes and between immune-inflammatory system markers or cumulative stress system dysregulations and SI+SA-. CONCLUSION: Although stress system markers could not differentiate between SI+SA- and non-suicidal patients, findings indicate that dysregulations of individual and cumulative immune-inflammatory markers are associated with suicide attempts in depressive and/or anxiety patients. Thus, immune-inflammatory system dysregulation may be involved in the pathophysiology of suicidal behavior, supporting further examination of the effects of anti-inflammatory interventions on suicidality.