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Background Information: The precise etiology of breast cancer is not completely understood, although women with BRCA1 gene mutations have a significantly increased risk of developing the disease. In addition, sporadic breast cancer is frequently associated with decreased BRCA1 gene expression. Growing evidence of Human papillomaviruses (HPVs) infections in breast tumors has raised the possibility of the involvement of HPVs in the pathogenesis of breast cancer. We investigated whether the effects of HPV oncoproteins E6 and E7 were influenced by the expression levels of BRCA1. HPV16E6E7 (prototype or E6D25E/E7N29S Asian variant type) were stably expressed in MDA-MB231 breast cancer cells, wild type for BRCA1, or with BRCA1 knocked down., Results: Expression of HPV16E6E7 oncogenes did not affect BRCA1 levels and the abundance of HPV16E6E7 was not altered by BRCA1 knockdown. BRCA1 levels did not alter HPV16E6E7-dependent degradation of G1-S cell cycle proteins p53 and pRb. However, we found that the expression of G2-M cell cycle protein cyclin B1 enhanced by HPV16E6E7 was impacted by BRCA1 levels. Especially, we found the correlation between BRCA1 and cyclin B1 expression and this was also confirmed in breast cancer samples from a Thai cohort. We further demonstrated that the combination of HPV oncoproteins and low levels of BRCA1 protein appears to enhance proliferation and invasion. Transactivation activities of HPV16E6E7 on genes regulating cell proliferation and invasion (TGF-β and vimentin) were significantly increased in BRCA1-deficient cells., Conclusions: Our results indicate that a deficiency of BRCA1 promotes the transactivation activity of HPV16E6E7 leading to increase of cell proliferation and invasion., Significance: HPV infection appears to have the potential to enhance the aggressiveness of breast cancers, especially those deficient in BRCA1., (© 2024 The Authors. Biology of the Cell published by Wiley‐VCH GmbH on behalf of Société Française des Microscopies and Société Biologie Cellulaire de France.)

Background: Elderly surgical patients have a high risk of postoperative complications. However, patients exhibit considerable diversity in health and functional status; thus, identifying the fragile may be necessary when selecting surgical candidates. We aimed to compare the prevalence of frailty in patients ≥90 years with patients aged 80-89. Second, we assessed the association between frailty and all-cause 30-day mortality., Methods: We performed a planned secondary analysis of the peri-interventional outcome study in the elderly (POSE), including 9497 patients (≥80 years) undergoing any surgical and nonsurgical procedures in 177 European centres from October 2017 to December 2018. The primary outcome assessment included frailty as a binary variable, and data were analysed using Fisher's exact test/Chi-squared test. The association between frailty and all-cause 30-day mortality was analysed using a multivariate logistic regression model adjusted for age, sex, surgical urgency, orthopaedic urgency, and surgical severity., Results: In total, 999 of 9497 (10.5%) patients were 90 years or above. Among patients ≥90 years, 274 (27.4%) were frail compared to 1062 (12.5%) of patients aged 80-89 (odds ratio (OR): 2.6; 95% CI 2.3-3.1). Frailty was associated with increased 30-day mortality in both the unadjusted (crude OR 6.3; 5.1-7.7) and adjusted analysis (OR 4.5; 3.6-5.7). In the adjusted analysis, age ≥90 was not associated with 30-day mortality., Conclusion: We found a high frequency of frailty in patients aged 90 years or above compared with patients aged 80-89. In addition, frailty was associated with an increased risk of 30-day mortality. Surprisingly, age was not a significant risk factor in the adjusted mortality analysis., (© 2023 Acta Anaesthesiologica Scandinavica Foundation.)

Objectives: Angiotensin II type 1 receptor blockade has neuroprotective effects in animal stroke models, but no effects in clinical stroke trials. We evaluated cerebral and peripheral changes in the renin angiotensin aldosterone system (RAAS) and stress responses in acute ischemic stroke patients., Materials and Methods: Blood from a jugular and cubital vein was collected within 48 h of stroke onset, after 24 and 48 h, and renin, angiotensin I, angiotensin II, aldosterone, norepinephrine, epinephrine, and cortisol were measured. Post-stroke cubital vein samples were collected after 8 (4.7-10) months., Results: The acute systolic blood pressure was significantly increased, 148 (141-168) vs 140 (130-147) mmHg post-stroke. Angiotensin I, renin and aldosterone levels were significantly lower, angiotensin II was unchanged, and ACE activity was higher in the acute phase compared to post-stroke. No differences in RAAS were detected between jugular and cubital plasma levels. Jugular venous plasma levels of epinephrine and cortisol were elevated in the acute phase compared to cubital levels (P < 0.05)., Conclusion: Increased epinephrine and cortisol levels in the jugular vein blood may reflect a higher peripheral turnover. The observed changes in RAAS in the acute stroke phase are consistent with responses to increased blood pressure., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The title compounds, [Mo(C5H5)(COCH3)P(CH3)2(C6H5)(CO)2], (1), and [Mo(C5H5)(COCH3)P(C2H5)(C6H5)2)(CO)2], (2), have been prepared by phosphine-induced migratory insertion from [Mo(C5H5)(CO)3(CH3)]. Both complex mol-ecules exhibit a four-legged piano-stool geometry with trans-disposed carbonyl ligands along with Mo-P bond lengths and C-Mo-P angles that reflect the relative steric pressure of the respective phosphine ligand. The structure of compound (1) exhibits a layered arrangement parallel to (100). Within the layers mol-ecules are linked into chains along [001] by non-classical C-H⋯O inter-actions between the acetyl ligand of one mol-ecule and the phenyl and methyl phosphine substituents of another. In the structure of complex (2), a chain motif of centrosymmetrical dimers is found along [010] through C-H⋯O inter-actions.

NDG-4 is a predicted transmembrane acyltransferase protein that acts in the distribution of lipophilic factors. Consequently, ndg-4 mutants lay eggs with a pale appearance due to lack of yolk, and they are resistant to sterility caused by dietary supplementation with the long-chain omega-6 polyunsaturated fatty acid dihommogamma-linolenic acid (DGLA). Two other proteins, NRF-5 and NRF-6, a homolog of a mammalian secreted lipid binding protein and a NDG-4 homolog, respectively, have previously been shown to function in the same lipid transport pathway. Here, we report that mutation of the NDG-4 protein results in increased organismal stress resistance and lifespan. When NDG-4 function and insulin/IGF-1 signaling are reduced simultaneously, maximum lifespan is increased almost fivefold. Thus, longevity conferred by mutation of ndg-4 is partially overlapping with insulin signaling. The nuclear hormone receptor NHR-80 (HNF4 homolog) is required for longevity in germline less animals. We find that NHR-80 is also required for longevity of ndg-4 mutants. Moreover, we find that nrf-5 and nrf-6 mutants also have extended lifespan and increased stress resistance, suggesting that altered lipid transport and metabolism play key roles in determining lifespan., (© 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Orexin/hypocretin (orx/hcrt) neurons are thought to ensure that reward-seeking is accompanied by alertness, but the underlying circuit organization is unclear. Reports of differential regulation of lateral versus medial orx/hcrt cells produced a hypothesis of 'efferent dichotomy', in which lateral orx/hcrt cells innervate the ventral tegmental area (VTA) and control reward, while medial orx/hcrt cells innervate locus coeruleus (LC) and control arousal. Two distinct types of orx/hcrt cells also emerged from analysis of intrinsic and input-driven single-cell electrical activity. To examine the projections of these emerging orx/hcrt subtypes to LC and VTA, we injected retrograde tracer into these regions in the mouse brain in vivo, and then examined the properties of tracer-containing orx/hcrt cells in hypothalamic slices. VTA- and LC-projecting orx/hcrt cells were found across the entire orx/hcrt field, including the zona incerta, perifornical area, dorsomedial/anterior and lateral hypothalamus. Within these areas, orx/hcrt cells had similar probabilities of projecting to VTA or LC. Examination of lateral versus medial sections revealed that VTA and LC received inputs from both lateral and medial orx/hcrt cells, but, unexpectedly, lateral orx/hcrt cells were more likely to project to LC than medial orx/hcrt cells. Finally, patch-clamp recordings revealed that VTA and LC received projections from both electrical classes of orx/hcrt cells, which had similar likelihoods of projecting to VTA or LC. Contrary to previous predictions, our data suggest that medial and lateral orx/hcrt cells, and the different electrical and morphological subclasses of orx/hcrt cells identified to date, send projections to both LC and VTA., (© 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

Protein misfolding is a common theme in aging and several age-related diseases such as Alzheimer's and Parkinson's disease. The processes involved in the development of these diseases are many and complex. Here, we show that components of the basement membrane (BM), particularly laminin, affect protein integrity of the muscle cells they support. We knocked down gene expression of epi-1, a laminin α-chain, and found that this resulted in increased proteotoxicity in different Caenorhabditis elegans transgenic models, expressing aggregating proteins in the body wall muscle. The effect could partially be rescued by decreased insulin-like signaling, known to slow the aging process and the onset of various age-related diseases. Our data points to an underlying molecular mechanism involving proteasomal degradation and HSP-16 chaperone activity. Furthermore, epi-1-depleted animals had altered synaptic function and displayed hypersensitivity to both levamisole and aldicarb, an acetylcholine receptor agonist and an acetylcholinesterase inhibitor, respectively. Our results implicate the BM as an extracellular modulator of protein homeostasis in the adjacent muscle cells. This is in agreement with previous research showing that imbalance in neuromuscular signaling disturbs protein homeostasis in the postsynaptic cell. In our study, proteotoxicity may indeed be mediated by the neuromuscular junction which is part of the BM, where laminins are present in high concentration, ensuring the proper microenvironment for neuromuscular signaling. Laminins are evolutionarily conserved, and thus the BM may play a much more causal role in protein misfolding diseases than currently recognized., (© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.)

The firing of hypothalamic hypocretin/orexin neurons is vital for normal sleep-wake transitions, but its molecular determinants are not well understood. It was recently proposed that TASK (TWIK-related acid-sensitive potassium) channels [TASK1 (K(2P)3.1) and/or TASK3 (K(2P)9.1)] regulate neuronal firing and may contribute to the specialized responses of orexin neurons to glucose and pH. Here we tested these theories by performing patch-clamp recordings from orexin neurons directly identified by targeted green fluorescent protein labelling in brain slices from TASK1/3 double-knockout mice. The deletion of TASK1/3 channels significantly reduced the ability of orexin cells to generate high-frequency firing. Consistent with reduced excitability, individual action potentials from knockout cells had lower rates of rise, higher thresholds and more depolarized after-hyperpolarizations. However, orexin neurons from TASK1/3 knockout mice retained typical responses to glucose and pH, and the knockout animals showed normal food-anticipatory locomotor activity. Our results support a novel role for TASK genes in enhancing neuronal excitability and promoting high-frequency firing, but suggest that TASK1/3 subunits are not essential for orexin cell responses to glucose and pH.