Oxytocin is involved in the regulation of social behaviors including parental behaviors in a variety of species. Oxytocin triggers social behaviors by binding to oxytocin receptors (OXTRs) in various ...parts of the brain. OXTRs are present in the preoptic area (POA) where hormone-sensitive sexually dimorphic nuclei exist. The present study was conducted to examine whether sex differences exist in the distribution of neurons expressing OXTRs in the POA. Using OXTR-Venus (an enhanced variant of yellow fluorescent protein) mice, the distribution of OXTR-Venus cells in the POA was compared between sexes. The total number of OXTR-Venus cells in the medial POA (MPOA) was significantly greater in females than in males. No detectable OXTR-Venus cells were observed in the anteroventral periventricular nucleus (AVPV) within the MPOA in most of the brain sections from males. We further examined the total number of OXTR-Venus cells in the AVPV and the rest of the MPOA between the sexes. The total number of OXTR-Venus cells in the AVPV in females (615 ± 43) was significantly greater than that in males (14 ± 2), whereas the total number of OXTR-Venus cells in the rest of the MPOA did not differ significantly between the sexes. Thus, the sexually dimorphic expression of OXTR-Venus specifically occurred in the AVPV, but not in the rest of the MPOA. We also examined whether the expression of OXTR in the AVPV is driven by the female gonadal hormone, estrogen. Immunocytochemistry and single-cell RT-PCR revealed the presence of the estrogen receptor α in OXTR-Venus cells in the female AVPV. Moreover, ovariectomy resulted in the absence of OXTR-Venus expression in the AVPV, whereas estrogen replacement therapy restored OXTR-Venus expression. These results demonstrate that the expression of OXTR in the AVPV is primarily female specific and estrogen dependent. The presence of the sexually dimorphic expression of OXTR in the AVPV suggests the involvement of OXTR neurons in the AVPV in the regulation of female-specific behavior and/or physiology.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Low energy availability (EA) underpins the female and male athlete triad and relative energy deficiency in sport (RED-S). The condition arises when insufficient calories are consumed to support ...exercise energy expenditure, resulting in compromised physiological processes, such as menstrual irregularities in active females. The health concerns associated with longstanding low EA include menstrual/libido, gastrointestinal and cardiovascular dysfunction and compromised bone health, all of which can contribute to impaired sporting performance. This narrative review provides an update of our previous review on the prevalence and risk of low EA, within-day energy deficiency, and the potential impact of low EA on performance. The methods to assess EA remain a challenge and contribute to the methodological difficulties in identifying "true" low EA. Screening female athletic groups using a validated screening tool such as the Low Energy Availability in Females Questionnaire (LEAF-Q) has shown promise in identifying endurance athletes at risk of low EA. Knowledge of RED-S and its potential implications for performance is low among coaches and athletes alike. Development of sport and gender-specific screening tools to identify adolescent and senior athletes in different sports at risk of RED-S is warranted. Education initiatives are required to raise awareness among coaches and athletes of the importance of appropriate dietary strategies to ensure that sufficient calories are consumed to support training.
Phylogenetic analysis indicates that microbial arsenic metabolism is ancient and probably extends back to the primordial Earth. In microbial biofilms growing on the rock surfaces of anoxic brine ...pools fed by hot springs containing arsenite and sulfide at high concentrations, we discovered light-dependent oxidation of arsenite As(III) to arsenate As(V) occurring under anoxic conditions. The communities were composed primarily of Ectothiorhodospira-like purple bacteria or Oscillatoria-like cyanobacteria. A pure culture of a photosynthetic bacterium grew as a photoautotroph when As(III) was used as the sole photosynthetic electron donor. The strain contained genes encoding a putative As(V) reductase but no detectable homologs of the As(III) oxidase genes of aerobic chemolithotrophs, suggesting a reverse functionality for the reductase. Production of As(V) by anoxygenic photosynthesis probably opened niches for primordial Earth's first As(V)-respiring prokaryotes.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Development is regulated by various factors, including protein methylation status. While PRMT5 is well known for its roles in oncogenesis by mediating symmetric di-methylation of arginine, its role ...in normal development remains elusive. Using Myod1Cre to drive Prmt5 knockout in embryonic myoblasts (Prmt5MKO), we dissected the role of PRMT5 in myogenesis. The Prmt5MKO mice are born normally but exhibit progressive muscle atrophy and premature death. Prmt5MKO inhibits proliferation and promotes premature differentiation of embryonic myoblasts, reducing the number and regenerative function of satellite cells in postnatal mice. Mechanistically, PRMT5 methylates and destabilizes FoxO1. Prmt5MKO increases the total FoxO1 level and promotes its cytoplasmic accumulation, leading to activation of autophagy and depletion of lipid droplets (LDs). Systemic inhibition of autophagy in Prmt5MKO mice restores LDs in myoblasts and moderately improves muscle regeneration. Together, PRMT5 is essential for muscle development and regeneration at least partially through mediating FoxO1 methylation and LD turnover.
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•PRMT5 is essential for muscle development and function in vivo•PRMT5 regulates fate of muscle stem cells and muscle regenerative capacity•PRMT5 governs autophagy through FoxO1 methylation, influencing its subcellular localization•Autophagy inhibition partially improves muscle regeneration in Prmt5 KO mice
Kim et al. report the role of PRMT5 in muscle development using knockout (KO) mice. Myoblast-specific Prmt5-KO impairs myogenesis and causes premature death. PRMT5 regulates subcellular localization of FoxO1, which influences autophagy of lipid droplets. The work uncovers an interplay between PRMT5, FoxO1, and lipophagy essential for muscle development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background We undertook a systematic review and meta-analysis of perinatal variables in relation to testicular cancer risk, with a specific focus upon characteristics of the son. Methods Literature ...databases Scopus, EMBASE, PubMed and Web of Science were searched using highly sensitive search strategies. Of 5865 references retrieved, 67 articles met the inclusion criteria, each of which was included in at least one perinatal analysis. Results Random effects meta-analysis produced the following results for association with testicular cancer risk: birth weight per kilogram, odds ratio (OR) = 0.94, 95% confidence interval (CI) 0.88–1.01, I2 = 12%, low birth weight (OR = 1.34, 95% CI 1.08–1.67, I2 = 51%), high birth weight (OR = 1.05, 95% CI 0.96–1.14, I2 = 0%), gestational age (per week, OR = 0.95, 95% CI 0.92–0.98, I2 = 38%; low vs not, OR = 1.31, 95% CI 1.07–1.59, I2 = 49%), cryptorchidism (OR = 4.30, 95% CI 3.62–5.11, I2 = 44%), inguinal hernia (OR = 1.63, 95% CI 1.37–1.94, I2 = 38%) and twinning (OR = 1.22, 95% CI 1.03–1.44, I2 = 22%). Meta-analyses of the variables birth length, breastfeeding and neonatal jaundice did not provide evidence for an association with testicular cancer risk. When low birth weight was stratified by data ascertainment (record/registry vs self-report), only the category of self-report was indicative of an association. Meta-regression of data ascertainment (record/registry vs self-report) inferred that record-/registry-based studies were less supportive of an association with gestational age (per week = 0.97, 95% CI 0.94–1.00, I2 = 29%; low vs not = 1.08, 95% CI 0.91–1.28, I2 = 32%). Conclusion In conclusion, this systematic review and meta-analysis finds evidence that cryptorchidism, inguinal hernia and twinning, and tentative evidence that birth weight and gestational age, are associated with risk of testicular cancer.
Athletes maintain a balance between stress and recovery and adopt recovery modalities that manage fatigue and enhance recovery and performance. Optimal TST is subject to individual variance. However, ...7-9 h sleep is recommended for adults, while elite athletes may require more quality sleep than non-athletes.
A total of 338 (elite
= 115, 74 males and 41 females, aged 23.44 ± 4.91 years; and sub-elite
= 223, 129 males and 94 females aged 25.71 ± 6.27) athletes were recruited from a variety of team and individual sports to complete a battery of previously validated and reliable widely used questionnaires assessing sleep, recovery and nutritional practices.
Poor sleep was reported by both the elite and sub-elite athlete groups (i.e., global PSQI score ≥5-elite 64%
= 74; sub-elite 65%
= 146) and there was a significant difference in sport-specific recovery practices (3.22 ± 0.90 vs. 2.91 ± 0.90;
< 0.001). Relatively high levels of fatigue (2.52 ± 1.32), stress (1.7 ± 1.31) and pain (50%,
= 169) were reported in both groups. A range of supplements were used regularly by athletes in both groups; indeed, whey (elite
= 22 and sub-elite
= 48) was the most commonly used recovery supplement in both groups. Higher alcohol consumption was observed in the sub-elite athletes (12%,
= 26) and they tended to consume more units of alcohol per drinking bout.
There is a need for athletes to receive individualised support and education regarding their sleep and recovery practices.
Despite efforts to identify modulatory neuroprotective mechanisms of damaging ischemic stroke cascade signaling, a void remains on an effective potential therapeutic. The present study defines ...neuroprotection by very long-chain polyunsaturated fatty acid (VLC-PUFA) Elovanoid (ELV) precursors C-32:6 and C-34:6 delivered intranasally following experimental ischemic stroke. We demonstrate that these precursors improved neurological deficit, decreased T2WI lesion volume, and increased SMI-71 positive blood vessels and NeuN positive neurons, indicating blood-brain barrier (BBB) protection and neurogenesis modulated by the free fatty acids (FFAs) C-32:6 and C-34:6. Gene expression revealed increased anti-inflammatory and pro-homeostatic genes and decreases in expression of pro-inflammatory genes in the subcortex. Additionally, the FFAs elicit a comprehensive downregulation of inflammatory microglia/monocyte-derived macrophages and astrocyte-associated genes in the subcortical region. Functional analysis reveals inhibition of immune-related pathways and production of upstream molecules related to detrimental signaling events in post-stroke acute and subacute phases.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Breast cancers classified by estrogen receptor (ER) and/or progesterone receptor (PR) expression have different clinical,
pathologic, and molecular features. We examined existing evidence from the ...epidemiologic literature as to whether breast cancers
stratified by hormone receptor status are also etiologically distinct diseases. Despite limited statistical power and nonstandardized
receptor assays, in aggregate, the critically evaluated studies ( n = 31) suggest that the etiology of hormone receptor–defined breast cancers may be heterogeneous. Reproduction-related exposures
tended to be associated with increased risk of ER-positive but not ER-negative tumors. Nulliparity and delayed childbearing
were more consistently associated with increased cancer risk for ER-positive than ER-negative tumors, and early menarche was
more consistently associated with ER-positive/PR-positive than ER-negative/PR-negative tumors. Postmenopausal obesity was
also more consistently associated with increased risk of hormone receptor–positive than hormone receptor–negative tumors,
possibly reflecting increased estrogen synthesis in adipose stores and greater bioavailability. Published data are insufficient
to suggest that exogenous estrogen use (oral contraceptives or hormone replacement therapy) increase risk of hormone-sensitive
tumors. Risks associated with breast-feeding, alcohol consumption, cigarette smoking, family history of breast cancer, or
premenopausal obesity did not differ by receptor status. Large population-based studies of determinants of hormone receptor–defined
breast cancers defined using state-of-the-art quantitative immunostaining methods are needed to clarify the role of ER/PR
expression in breast cancer etiology.
Safe and effective pain management is a critical healthcare and societal need. The potential for acute liver injury from paracetamol (ApAP) overdose; nephrotoxicity and gastrointestinal damage from ...chronic non-steroidal anti-inflammatory drug (NSAID) use; and opioids' addiction are unresolved challenges. We developed SRP-001, a non-opioid and non-hepatotoxic small molecule that, unlike ApAP, does not produce the hepatotoxic metabolite N-acetyl-p-benzoquinone-imine (NAPQI) and preserves hepatic tight junction integrity at high doses. CD-1 mice exposed to SRP-001 showed no mortality, unlike a 70% mortality observed with increasing equimolar doses of ApAP within 72 h. SRP-001 and ApAP have comparable antinociceptive effects, including the complete Freund's adjuvant-induced inflammatory von Frey model. Both induce analgesia via N-arachidonoylphenolamine (AM404) formation in the midbrain periaqueductal grey (PAG) nociception region, with SRP-001 generating higher amounts of AM404 than ApAP. Single-cell transcriptomics of PAG uncovered that SRP-001 and ApAP also share modulation of pain-related gene expression and cell signaling pathways/networks, including endocannabinoid signaling, genes pertaining to mechanical nociception, and fatty acid amide hydrolase (FAAH). Both regulate the expression of key genes encoding FAAH, 2-arachidonoylglycerol (2-AG), cannabinoid receptor 1 (CNR1), CNR2, transient receptor potential vanilloid type 4 (TRPV4), and voltage-gated Ca
channel. Phase 1 trial (NCT05484414) (02/08/2022) demonstrates SRP-001's safety, tolerability, and favorable pharmacokinetics, including a half-life from 4.9 to 9.8 h. Given its non-hepatotoxicity and clinically validated analgesic mechanisms, SRP-001 offers a promising alternative to ApAP, NSAIDs, and opioids for safer pain treatment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Mutations in GNAQ/11 genes are considered an early event in the development of uveal melanoma that may derive from a pre-existing nevus. The Hippo pathway, by way of YAP activation, rather than MAP ...kinase, has a role in the oncogenic capacity of GNAQ/11 mutations.
We investigated 16 nevi from 13 human eyes for driver GNAQ/11 mutations using droplet digital PCR and determined whether nevi are clonal by quantifying mutant nevus cell fractions. Immunohistochemistry was performed on 15 nevi to analyse YAP activation.
For 15 out of 16 nevi, a GNAQ/11 mutation was detected in the nevus cells albeit at a low frequency with a median of 13%. Nuclear YAP, a transcriptional co-activator in the Hippo tumour-suppressor pathway, was detected in 14/15 nevi.
Our analysis suggests that a mutation in GNAQ/11 occurs in a subset of choroidal nevus cells. We hypothesise that GNAQ/11 mutant-driven extracellular mitogenic signalling involving YAP activation leads to accumulation of wild-type nevus cells.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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