The antipsychotic medications aripiprazole, brexpiprazole and cariprazine are off-target respiratory chain complex I inhibitors.

Antipsychotic drugs are the mainstay of treatment for schizophrenia and provide adjunct therapies for other prevalent psychiatric conditions, including bipolar disorder and major depressive disorder. However, they also induce debilitating extrapyramidal syndromes (EPS), such as Parkinsonism, in a significant minority of patients. The majority of antipsychotic drugs function as dopamine receptor antagonists in the brain while the most recent 'third'-generation, such as aripiprazole, act as partial agonists. Despite showing good clinical efficacy, these newer agents are still associated with EPS in ~ 5 to 15% of patients. However, it is not fully understood how these movement disorders develop. Here, we combine clinically-relevant drug concentrations with mutliscale model systems to show that aripiprazole and its primary active metabolite induce mitochondrial toxicity inducing robust declines in cellular ATP and viability. Aripiprazole, brexpiprazole and cariprazine were shown to directly inhibit respiratory complex I through its ubiquinone-binding channel. Importantly, all three drugs induced mitochondrial toxicity in primary embryonic mouse neurons, with greater bioenergetic inhibition in ventral midbrain neurons than forebrain neurons. Finally, chronic feeding with aripiprazole resulted in structural damage to mitochondria in the brain and thoracic muscle of adult Drosophila melanogaster consistent with locomotor dysfunction. Taken together, we show that antipsychotic drugs acting as partial dopamine receptor agonists exhibit off-target mitochondrial liabilities targeting complex I.

Job security among healthcare workers in Guangdong, China.

Objective: The objective of this study was to explore the sense of job security and its influencing factors among healthcare workers in Guangdong, China. Methods: This cross-sectional study used stratified random sampling to enroll healthcare workers employed by hospitals across Guangdong province between September 2020 and October 2020. Results: A total of 4,173 questionnaires were distributed, and 4,076 were returned for an effective recovery rate of 97.68%. The overall score for the sense of security was 64.85 ± 20.09, and the item means score was 2.95 ± 0.91. Multiple-linear regression analysis showed that work experience (years), education level, job position, specialty unit, employment type, marital status, job satisfaction, WPV frequency, daily sleep duration, weekly overtime hours, average monthly earnings (RMB), hospital level, and region were significantly associated with senses of poor security among healthcare workers (all P < 0.05). Conclusions: Hospital workers in Guangdong reported relatively low levels of job security. Levels of job security were significantly associated with multiple factors which could be addressed by hospital practices to improve the sense of job security among healthcare workers.

The impact of nurses' sense of security on turnover intention during the normalization of COVID-19 epidemic: The mediating role of work engagement.

Background: COVID-19 pandemic has entered a normal stage in China. During this phase, nurses have an increased workload and mental health issues that threaten the sense of security. Poor sense of security may have a considerable impact on turnover intention through low work engagement. It was challenging to maintain the nurse workforce. Fewer studies have been conducted on the effect of nurses' sense of security on their turnover intention in that phase. This study aimed to investigate the interrelationship between nurses' sense of security, work engagement, and turnover intention during the normalization phase of the epidemic in China and to explore the impact of sense of security on turnover intention. Methods: A cross-sectional survey was conducted from September 2020 to May 2021 in Guangdong Province, China. Data were collected online using Sense of Security Scale for Medical Staff (SSS-MS), Utrecht Work Engagement Scale (UWES), and Turnover Intention Scale. Pearson's correlation analysis was used to assess the correlation between sense of security, work engagement, and turnover intention. The hypothesis model used multiple linear regression models and the bootstrapping procedure to analyze the relationship between these variables. Results: Data were collected from 2,480 nurses who met the inclusion criteria. Over half(64.5%) of nurses had a high and very high turnover intention. After controlling the demographic and working variables, sense of security (ß = 0.291, P < 0.001) had a direct positive effect on work engagement. Sense of security (ß = -0.447, P < 0.001) and work engagement (ß = -0.484, P < 0.001) had a direct negative effect on turnover intention. Sense of security and all of its components were associated with turnover intention through the partially mediating effects of work engagement. Conclusions: Nurses' turnover intention was at a high level during the normalization phase of the epidemic. Sense of security and its components act as positive resources to reduce turnover intention by improving work engagement. Policy makers and managers may pay attention to the needs of nurses' sense of security, which may be a new perspective to help managers reduce their turnover intention and stabilize the nurse team.

Inertial Data-Based AI Approaches for ADL and Fall Recognition.

The recognition of Activities of Daily Living (ADL) has been a widely debated topic, with applications in a vast range of fields. ADL recognition can be accomplished by processing data from wearable sensors, specially located at the lower trunk, which appears to be a suitable option in uncontrolled environments. Several authors have addressed ADL recognition using Artificial Intelligence (AI)-based algorithms, obtaining encouraging results. However, the number of ADL recognized by these algorithms is still limited, rarely focusing on transitional activities, and without addressing falls. Furthermore, the small amount of data used and the lack of information regarding validation processes are other drawbacks found in the literature. To overcome these drawbacks, a total of nine public and private datasets were merged in order to gather a large amount of data to improve the robustness of several ADL recognition algorithms. Furthermore, an AI-based framework was developed in this manuscript to perform a comparative analysis of several ADL Machine Learning (ML)-based classifiers. Feature selection algorithms were used to extract only the relevant features from the dataset's lower trunk inertial data. For the recognition of 20 different ADL and falls, results have shown that the best performance was obtained with the K-NN classifier with the first 85 features ranked by Relief-F (98.22% accuracy). However, Ensemble Learning classifier with the first 65 features ranked by Principal Component Analysis (PCA) presented 96.53% overall accuracy while maintaining a lower classification time per window (0.039 ms), showing a higher potential for its usage in real-time scenarios in the future. Deep Learning algorithms were also tested. Despite its outcomes not being as good as in the prior procedure, their potential was also demonstrated (overall accuracy of 92.55% for Bidirectional Long Short-Term Memory (LSTM) Neural Network), indicating that they could be a valid option in the future.

An investigation of cross-reactivity between the poultry red mite and house dust and storage mites in dogs with contact with chickens infested with red mites.

BACKGROUND: The European poultry red mite (PRM) Dermanyssus gallinae, a common ectoparasite of laying chickens and pigeons; it also can feed on other birds, humans and domestic animals, causing clinical signs ranging from mild discomfort to severe dermatitis. Little is known about possible hypersensitivity to PRM or cross-sensitization with house dust or storage mites. HYPOTHESIS/OBJECTIVES: Knowledge on possible PRM immunoglobulin E (IgE)-mediated allergy and possible cross-sensitization with house dust and storage mites may facilitate the clinical approach. The aim herein was to clarify possible evidence of type I hypersensitivity to PRM in dogs and possible occurrence of cross-sensitization with house dust and storage mites. ANIMALS: Sixteen dogs with chronic contact with PRM-infested chickens from traditional bird houses and 10 control dogs with no contact with birds. METHODS AND MATERIALS: Dogs were subjected to intradermal testing (IDT) and serum specific IgE (sIgE) determination for house dust and storage mites and D. gallinae. RESULTS: The highest wheal score was obtained with 0.1 mg/mL D. gallinae extract. Positive IDT reactions to PRM were found in four of 10 control dogs and in 10 of 16 from the chicken-exposed group. SIgE to PRM was detected in one control and in seven dogs exposed to chickens. No significant correlation was found between IDT or sIgE scores to PRM and house dust and storage mites. CONCLUSIONS AND CLINICAL SIGNIFICANCE: Contact with PRM-infested chickens may lead to sensitization without allergy, independently from sensitization to house dust and storage mites.

High Purcell factor generation of indistinguishable on-chip single photons.

On-chip single-photon sources are key components for integrated photonic quantum technologies. Semiconductor quantum dots can exhibit near-ideal single-photon emission, but this can be significantly degraded in on-chip geometries owing to nearby etched surfaces. A long-proposed solution to improve the indistinguishablility is to use the Purcell effect to reduce the radiative lifetime. However, until now only modest Purcell enhancements have been observed. Here we use pulsed resonant excitation to eliminate slow relaxation paths, revealing a highly Purcell-shortened radiative lifetime (22.7 ps) in a waveguide-coupled quantum dot-photonic crystal cavity system. This leads to near-lifetime-limited single-photon emission that retains high indistinguishablility (93.9%) on a timescale in which 20 photons may be emitted. Nearly background-free pulsed resonance fluorescence is achieved under π-pulse excitation, enabling demonstration of an on-chip, on-demand single-photon source with very high potential repetition rates.

An artificial neural network for membrane-bound catechol-O-methyltransferase biosynthesis with Pichia pastoris methanol-induced cultures.

BACKGROUND: Membrane proteins are important drug targets in many human diseases and gathering structural information regarding these proteins encourages the pharmaceutical industry to develop new molecules using structure-based drug design studies. Specifically, membrane-bound catechol-O-methyltransferase (MBCOMT) is an integral membrane protein that catalyzes the methylation of catechol substrates and has been linked to several diseases such as Parkinson's disease and Schizophrenia. Thereby, improvements in the clinical outcome of the therapy to these diseases may come from structure-based drug design where reaching MBCOMT samples in milligram quantities are crucial for acquiring structural information regarding this target protein. Therefore, the main aim of this work was to optimize the temperature, dimethylsulfoxide (DMSO) concentration and the methanol flow-rate for the biosynthesis of recombinant MBCOMT by Pichia pastoris bioreactor methanol-induced cultures using artificial neural networks (ANN). RESULTS: The optimization trials intended to evaluate MBCOMT expression by P. pastoris bioreactor cultures led to the development of a first standard strategy for MBCOMT bioreactor biosynthesis with a batch growth on glycerol until the dissolved oxygen spike, 3 h of glycerol feeding and 12 h of methanol induction. The ANN modeling of the aforementioned fermentation parameters predicted a maximum MBCOMT specific activity of 384.8 nmol/h/mg of protein at 30°C, 2.9 mL/L/H methanol constant flow-rate and with the addition of 6% (v/v) DMSO with almost 90% of healthy cells at the end of the induction phase. These results allowed an improvement of MBCOMT specific activity of 6.4-fold in comparison to that from the small-scale biosynthesis in baffled shake-flasks. CONCLUSIONS: The ANN model was able to describe the effects of temperature, DMSO concentration and methanol flow-rate on MBCOMT specific activity, as shown by the good fitness between predicted and observed values. This experimental procedure highlights the potential role of chemical chaperones such as DMSO in improving yields of recombinant membrane proteins with a different topology than G-coupled receptors. Finally, the proposed ANN shows that the manipulation of classic fermentation parameters coupled with the addition of specific molecules can open and reinforce new perspectives in the optimization of P. pastoris bioprocesses for membrane proteins biosynthesis.

Patient reactions to community pharmacies' roles: evidence from the Portuguese market.

BACKGROUND: There is little knowledge about how patients perceive and react to the extended role of community pharmacies. AIM: To develop a model describing the expanded role of Portuguese community pharmacies as comprising three roles - medicines supplier, advice provider and community health promoter - and two important patient reactions: satisfaction and loyalty. DESIGN: In 2010, 1200 face-to-face interviews were conducted with patients of community pharmacies in Portugal. A model comprising the three pharmacy roles and the two patient reactions was developed and tested using structural equation modelling. RESULTS: The results showed that the model was appropriate and that the roles of medicines supplier, advice provider and community health promoter were positively related to patients' satisfaction and loyalty. CONCLUSIONS: These results show that patients are aware of the different roles played by community pharmacies in Portugal. The data support the idea that the movement of Portuguese pharmacists' extended role, framed within a global context where society sends expectations regarding the role of organizations in the community in which they operate, is producing positive results for both patients and pharmacists.

Trends in protein-based biosensor assemblies for drug screening and pharmaceutical kinetic studies.

The selection of natural and chemical compounds for potential applications in new pharmaceutical formulations constitutes a time-consuming procedure in drug screening. To overcome this issue, new devices called biosensors, have already demonstrated their versatility and capacity for routine clinical diagnosis. Designed to perform analytical analysis for the detection of a particular analyte, biosensors based on the coupling of proteins to amperometric and optical devices have shown the appropriate selectivity, sensibility and accuracy. During the last years, the exponential demand for pharmacokinetic studies in the early phases of drug development, along with the need of lower molecular weight detection, have led to new biosensor structure materials with innovative immobilization strategies. The result has been the development of smaller, more reproducible biosensors with lower detection limits, and with a drastic reduction in the required sample volumes. Therefore in order to describe the main achievements in biosensor fields, the present review has the main aim of summarizing the essential strategies used to generate these specific devices, that can provide, under physiological conditions, a credible molecule profile and assess specific pharmacokinetic parameters.

PINK1 deficiency sustains cell proliferation by reprogramming glucose metabolism through HIF1.

PTEN-induced kinase-1 (PINK1) is a Ser/Thr kinase implicated in familial early-onset Parkinson's disease, and was first reported as a growth suppressor. PINK1 loss-of-function compromises both mitochondrial autophagy and oxidative phosphorylation. Here we report that PINK1 deficiency triggers hypoxia-inducible factor-1α (HIF1α) stabilization in cultured Pink1(-/-) mouse embryonic fibroblasts and primary cortical neurons as well as in vivo. This effect, mediated by mitochondrial reactive oxygen species, led to the upregulation of the HIF1 target, pyruvate dehydrogenase kinase-1, which inhibits PDH activity. Furthermore, we show that HIF1α stimulates glycolysis in the absence of Pink1, and that the promotion of intracellular glucose metabolism by HIF1α stabilization is required for cell proliferation in Pink1(-/-) mice. We propose that loss of Pink1 reprograms glucose metabolism through HIF1α, sustaining increased cell proliferation.

Different DNA-PKcs functions in the repair of radiation-induced and spontaneous DSBs within interstitial telomeric sequences.

Interstitial telomeric sequences (ITSs) in hamster cells are hot spots for spontaneous and induced chromosome aberrations (CAs). Most data on ITS instability to date have been obtained in DNA repair-proficient cells. The classical non-homologous end joining repair pathway (C-NHEJ), which is the principal double strand break (DSB) repair mechanism in mammalian cells, is thought to restore the morphologically correct chromosome structure. The production of CAs thus involves DNA-PKcs-independent repair pathways. In our current study, we investigated the participation of DNA-PKcs from the C-NHEJ pathway in the repair of spontaneous or radiation-induced DSBs in ITSs using wild-type and DNA-PKcs mutant Chinese hamster ovary cells. Our data demonstrate that DNA-PKcs stabilizes spontaneous DSBs within ITSs from the chromosome 9 long arm, leading to the formation of terminal deletions. In addition, we show that DNA-PKcs-dependent C-NHEJ is employed following radiation-induced DSBs in other ITSs and restores morphologically correct chromosomes, whereas DNA-PKcs independent mechanisms co-exist in DNA-PKcs proficient cells leading to an excess of CAs within ITSs.

Specific downregulation of bcl-2 and xIAP by RNAi enhances the effects of chemotherapeutic agents in MCF-7 human breast cancer cells.

Antiapoptotic genes such as bcl-2 or xIAP may be responsible for resistance to apoptosis induced by cytotoxic drugs. The aim of this study was to investigate if downregulation of bcl-2 or xIAP by RNA interference (RNAi) would sensitize MCF-7 cells to etoposide and doxorubicin. FITC-siRNAs uptake was verified by fluorescence microscopy and downregulation of Bcl-2 or XIAP was confirmed by Western Blotting. Both siRNAs reduced the number of viable cells and increased cellular apoptosis. Treatment with siRNAs followed by treatment with etoposide or doxorubicin further reduced the number of viable cells, when compared to either of the treatments alone. Therefore, downregulation of bcl-2 or xIAP by RNAi enhances the effects of etoposide and doxorubicin.