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The formulation of objective procedures for the delineation of homogeneous groups of catchments is a fundamental issue in both operational and research hydrology. For assessing catchment similarity, a variety of hydrological information may be considered; in this paper, gauged sites are characterised by a set of streamflow signatures that include a representation, albeit simplified, of the properties of fine time-scale flow series and in particular of the dynamic components of the data, in order to keep into account the sequential order and the stochastic nature of the streamflow process. The streamflow signatures are provided in input to a clustering algorithm based on unsupervised SOM neural networks, obtaining groups of catchments with a clear hydrological distinctiveness, as highlighted by the identification of the main patterns of the input variables in the different classes and the interpretation of their interrelations. In addition, even if no geographical, morphological nor climatological information is provided in input to the SOM network, the clusters exhibit an overall consistency as far as location, altitude and precipitation regime are concerned. In order to assign ungauged sites to such groups, the catchments are represented through a parsimonious set of morphometric and pluviometric variables, including also indexes that attempt to synthesise the variability and correlation properties of the precipitation time series, thus providing information on the type of weather forcing that is specific to each basin. Following a principal components analysis, needed for synthesizing and better understanding the morpho-pluviometric catchment properties, a discriminant analysis finally assigns the ungauged catchments, through a leave-one-out cross validation, to one of the above identified hydrologic response classes. The approach delivers a quite satisfactory identification of the membership of ungauged catchments to the streamflow-based classes, since the comparison of the two cluster sets shows a misclassification rate of around 20%. Overall results indicate that the inclusion of information on the properties of the fine time-scale streamflow and rainfall time series may be a promising way for better representing the hydrologic and climatic character of the study catchments.

SummaryThis study examined the imminent risk of a future fracture within 1 and 2 years following a first fracture in women aged 50 years and older and assessed independent factors associated with risk of subsequent fractures. The study highlights the need to intervene rapidly after a fracture to prevent further fractures.IntroductionThis study aims to determine the imminent risk of subsequent fractures within 1 and 2 years following a first fracture and to assess independent factors associated with subsequent fractures.MethodsRetrospective, observational cohort study of women aged ≥ 50 years with a fragility fracture was identified from Swedish national registers. Clinical/demographic characteristics at the time of index fracture and cumulative fracture incidences up to 12 and 24 months following index fracture were calculated. Risk factors for subsequent fracture were identified using multivariate regression analysis.ResultsTwo hundred forty-two thousand one hundred eight women (mean [SD] age 74 [12.5] years) were included. The cumulative subsequent fracture incidence at 12 months was 7.1% (95% confidence interval [CI], 6.9–7.2) and at 24 months was 12.0% (95% CI, 11.8–12.1). The rate of subsequent fractures was highest in the first month (~ 15 fractures per 1000 patient-years) and remained steady between 4 and 24 months (~ 5 fractures/1000 patient-years). Higher age was an independent risk factor for imminent subsequent fractures (at 24 months, sub-distribution hazard ratio [HR], 3.07; p < 0.001 for women 80–89 years [reference 50–59 years]). Index vertebral fracture was a strong independent risk factor for subsequent fracture (sub-distribution HR, 2.72 versus hip fracture; p < 0.001 over 12 months; HR, 2.23; p < 0.001 over 24 months).ConclusionsOur findings highlight the need to intervene rapidly after any fragility fracture in postmenopausal women. The occurrence of a fragility fracture provides healthcare systems with a unique opportunity to intervene to reduce the increased risk of subsequent fractures.

Antioxidants play a crucial role in mitigating oxidative stress and preventing cellular damage caused by free radicals. This study aimed to compare the effectiveness of three antioxidant assays—DPPH, TEAC, and FRAP—in quantifying the antioxidant capacity of 15 plant-based spices, herbs, and food materials from five distinct plant families. The relationship between these assays and total polyphenol content (TPC) as well as total flavonoid content (TFC) was also investigated. The results showed that FRAP exhibited the strongest correlation with TPC (r = 0.913), followed by TEAC (r = 0.856) and DPPH (r = 0.772). Lamiaceae species, such as rosemary and thyme, consistently demonstrated high antioxidant activities across all assays. The study highlights the complementary nature of these assays in assessing antioxidant capacity and underscores their utility in profiling polyphenol- and flavonoid-rich plants for potential nutritional and therapeutic applications.

Purpose Fear of stigma may lead employees to choose not to disclose a mental disorder in the workplace, thereby limiting help-seeking through workplace accommodation. Research suggests that various factors are considered in making decisions related to disclosure of concealable stigmatizing attributes, yet limited literature explores such decision-making in the context of mental disorder and work. The purpose of this grounded theory study was to develop a model of disclosure specific to mental health issues in a work context. Methods In-depth interviews were conducted with 13 employees of a post-secondary educational institution in Canada. Data were analyzed according to grounded theory methods through processes of open, selective, and theoretical coding. Results Findings indicated that employees begin from a default position of nondisclosure that is attributable to fear of being stigmatized in the workplace as a result of the mental disorder. In order to move from the default position, employees need a reason to disclose. The decision-making process itself is a risk–benefit analysis, during which employees weigh risks and benefits within the existing context as they assess it. The model identifies that fear of stigmatization is one of the problems with disclosure at work and describes the disclosure decision-making process. Conclusions Understanding of how employees make decisions about disclosure in the workplace may inform organizational policies, practices, and programs to improve the experiences of individuals diagnosed with a mental disorder at work. The findings suggest possible intervention strategies in education, policy, and culture for reducing stigma of mental disorders in the workplace.

Small heat shock proteins (sHSPs) are present in all kingdoms of life and play fundamental roles in cell biology. sHSPs are key components of the cellular protein quality control system, acting as the first line of defense against conditions that affect protein homeostasis and proteome stability, from bacteria to plants to humans. sHSPs have the ability to bind to a large subset of substrates and to maintain them in a state competent for refolding or clearance with the assistance of the HSP70 machinery. sHSPs participate in a number of biological processes, from the cell cycle, to cell differentiation, from adaptation to stressful conditions, to apoptosis, and, even, to the transformation of a cell into a malignant state. As a consequence, sHSP malfunction has been implicated in abnormal placental development and preterm deliveries, in the prognosis of several types of cancer, and in the development of neurological diseases. Moreover, mutations in the genes encoding several mammalian sHSPs result in neurological, muscular, or cardiac age-related diseases in humans. Loss of protein homeostasis due to protein aggregation is typical of many age-related neurodegenerative and neuromuscular diseases. In light of the role of sHSPs in the clearance of un/misfolded aggregation-prone substrates, pharmacological modulation of sHSP expression or function and rescue of defective sHSPs represent possible routes to alleviate or cure protein conformation diseases. Here, we report the latest news and views on sHSPs discussed by many of the world's experts in the sHSP field during a dedicated workshop organized in Italy (Bertinoro, CEUB, October 12-15, 2016).

Background Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects.  Methods This pilot study enrolled 5 subjects with early AD. Participants were randomized to placebo ( n  = 1) or two daily efavirenz doses (50 mg and 200 mg, n  = 2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain the statistical significance of target engagement . We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain. Results In subjects receiving efavirenz, there was a statistically significant within-group increase ( P  ≤ 0.001) in the levels of plasma 24HC from baseline. The levels of 24HC in the CSF of subjects on the 200-mg dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects. Conclusions Our findings suggest efavirenz target engagement in human subjects with early AD. This supports the pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug’s effects on AD biomarkers and clinical symptomatology. Trial registration ClinicalTrials.gov, NCT03706885.

This paper presents the application of a modular approach for real-time streamflow forecasting that uses different system-theoretic rainfall-runoff models according to the situation characterising the forecast instant. For each forecast instant, a specific model is applied, parameterised on the basis of the data of the similar hydrological and meteorological conditions observed in the past. In particular, the hydro-meteorological conditions are here classified with a clustering technique based on Self-Organising Maps (SOM) and, in correspondence of each specific case, different feed-forward artificial neural networks issue the streamflow forecasts one to six hours ahead, for a mid-sized case study watershed. The SOM method allows a consistent identification of the different parts of the hydrograph, representing current and near-future hydrological conditions, on the basis of the most relevant information available in the forecast instant, that is, the last values of streamflow and areal-averaged rainfall. The results show that an adequate distinction of the hydro-meteorological conditions characterising the basin, hence including additional knowledge on the forthcoming dominant hydrological processes, may considerably improve the rainfall-runoff modelling performance.

Background/objectivesDysfunction in reward-related aspects of feeding, and consequent overeating in humans, is a major contributor to obesity. Intrauterine undernutrition and overnutrition are among the predisposing factors, but the exact mechanism of how overeating develops is still unclear. Consummatory behavior is regulated by the medial shell (mSh) of the accumbens nucleus (Nac) through direct connections with the rostral part of the lateral hypothalamic area (LHA). Our aim was to investigate whether an altered Nac-LHA circuit may underlie hyperphagic behavior.Subjects/methodsIntrauterine protein-restricted (PR) male Wistar rats were used as models for hyperphagia. The experiments were performed using young adult control (normally nourished) and PR animals. Sweet condensed milk (SCM) served as a reward to test consumption and subsequent activation (Fos+) of Nac and LHA neurons. Expression levels of type 1 and 2 dopamine receptors (D1R, D2R) in the Nac, as well as tyrosine hydroxylase (TH) levels in the ventral tegmental area, were determined. The D1R agonist SKF82958 was injected into the mSh-Nac of control rats to test the effect of D1R signaling on SCM intake and neuronal cell activation in the LHA.ResultsA group of food reward-representing D1R+ neurons was identified in the mSh-Nac. Activation (Fos+) of these neurons was highly proportional to the consumed palatable food. D1R agonist treatment attenuated SCM intake and diminished the number of SCM-activated cells in the LHA. Hyperphagic PR rats showed increased intake of SCM, reduced D1R expression, and an impaired response to SCM-evoked neuronal activation in the mSh-Nac, accompanied by an elevated number of Fos+ neurons in the LHA compared to controls.ConclusionsSensitivity of food reward-representing neurons in the mSh-Nac determines the level of satisfaction that governs cessation of consumption, probably through connections with the LHA. D1R signaling is a key element in this function, and is impaired in obesity-prone rats.

Previously, the presence of a blood-myenteric plexus barrier and its disruption was reported in experimentally induced colitis via a macrophage-dependent process. The aim of this study is to reveal how myenteric barrier disruption and subsequent neuronal injury affects gut motility in vivo in a murine colitis model. We induced colitis with dextran sulfate sodium (DSS), with the co-administration of liposome-encapsulated clodronate ( l -clodronate) to simultaneously deplete blood monocytes contributing to macrophage infiltration in the inflamed muscularis of experimental mice. DSS-treated animals receiving concurrent l -clodronate injection showed significantly decreased blood monocyte numbers and colon muscularis macrophage (MM) density compared to DSS-treated control (DSS-vehicle). DSS-clodronate-treated mice exhibited significantly slower whole gut transit time than DSS-vehicle-treated animals and comparable to that of controls. Experiments with oral gavage-fed Evans-blue dye showed similar whole gut transit times in DSS-clodronate-treated mice as in control animals. Furthermore, qPCR-analysis and immunofluorescence on colon muscularis samples revealed that factors associated with neuroinflammation and neurodegeneration, including Bax1, Hdac4, IL-18, Casp8 and Hif1a are overexpressed after DSS-treatment, but not in the case of concurrent l -clodronate administration. Our findings highlight that MM-infiltration in the muscularis layer is responsible for colitis-associated dysmotility and enteric neuronal dysfunction along with the release of mediators associated with neurodegeneration in a murine experimental model.

Type 2 transglutaminase (TG2) is an important cancer stem cell survival protein that exists in open and closed conformations. The major intracellular form is the closed conformation that functions as a GTP-binding GTPase and is required for cancer stem cell survival. However, at a finite rate, TG2 transitions to an open conformation that exposes the transamidase catalytic site involved in protein–protein crosslinking. The activities are mutually exclusive, as the closed conformation has GTP binding/GTPase activity, and the open conformation transamidase activity. We recently showed that GTP binding, but not transamidase activity, is required for TG2-dependent cancer stem cell invasion, migration and tumour formation. However, we were surprised that transamidase site-specific inhibitors reduce cancer stem cell survival. We now show that compounds NC9, VA4 and VA5, which react exclusively at the TG2 transamidase site, inhibit both transamidase and GTP-binding activities. Transamidase activity is inhibited by direct inhibitor binding at the transamidase site, and GTP binding is blocked because inhibitor interaction at the transamidase site locks the protein in the extended/open conformation to disorganize/inactivate the GTP binding/GTPase site. These findings suggest that transamidase site-specific inhibitors can inhibit GTP binding/signalling by driving a conformation change that disorganizes the TG2 GTP binding to reduce TG2-dependent signalling, and that drugs designed to target this site may be potent anti-cancer agents.