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Thousand-year-old Buddhist traditions have developed a wide range of methods for the subjective exploration of consciousness through meditation. Combining their subjective research with the possibilities of modern neuroscience can help us better understand the physiological mechanisms of consciousness. Therefore, we have been guided by specifically Buddhist explanations when studying the physiological mechanisms of altered states of consciousness during Buddhist meditations. In Buddhism, meditations are generally divided into two large categories: (1) one-pointed concentration and (2) analytical meditation. Maintaining both one-pointed concentration and analytical meditation on 'bodhicitta' ("the thought of awakening") and 'emptiness' is a necessary condition for transitioning into tantric practices. Tantric practices involve sophisticated visualizations of Buddhist deities, the 'energy structure' of the human body, and the visualization of the stage-by-stage process of dying accompanied with the dissolution of body elements. According to Buddhism, these meditations are characterized by the gradual withdrawal from "gross levels" of consciousness associated with the five senses. From a psychophysiological perspective, this withdrawal of sensory consciousness can be considered as the decrease of sensory stimuli recognition and attentional disengagement from the external world. We concentrated on how considered meditations affect sensory and cognitive processing of external stimuli. Auditory event-related potentials (ERPs) in the passive oddball paradigm were studied both during meditations and in a controlled state of relaxed wakefulness. It was shown with a group of 115 Buddhist monks that during meditation, mismatch negativity amplitudes, amplitudes of N1 and P2 components of ERPs to deviant stimuli, and the amplitudes of the P3a component to novel stimuli all decrease. These outcomes suggest that the considered Buddhist meditations, compared to the control state of relaxed wakefulness, are accompanied by a decrease in physiological processes responsible for maintaining attention on the outside world and recognizing changes in the stream of sensory stimuli.

As depression is common in older people and confers significant risk for dementia, its accurate assessment is essential. The 15-item Geriatric Depression Scale (GDS-15) is a widely used assessment tool for measuring depression in aged populations, and its psychometric properties have been recently improved using Rasch analysis. However, its temporal reliability and ability to distinguish between dynamic and enduring symptoms of depression have not been examined using the appropriate methodology. Generalizability theory (G theory) is a suitable method to distinguish between enduring and dynamic symptoms of depression and to evaluate the reliability of the GDS-15 scores and sources of measurement error. We applied G theory to the longitudinal GDS-15 data of 354 participants from the Sydney Memory and Ageing Study, collected biennially over 10 years, from individuals aged 70 years and older. The GDS-15 demonstrated strong reliability and generalizability of its test scores in measuring enduring symptoms of depression (

MotivationGenome annotations are a common way to represent genomic features such as genes, regulatory elements or epigenetic modifications. The amount of overlap between two annotations is often used to ascertain if there is an underlying biological connection between them. In order to distinguish between true biological association and overlap by pure chance, a robust measure of significance is required. One common way to do this is to determine if the number of intervals in the reference annotation that intersect the query annotation is statistically significant. However, currently employed statistical frameworks are often either inefficient or inaccurate when computing p-values on the scale of the whole human genome.ResultsWe show that finding the p-values under the typically used “gold” null hypothesis is 𝒩𝒫-hard. This motivates us to reformulate the null hypothesis using Markov chains. To be able to measure the fidelity of our Markovian null hypothesis, we develop a fast direct sampling algorithm to estimate the p-value under the gold null hypothesis. We then present an open-source software tool MCDP that computes the p-values under the Markovian null hypothesis in 𝒪 (m2 + n) time and 𝒪 (m) memory, where m and n are the numbers of intervals in the reference and query annotations, respectively. Notably, MCDP runtime and memory usage are independent from the genome length, allowing it to outperform previous approaches in runtime and memory usage by orders of magnitude on human genome annotations, while maintaining the same level of accuracy.AvailabilityThe software is available at https://github.com/fmfi-compbio/mc-overlaps. All data for reproducibility are available at https://github.com/fmfi-compbio/mc-overlaps-reproducibility

Caveola membrane structures harbor mechanosensitive chloride channels (MCCs; including chloride channel 2, chloride channel 3, and SWELL1, also known as LRRC8A) that form a swelling-activated chloride current (I(Cl,swell)) and play an important role in cell volume regulation and mechanoelectrical signal transduction. However, the role of the muscle-specific caveolar scaffolding protein caveolin-3 (Cav3) in regulation of MCC expression, activity, and contribution to membrane integrity in response to mechanical stress remains unclear. Here we showed that Cav3-transfected (Cav3-positive) HEK293 cells were significantly resistant to extreme (

There is an urgent need for a malaria vaccine that can prevent severe disease in young children and adults. Despite earlier work showing an immunological mechanism for preventing infection and reducing disease severity, there is currently no reliable vaccine that can provide durable protection. In part, this may reflect a limited number of ways that the host can respond to the NANP repeat sequences of circumsporozoite protein (CSP) in the parasite. In addition, it may reflect antigenic escape by the parasite from protective antibodies. To be successful, a vaccine must protect against repeated exposure to infected mosquitoes in endemic areas. We have created a series of live viral vectors based on the rubella vaccine strain that express multiple tandem repeats of NANP, and we demonstrate immunogenicity in a rhesus macaque model. We tested the vectors in a sequential immunization strategy. In the first step, the animals were primed with CSP-DNA vaccine and boosted with rubella/CSP vectors. In the second step, we gave rubella/CSP vectors again, followed by recombinant CSP protein. Following the second step, antibody titers were comparable to adult exposure to malaria in an endemic area. The antibodies were specific for native CSP protein on sporozoites, and they persisted for at least 1½ years in two out of three macaques. Given the safety profile of rubella vaccine in children, these vectors could be most useful in protecting young children, who are at greatest risk of severe malarial disease.

Most patients over 50 years of age are diagnosed with diseases of the dentoalveolar apparatus, in particular, bone tissue disorders, which leads to a decrease in the survival rate of implants. Identification of the causes, as well as the development of a methodology for predicting survival by minimally invasive methods, is relevant. The aim of the study was to study the markers of tight junctions in the buccal epithelium (BE) in people of different ages. BE scrapings were taken before and after implantation in patients divided into 5 age groups, from young to centenarians. Immunocytochemical method was used to study markers for tight junction proteins - claudin-1, -7 and 10. It has been shown that with age there is a decrease in the intensity of expression of adhesion molecules, in particular claudin -1, -7 and -10 in the mucous membranes, the minimum values were recorded in the group of centenarians. The study found that after dental implantation, there was a decrease in the expression of claudin-1 and -10 and an increase in the expression of claudin-7. Changes in the expression of claudins may indicate the development of a pathological process in the body, including the success of implantation, especially in people of older age groups.У большинства пациентов старше 50 лет диагностируют заболевания зубочелюстного аппарата, в частности нарушения костной ткани, что приводит к снижению процента приживаемости имплантов. Выявление причин, а также разработка методики прогнозирования приживаемости малоинвазивными методами являются актуальными проблемами. Цель исследования — изучение маркеров плотных контактов в буккальном эпителии у людей разного возраста. Соскоб буккального эпителия брали до и после имплантации у пациентов, разделенных на пять возрастных групп — от молодого возраста до долгожителей. Иммуноцитохимическим методом изучали маркеры к белкам плотных контактов — клаудину-1, -7 и -10. Показано, что с возрастом происходит снижение интенсивности экспрессии молекул адгезии, в частности клаудина -1, -7 и -10, в слизистых оболочках, минимальные значения зафиксированы в группе долгожителей. В исследовании установлено, что после дентальной имплантации снижается экспрессия клаудинов-1 и -10 и увеличивается — клаудина-7. Изменение экспрессии клаудинов может свидетельствовать о развитии патологического процесса в организме, в том числе об успехе имплантации, особенно у людей старших возрастных групп.

DJ-1, also known as Parkinson's disease protein 7, is a multifunctional protein ubiquitously expressed in cells and tissues. Interacting with proteins of various intracellular compartments, DJ-1 plays an important role in maintaining different cellular functions. Mutant DJ-1 forms containing amino acid substitutions (especially L166P), typical of Parkinson's disease, are characterized by impaired dimerization, stability, and folding. DJ-1 exhibits several types of catalytic activity; however, in the enzyme classification it exists as protein deglycase (EC 3.5.1.124). Apparently, in different cell compartments DJ-1 exhibits catalytic and non-catalytic functions, and their ratio still remains unknown. Oxidative stress promotes dissociation of cytoplasmic DJ-1 dimers into monomers, which are translocated to the nucleus, where this protein acts as a coactivator of various signaling pathways, preventing cell death. In mitochondria, DJ-1 is found in the synthasome, where it interacts with the β ATP synthase subunit. Downregulation of the DJ-1 gene under conditions of experimental PD increases sensitivity of the cells to neurotoxins, and introduction of the recombinant DJ-1 protein attenuates manifestation of this pathology. The thirteen-membered fragment of the DJ-1 amino acid sequence attached to the heptapeptide of the TAT protein penetrating into the cells exhibited neuroprotective properties in various PD models both in cell cultures and after administration to animals. Low molecular weight DJ-1 ligands also demonstrate therapeutic potential, providing neuroprotective effects seen during their incubation with cells and administration to animals.

Objectives Pressures in daily life limit one’s ability to be authentic and research shows that inauthenticity can be detrimental to mental health. Mindfulness is known to have a protective effect on mental health through an accepting and nonjudgmental stance. This study aimed to establish whether mindfulness buffers the relationship between inauthenticity and depression. Method A cross-sectional sample of employed individuals in New Zealand ( n=301) completed an online survey assessing their levels of authenticity, mindfulness, and depression. Results Findings indicate that authenticity and mindfulness together explain 29% of variance in depression. In addition, mindfulness can buffer the negative impact of low authenticity on depression. Conclusion Inauthenticity is related to higher levels of depression, but mindfulness is able to buffer this impact. These findings imply that engaging in mindfulness practice may be beneficial for mental health when individuals experience reduced authenticity.

BACKGROUND There were gaps between guidelines and practice when surgery was the only treatment for aortic stenosis (AS). OBJECTIVES This study analyzed the decision to intervene in patients with severe AS in the EORP VHD (EURObservational Research Programme Valvular Heart Disease) II survey. METHODS Among 2,152 patients with severe AS, 1,271 patients with high-gradient AS who were symptomatic fulfilled a Class I recommendation for intervention according to the 2012 European Society of Cardiology guidelines; the primary end point was the decision for intervention. RESULTS A decision not to intervene was taken in 262 patients (20.6%). In multivariate analysis, the decision not to intervene was associated with older age (odds ratio [OR]: 1.34 per 10-year increase; 95% CI: 1.11 to 1.61; P = 0.002), New York Heart Association functional classes I and II versus III (OR: 1.63; 95% CI: 1.16 to 2.30; P = 0.005), higher age adjusted Charlson comorbidity index (OR: 1.09 per 1-point increase; 95% CI: 1.01 to 1.17; P = 0.03), and a lower transaortic mean gradient (OR: 0.81 per 10-mm Hg decrease; 95% CI: 0.71 to 0.92; P < 0.001). During the study period, 346 patients (40.2%, median age 84 years, median EuroSCORE II [European System for Cardiac Operative Risk Evaluation II] 3.1%) underwent transcatheter intervention and 515 (59.8%, median age 69 years, median EuroSCORE II 1.5%) underwent surgery. A decision not to intervene versus intervention was associated with lower 6-month survival (87.4%; 95% CI: 82.0 to 91.3 vs 94.6%; 95% CI: 92.8 to 95.9; P < 0.001). CONCLUSIONS A decision not to intervene was taken in 1 in 5 patients with severe symptomatic AS despite a Class I recommendation for intervention and the decision was particularly associated with older age and combined comorbidities. Transcatheter intervention was extensively used in octogenarians. (J Am Coll Cardiol 2021;78:2131-2143) (c) 2021 by the American College of Cardiology Foundation.

Selenium is an important micronutrient that is essential for the functioning of the human body. Being a component of the active center of several antioxidant enzymes selenium prevents cell injury by free radicals. Decline in selenium-containing enzymes results in progression of oxidative stress and chronic inflammation, which are considered as possible causes for the development of many cardiovascular diseases. This review focuses on mechanisms for prevention of myocardial and vascular injury through the adequate selenium supply to the body. The importance of monitoring and correction of the selenium status in appropriate patients is underlined.

The care of a patient with Alzheimer's disease (AD) is considered from the perspective of an ecosystem, that is, a systemic approach describing effective partnership, collaboration and research aimed at creating value, involving all participants in the AD patient journey. The effectiveness of this ecosystem is only possible with the involvement of all stakeholders in its development, including patients, healthcare professionals at all levels, government agencies, private companies, and patient organizations. The unmet health care and information needs of patients with AD are a consequence of barriers in the AD ecosystem. Key barriers for the patient include low awareness and stigmatization of the disease in society, lack of quality epidemiological data, difficulties in timely diagnosis, lack of prevention programs, unpreparedness of most physicians to conduct AD patient rehabilitation, and other factors. Based on the analysis of the ecosystem of AD and the patient pathway, 10 main directions (strategies) necessary for the formation of the ecosystem were identified: conducting research in the diagnosis and epidemiology of AD, creating and implementing a cognitive health program, forming a legal framework, raising public awareness, optimizing patient routing for timely diagnosis, organizing a network of memory clinics/laboratories, creating a register of patients with dementia, developing digital solutions and supporting social projects.Рассмотрено оказание помощи пациенту с болезнью Альцгеймера (БА) с точки зрения экосистемы, т.е. системного подхода, описывающего эффективное партнерство, сотрудничество и исследования пациентов с БА. Эффективность данной экосистемы возможна только при условии вовлечения в ее развитие всех заинтересованных в ней участников, включая пациентов, медицинских работников всех уровней, государственные органы, частные компании и организации пациентов. Неудовлетворенные потребности пациентов с БА в оказании медицинской помощи, уходе и информационной поддержке являются следствием барьеров в экосистеме БА. К ключевым барьерам для пациента следует отнести низкую осведомленность о заболевании и его стигматизация в обществе, отсутствие качественных эпидемиологических данных, сложности своевременной диагностики, недостаток программ профилактики, неготовность к проведению реабилитации пациента с БА большинства врачей и другие факторы. На основании анализа экосистемы БА и пути пациента выделено 10 основных направлений (стратегий), необходимых для формирования экосистемы: проведение исследований в области диагностики и эпидемиологии БА, создания и осуществления программы когнитивного здоровья, формирование правовой базы, повышение осведомленности населения, оптимизация маршрутизации пациента для своевременной диагностики, организация сети клиник/лабораторий памяти, создание регистра пациентов с деменцией, разработка цифровых решений и поддержка социальных проектов.

OBJECTIVE Late preterm infants have an increased risk of morbidity relative to term infants. We sought to determine the rate, temporal trend, risk factors, and reasons for 30-day readmission. METHODS This is a retrospective cohort study of infants born at 34 to 42 weeks’ gestation in California between January 1, 2011, and December 31, 2017. Birth certificates maintained by California Vital Statistics were linked to discharge records maintained by the California Office of Statewide Health Planning and Development. Multivariable logistic regression was used to identify risk factors and derive a predictive model. RESULTS Late preterm infants represented 4.3% (n = 122 014) of the study cohort (n = 2 824 963), of which 5.9% (n = 7243) were readmitted within 30 days. Compared to term infants, late preterm infants had greater odds of readmission (odds ratio [OR]: 2.34 [95% confidence interval (CI): 2.28–2.40]). The temporal trend indicated increases in all-cause and jaundice-specific readmission infants (P < .001). The common diagnoses at readmission were jaundice (58.9%), infections (10.8%), and respiratory complications (3.5%). In the adjusted model, factors that were associated with greater odds of readmission included assisted vaginal birth, maternal age ≥34 years, diabetes, chorioamnionitis, and primiparity. The model had predictive ability of 60% (c-statistic 0.603 [95% CI: 0.596–0.610]) in late preterm infants who had CONCLUSION The findings contribute important information on what factors increase or decrease the risk of readmission. Longitudinal studies are needed to examine promising hospital predischarge and follow-up care practices.

ObjectiveLate preterm infants have an increased risk of morbidity relative to term infants. We sought to determine the rate, temporal trend, risk factors, and reasons for 30-day readmission.MethodsThis is a retrospective cohort study of infants born at 34 to 42 weeks' gestation in California between January 1, 2011, and December 31, 2017. Birth certificates maintained by California Vital Statistics were linked to discharge records maintained by the California Office of Statewide Health Planning and Development. Multivariable logistic regression was used to identify risk factors and derive a predictive model.ResultsLate preterm infants represented 4.3% (n = 122 014) of the study cohort (n = 2 824 963), of which 5.9% (n = 7243) were readmitted within 30 days. Compared to term infants, late preterm infants had greater odds of readmission (odds ratio [OR]: 2.34 [95% confidence interval (CI): 2.28-2.40]). The temporal trend indicated increases in all-cause and jaundice-specific readmission infants (P < .001). The common diagnoses at readmission were jaundice (58.9%), infections (10.8%), and respiratory complications (3.5%). In the adjusted model, factors that were associated with greater odds of readmission included assisted vaginal birth, maternal age ≥34 years, diabetes, chorioamnionitis, and primiparity. The model had predictive ability of 60% (c-statistic 0.603 [95% CI: 0.596-0.610]) in late preterm infants who had

The pandemic of coronavirus infection, which has begun in 2019, has not ended to this day. COVID-19 adversely affects human health not only in the acute period of the disease, but also in the long-run: in a large percentage of cases, recovery takes very long, patients require and often have problems returning to their baseline. During the first wave of the pandemic in 2020, researchers noted that about 10-20% of patients didn't fully recover three weeks after the onset of the disease. It is still not clear how long the recovery period can last, and what are the reasons of different time course of the recovery. Long-term recovery after a viral infection is a non-unique feature of COVID-19, which does not facilitate the management of patients with post-COVID syndrome. The impact on mental health after COVID-19 is significant, and at least 30% of those, who have been ill, may have symptoms of anxiety and/or depression after the acute phase of the disease. Since the emergence of the SARS-CoV-2 virus, there has been an increase in somnological disorders by 42%, while every third COVID-19 patient reports altered sleep patterns. In post-COVID-19 syndrome, this condition is referred to as Coronasomnia (COVID-somnia). The success of therapy of this condition depends on reporting and treating mental disorders in patients, as anxiety and depression are often accompanied by sleep disorders, that is, there is a bidirectional influence of mental disorders on the quality of sleep. The article provides data on two anti-anxiety drugs (noofen and adaptol) that help to treat the manifestations of post-COVID syndrome accompanied by sleep disorders.Пандемия коронавирусной инфекции, начавшаяся в 2019 г., по сей день не завершилась. COVID-19 пагубно влияет на здоровье человека не только в острый, но и в отдаленный период заболевания: в большом проценте случаев здоровье полностью не восстанавливается длительное время, требует медицинского вмешательства, зачастую трудно поддается коррекции. Исследователи еще во время первой волны пандемии в 2020 г. отметили, что около 10—20% пациентов не полностью выздоровели через 3 нед от начала заболевания, до сих пор недостаточно ясно, как долго может длиться период выздоровления, и причины разного течения этого периода. Длительное восстановление после перенесенной вирусной инфекции не является исключительной особенностью COVID-19, что не облегчает курацию пациентов с постковидным синдромом (ПКС). Влияние на психическое здоровье перенесенного COVID-19 значительно, по крайней мере, у 30% переболевших могут быть симптомы тревоги и/или депрессии после минования острой фазы. С момента появления COVID-19 отмечено увеличение сомнологических расстройств на 42%, при этом каждый 3-й переболевший COVID-19 отмечает жалобы со стороны сна. При ПКС такое состояние обозначают как Coronasomnia (коронасомния). Успех терапии этого состояния зависит от учета и коррекции психических расстройств у пациента, так как тревога и депрессия часто сопровождаются нарушениями сна, существует двунаправленное влияние психических расстройств на качество сна. В статье приводятся данные о противотревожных препаратах Ноофен и Адаптол, помогающих корректировать проявления ПКС с расстройствами сна.

This work considers the estimation of impulsive time series pertaining to biomedical systems and, in particular, to endocrine ones. We assume a signal model in the form of the output of a continuous linear time-invariant system driven by a sequence of instantaneous impulses, which concept is utilized here, in particular, for modeling of the male reproductive hormone axis. An estimation method to identify the impulsive sequence and the continuous system dynamics from sampled measurements of the output is proposed. Hinging on thorough mathematical analysis, the method improves upon a previously developed least-squares algorithm by resolving the trade-off between model fit and input sparsity, thus removing the need for manual tuning of user-defined estimation algorithm parameters. Experiments with synthetic data and Markov chain Monte-Carlo estimation demonstrate the viability of the proposed method, but also indicate that measurement noise renders the estimation problem ill-posed, as multiple estimates along a curve in the parameter space yield similar fits to data. The method is furthermore applied to clinical luteinizing hormone data collected from healthy males and, for comparability, one female, with similar results. Comparison between the estimated and theoretical elimination rates, as well as simulation of the estimated models, demonstrate the efficacy of the method. The sensitivity of the impulse distribution to the estimated elimination rates is investigated on a subject-specific data subset, revealing that the input sequence and elimination rate estimates can be interdependent. The dose-dependent effect of a selective gonadotropin releasing hormone receptor antagonist on the frequency and weights of the estimated impulses is also analyzed; a significant impact of the medication on the impulse weights is confirmed. To demonstrate the feasibility of the estimation approach for other hormones with pulsatile secretion, the modeling of cortisol data sets collected from three female adolescents was performed.

Intravenous thrombolysis with alteplase bolus followed by infusion is a global standard of care for patients with acute ischaemic stroke. We aimed to determine whether tenecteplase given as a single bolus might increase reperfusion compared with this standard of care.In this multicentre, open-label, parallel-group, registry-linked, randomised, controlled trial (AcT), patients were enrolled from 22 primary and comprehensive stroke centres across Canada. Patients were eligible for inclusion if they were aged 18 years or older, with a diagnosis of ischaemic stroke causing disabling neurological deficit, presenting within 4·5 h of symptom onset, and eligible for thrombolysis per Canadian guidelines. Eligible patients were randomly assigned (1:1), using a previously validated minimal sufficient balance algorithm to balance allocation by site and a secure real-time web-based server, to either intravenous tenecteplase (0·25 mg/kg to a maximum of 25 mg) or alteplase (0·9 mg/kg to a maximum of 90mg; 0·09 mg/kg as a bolus and then a 60 min infusion of the remaining 0·81 mg/kg). The primary outcome was the proportion of patients who had a modified Rankin Scale (mRS) score of 0-1 at 90-120 days after treatment, assessed via blinded review in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment who did not withdraw consent). Non-inferiority was met if the lower 95% CI of the difference in the proportion of patients who met the primary outcome between the tenecteplase and alteplase groups was more than -5%. Safety was assessed in all patients who received any of either thrombolytic agent and who were reported as treated. The trial is registered with ClinicalTrials.gov, NCT03889249, and is closed to accrual.Between Dec 10, 2019, and Jan 25, 2022, 1600 patients were enrolled and randomly assigned to tenecteplase (n=816) or alteplase (n=784), of whom 1577 were included in the ITT population (n=806 tenecteplase; n=771 alteplase). The median age was 74 years (IQR 63-83), 755 (47·9%) of 1577 patients were female and 822 (52·1%) were male. As of data cutoff (Jan 21, 2022), 296 (36·9%) of 802 patients in the tenecteplase group and 266 (34·8%) of 765 in the alteplase group had an mRS score of 0-1 at 90-120 days (unadjusted risk difference 2·1% [95% CI - 2·6 to 6·9], meeting the prespecified non-inferiority threshold). In safety analyses, 27 (3·4%) of 800 patients in the tenecteplase group and 24 (3·2%) of 763 in the alteplase group had 24 h symptomatic intracerebral haemorrhage and 122 (15·3%) of 796 and 117 (15·4%) of 763 died within 90 days of starting treatment INTERPRETATION: Intravenous tenecteplase (0·25 mg/kg) is a reasonable alternative to alteplase for all patients presenting with acute ischaemic stroke who meet standard criteria for thrombolysis.Canadian Institutes of Health Research, Alberta Strategy for Patient Oriented Research Support Unit.

While the effectiveness of mindfulness-based interventions (MBIs) with respect to distress has been widely researched, unemployed individuals, who often suffer from high levels of distress, have largely been neglected in MBI research. The present study aimed to investigate the effects of a low-dose MBI on distress in a sample of young unemployed adults. The sample included 239 young unemployed adults enrolled for a 6-week long employability-related training camp. Participants were allocated into an intervention group that received weekly 1-hour mindfulness training over 4 weeks, and a control group. Dispositional mindfulness, distress and well-being were assessed in the entire sample prior to the start and upon completion of the mindfulness training. A mixed model ANCOVA showed that distress was inversely and significantly predicted by baseline levels of mindfulness and well-being. After accounting for the baseline levels of mindfulness and well-being, a significant effect of the mindfulness intervention was evident. This result shows that a low-dose MBI can decrease distress in a sample of young unemployed adults and its effectiveness is positively associated with initial levels of dispositional mindfulness and well-being.

Significance The male-specific Y chromosome harbors genes important for sperm production. Because Y is repetitive, its DNA sequence was deciphered for only a few species, and its evolution remains elusive. Here we compared the Y chromosomes of great apes (human, chimpanzee, bonobo, gorilla, and orangutan) and found that many of their repetitive sequences and multicopy genes were likely already present in their common ancestor. Y repeats had increased intrachromosomal contacts, which might facilitate preservation of genes and gene regulatory elements. Chimpanzee and bonobo, experiencing high sperm competition, underwent many DNA changes and gene losses on the Y. Our research is significant for understanding the role of the Y chromosome in reproduction of nonhuman great apes, all of which are endangered., The mammalian male-specific Y chromosome plays a critical role in sex determination and male fertility. However, because of its repetitive and haploid nature, it is frequently absent from genome assemblies and remains enigmatic. The Y chromosomes of great apes represent a particular puzzle: their gene content is more similar between human and gorilla than between human and chimpanzee, even though human and chimpanzee share a more recent common ancestor. To solve this puzzle, here we constructed a dataset including Ys from all extant great ape genera. We generated assemblies of bonobo and orangutan Ys from short and long sequencing reads and aligned them with the publicly available human, chimpanzee, and gorilla Y assemblies. Analyzing this dataset, we found that the genus Pan, which includes chimpanzee and bonobo, experienced accelerated substitution rates. Pan also exhibited elevated gene death rates. These observations are consistent with high levels of sperm competition in Pan. Furthermore, we inferred that the great ape common ancestor already possessed multicopy sequences homologous to most human and chimpanzee palindromes. Nonetheless, each species also acquired distinct ampliconic sequences. We also detected increased chromatin contacts between and within palindromes (from Hi-C data), likely facilitating gene conversion and structural rearrangements. Our results highlight the dynamic mode of Y chromosome evolution and open avenues for studies of male-specific dispersal in endangered great ape species.

Allosteric regulation of protein functions is ubiquitous in organismal biology, but the principles governing its evolution are not well understood. Here we discuss recent studies supporting the large-scale existence of latent allostery in ancestor proteins of superfamilies. As suggested, the evolution of allostery could be driven by the need for specificity in paralogs of slow evolving protein complexes with conserved active sites. The same slow evolution is displayed by purifying selection exhibited in allosteric proteins with somatic mutations involved in cancer, where disease-associated mutations are enriched in both orthosteric and allosteric sites. Consequently, disease-associated variants can be used to identify druggable allosteric sites that are specific for paralogs in protein superfamilies with otherwise similar functions.

Background Hypereosinophilia (HE, persistent peripheral blood eosinophilia > 1.5 × 109 /L) and hypereosinophilic syndrome (HES, HE with end-organ damage) are classified as primary (due to a myeloid clone), secondary (due to a wide variety of reactive causes), or idiopathic. Diagnostic evaluation of eosinophilia is challenging, in part because secondary causes of HE/HES such as lymphocyte-variant HES (L-HES) and vasculitis are difficult to diagnose, and emerging causes such as immunoglobulin G4-related disease (IgG4-RD) have rarely been examined. Objective and methods We reviewed 100 consecutive patients with HE/HES who underwent extensive evaluation for primary and secondary eosinophilia at a single tertiary care center to determine causes of HE/HES in a modern context. Results Six patients had primary HE/HES, 80 had a discrete secondary cause identified, and 14 had idiopathic HE/HES. The most common causes of secondary eosinophilia were L-HES/HES of unknown significance (L-HESus) (20), IgG4-RD (9), and eosinophilic granulomatosis with polyangiitis (EGPA) (8). Conclusions In contrast to other large published series of HE/HES, most patients in this study were found to have a discrete secondary cause of eosinophilia and only 14 were deemed idiopathic. These findings highlight the importance of extensive evaluation for secondary causes of eosinophilia such as L-HES, IgG4-RD, and EGPA.

AimAnalyzing a 5-year experience of surgical treatment of cardiosurgical patients with atrial fibrillation (AF).Material and methodsThe study analyzed results of surgical treatment with extracorporeal circulation in 132 patients with AF who underwent the Maze-IV procedure using a radiofrequency ablator with transmurality feedback from 2013 through 2018.ResultsTwo fatal outcomes were observed in the study group. These outcomes took place in the early postoperative period and were associated with progressive acute heart failure in patients with repeated surgery for mitral valve restenosis. 61.2% of the patients had no AF. Recurrent AF was observed during the first three years after surgery in association with withdrawal of the antiarrhythmic medication, which confirmed a need for long-term antiarrhythmic therapy. Analysis of risk factors for AF relapse identified significant predictors, including left ventricular dilatation larger than 5.5 cm at baseline and more than two-year duration of a history of arrhythmias.ConclusionThe Maze-IV procedure proved an effective and safe method of surgical treatment in AF patients with acquired heart defects and ischemic heart disease, which allowed maintaining sinus rhythm in 61.2% of patients for 5 years. Preventive amiodarone saturation reduced the risk of AF relapse by 24.2 % (p=0.038) and incidence of postoperative arrhythmic complications by 34.9 % (p=0.008) in cardiosurgical patients.

Background Depression is a common problem in older adults. The 15-item Geriatric Depression Scale (GDS-15) is a widely used psychometric tool for measuring depression in the elderly, but its psychometric properties have not been yet rigorously investigated. The aim was to evaluate psychometric properties of the GDS-15 and improve precision of the instrument by applying Rasch analysis and deriving conversion tables for transformation of raw scores into interval level data. Methods The data was extracted from the prospective cohort Sydney Memory and Ageing Study of initially not demented individuals aged 70 years and older. The GDS-15 items scores of 212 participants (47.2% males) were analysed using the dichotomous Rasch model. Results Initially poor reliability of the GDS-15, Person Separation Index (PSI) = 0.68, was improved by combining locally dependent items into seven super-items. These modifications improved reliability of the GDS-15 (PSI = 0.78) and resulted in the best Rasch model fit (χ2(28)=37.72, p = =0.104), strict unidimensionality and scale invariance across personal factors such as gender, diagnostic and language background. Limitations Presence of participants with cognitive impairment may be a potential limitation. Conclusions Reliability and psychometric characteristics of the GDS-15 were improved by minor modifications and now satisfy expectations of the unidimensional Rasch model. By using Rasch transformation tables published here psychiatrists, psychologists and researchers can transform GDS raw scores into interval-level data, which improves reliability of the GDS-15 without the need to modify its original response format. These findings increase accuracy of clinical psychometric assessments, leading to more precise diagnosis of depression in the elderly.

Background Prioritizing the maintenance of healthy cognitive aging and personalizing preventive interventions to enhance their effectiveness is crucial as the global population ages. Systemic inflammation and depression in older people have been associated with decreased levels of cognition but results have been inconsistent. Aims To explore the interactive network of inflammation, depression and cognition by sex in older people. Methods We used novel network analysis to explore the unique associations between inflammatory biomarkers, depression, cognition, and somatic, genetic, and lifestyle risk factors in an older (aged 70–90 years), non-demented, community-dwelling sample from the longitudinal Sydney Memory and Aging Study (N = 916) at baseline and at a two-year follow-up. Results The networks of biomarkers, depression, cognition, and relevant covariates were significantly different between males and females. A stable negative link between depression and cognition was found in females only; a stable positive association between biomarker interleukin-6 and depression was found in females only; and a stable positive association between biomarker interleukin-8 and alcohol was found in females only. For both males and females, a stable, positive relationship was found between the presence of APOE-ε4 gene and biomarker C-reactive protein; between education and cognition; and between biomarker interleukin-6 and all other biomarkers. Conclusions These findings suggest different psychophysiological mechanisms underlie the interactive network of biomarkers, depression and cognition in males and females that should be considered when designing personalized preventive interventions to maintain cognitively healthy aging.

We studied the effect of molecular hydrogen (H

This study examined whether pupil size and response time would distinguish directed exploration from random exploration and exploitation. Eighty-nine participants performed the two-choice probabilistic learning task while their pupil size and response time were continuously recorded. Using LMM analysis, we estimated differences in the pupil size and response time between the advantageous and disadvantageous choices as a function of learning success, i.e., whether or not a participant has learned the probabilistic contingency between choices and their outcomes. We proposed that before a true value of each choice became known to a decision-maker, both advantageous and disadvantageous choices represented a random exploration of the two options with an equally uncertain outcome, whereas the same choices after learning manifested exploitation and direct exploration strategies, respectively. We found that disadvantageous choices were associated with increases both in response time and pupil size, but only after the participants had learned the choice-reward contingencies. For the pupil size, this effect was strongly amplified for those disadvantageous choices that immediately followed gains as compared to losses in the preceding choice. Pupil size modulations were evident during the behavioral choice rather than during the pretrial baseline. These findings suggest that occasional disadvantageous choices, which violate the acquired internal utility model, represent directed exploration. This exploratory strategy shifts choice priorities in favor of information seeking and its autonomic and behavioral concomitants are mainly driven by the conflict between the behavioral plan of the intended exploratory choice and its strong alternative, which has already proven to be more rewarding.

This study investigated the relationship between fear of COVID-19, previous exposure to COVID-19, perceived vulnerability to disease, sleep quality, and psychological distress among healthcare workers (HCWs) in Taif city in Saudi Arabia, which has a population of 702,000 people. A cross-sectional study design was adopted. HCWs (n = 202) completed a survey containing the Fear of COVID-19 Scale (FCV-19S), Perceived Vulnerability to Disease (PVD), Pittsburgh Sleep Quality Index (PSQI), and Depression, Anxiety, and Stress Scale (DASS-21). FCV-19S and sleep quality were significant predictors for psychological distress. Female gender was a significant predictor for depression and stress. Single, divorced, and widowed marital status were predictive for anxiety. FCV-19S was weakly correlated with PVD but moderately with depression, anxiety, and stress. Of the two PVD subscales, perceived infectability was weakly correlated with psychological distress. PVD and previous experience with COVID-19 were not significant predictors. Sleep quality and FCV-19S were major predictors of psychological distress. Findings indicated that poor sleep quality was strongly associated with psychological distress, while fear of COVID-19 had a moderate association. Such results support the need to design and implement psychological programs to assist HCWs in dealing with the psychological impact of this ongoing pandemic.

Severe internal carotid stenosis, if left untreated, can pose serious risks for ischemic stroke and cognitive impairments. The effects of revascularization on any aspects of cognition, however, are not well understood, as conflicting results are reported, which have mainly been centered on paper-based cognitive analyses. Here, we summarized and evaluated the publications to date of functional MRI (fMRI) studies that examined the mechanisms of functional brain activation and connectivity as a way to reflect cognitive effects of revascularization on patients with carotid stenosis.A PubMed and Google Scholar (covering the relevant literature until November 1, 2021) search yielded eight original studies of the research line, including seven resting-state and one task-based fMRI reports.Findings demonstrated treatment-related alterations in fMRI signal intensity and symmetry level, regional fMRI activation pattern, and functional brain network connectivity. The functional brain changes were associated largely with improvement in cognitive function assessed using standard cognitive test scores.These findings support the contribution of fMRI to the understanding of brain functional activation and connectivity changes revealing cognitive effects of revascularization in the management of severe carotid stenosis. The review also highlighted the importance of reproducibility through enhancing experimental designs and cognitive task applications with future research for potential clinical translation.

To understand the pathogenesis of dilated cardiomyopathy (DCMP), it is necessary to establish the molecular-cellular mechanisms of myocardial aging, including those associated with programmed cell death, the molecular mechanisms of which have not been practically studied. The aim of this work is to study markers of apoptosis in cardiomyocytes of patients with DCMP in vitro. We used the method of primary dissociated cell cultures and the method of immunofluorescence confocal laser microscopy. Cells of the 3rd and 14th passages, corresponding to «young» and «old» cultures, were used to simulate cellular senescence. Results. At the molecular level, aging of cardiomyocyte cells was accompanied by a twofold increase in the expression of p16INK4a compared to «young cultures» both in the control group and in the group with DCMP. It was also found that the expression of p16INK4a in cultures taken from patients with pathology was 2 times higher than in similar cultures from healthy patients. The expression of p21 was increased in the group with DCMP compared to the control; however, with aging of the culture, the expression of p21 did not change, remaining at a significant level. The most significant differences were obtained when comparing the expression of Bax in the cell culture of cardiomyocytes from the group with DCMP in a «young» culture compared with the norm, 3,2 times. Aging of myocardial cells at the molecular level was manifested in an increase in the expression of the Bax protein, which is the triggering mechanism of the mitochondrial apoptosis pathway. It is possible that this pathway of cell death is prevalent in DCMP.Для понимания патогенеза дилатационной кардиомиопатии (ДКМП) необходимо установить молекулярно-клеточные механизмы старения миокарда, в том числе связанные с программируемой клеточной гибелью, молекулярные механизмы которого практически не изучены. Цель работы — изучение маркеров апоптоза в кардиомиоцитах у пациентов с ДКМП in vitro. В работе использовали метод первичных диссоциированных клеточных культур и метод иммунофлюоресцентной конфокальной лазерной микроскопии. Для моделирования клеточного старения использовали клетки 3-го и 14-го пассажей, соответствующие «молодым» и «старым» культурам. На молекулярном уровне старение клеток кардиомиоцитов сопровождалось повышением экспрессии р16INK4a в 2 раза по сравнению с «молодыми культурами» как в контрольной, так и в группе с ДКМП. Также установлено, что экспрессия р16INK4a в культурах, взятых от пациентов с патологией, была в 2 раза выше, чем в аналогичных культурах от здоровых пациентов. Экспрессия р21 была повышена в группе с ДКМП по сравнению с контрольной группой, однако при старении культуры экспрессия p21 не изменялась, оставаясь на высоком уровне. Наиболее значимые различия были получены при сравнении экспрессии Bax в культуре клеток кардиомиоцитов из группы с ДКМП в «молодой» культуре по сравнению с нормой в 3,2 раза. Старение клеток миокарда на молекулярном уровне проявлялось в повышении экспрессии белка Baх, именно он является запускающим механизмом митохондриального пути апоптоза. Возможно, этот путь клеточной гибели является превалирующем при ДКМП.

Classifying the degree of relatedness between pairs of individuals has both scientific and commercial applications. As an example, genome-wide association studies (GWAS) may suffer from high rates of false positive results due to unrecognized population structure. This problem becomes especially relevant with recent increases in large-cohort studies. Accurate relationship classification is also required for genetic linkage analysis to identify disease-associated loci. Additionally, DNA relatives matching service is one of the leading drivers for the direct-to-consumer genetic testing market. Despite the availability of scientific and research information on the methods for determining kinship and the accessibility of relevant tools, the assembly of the pipeline, which stably operates on a real-world genotypic data, requires significant research and development resources. Currently, there is no open source end-to-end solution for relatedness detection in genomic data, that is fast, reliable and accurate for both close and distant degrees of kinship, combines all the necessary processing steps to work on a real data, and is ready for production integration. To address this, we developed GRAPE: Genomic RelAtedness detection PipelinE. It combines data preprocessing, identity-by-descent (IBD) segments detection, and accurate relationship estimation. The project uses software development best practices, as well as Global Alliance for Genomics and Health (GA4GH) standards and tools. Pipeline efficiency is demonstrated on both simulated and real-world datasets. GRAPE is available from: https://github.com/genxnetwork/grape.

The atrial myocardium demonstrates the highly heterogeneous organization of the transversal-axial tubule system (TATS), although its anatomical distribution and region-specific impact on Ca(2+) dynamics remain unknown. Here, we developed a novel method for high-resolution confocal imaging of TATS in intact live mouse atrial myocardium and applied a custom-developed MATLAB-based computational algorithm for the automated analysis of TATS integrity. We observed a twofold higher (P < 0.01) TATS density in the right atrial appendage (RAA) than in the intercaval regions (ICR, the anatomical region between the superior vena cava and atrioventricular junction and between the crista terminalis and interatrial septum). Whereas RAA predominantly consisted of well-tubulated myocytes, ICR showed partially tubulated/untubulated cells. Similar TATS distribution was also observed in healthy human atrial myocardium sections. In both mouse atrial preparations and isolated mouse atrial myocytes, we observed a strong anatomical correlation between TATS distribution and Ca(2+) transient synchronization and rise-up time. This region-specific difference in Ca(2+) transient morphology disappeared after formamide-induced detubulation. ICR myocytes showed a prolonged action potential duration at 80% of repolarization as well as a significantly lower expression of RyR2 and Ca(v)1.2 proteins but similar levels of NCX1 and Ca(v)1.3 compared with RAA tissue. Our findings provide a detailed characterization of the region-specific distribution of TATS in mouse and human atrial myocardium, highlighting the structural foundation for anatomical heterogeneity of Ca(2+) dynamics and contractility in the atria. These results could indicate different roles of TATS in Ca(2+) signaling at distinct anatomical regions of the atria and provide mechanistic insight into pathological atrial remodeling. NEW & NOTEWORTHY Mouse and human atrial myocardium demonstrate high variability in the organization of the transversal-axial tubule system (TATS), with more organized TATS expressed in the right atrial appendage. TATS distribution governs anatomical heterogeneity of Ca(2+) dynamics and thus could contribute to integral atrial contractility, mechanics, and arrhythmogenicity.

PURPOSE OF REVIEW Artificial intelligence and its division machine learning are emerging technologies that are increasingly applied in medicine. Artificial intelligence facilitates automatization of analytical modelling and contributes to prediction, diagnostics and treatment of diseases. This article presents an overview of the application of artificial intelligence in dementia research. RECENT FINDINGS Machine learning and its branch Deep Learning are widely used in research to support in diagnosis and prediction of dementia. Deep Learning models in certain tasks often result in better accuracy of detection and prediction of dementia than traditional machine learning methods, but they are more costly in terms of run times and hardware requirements. Both machine learning and Deep Learning models have their own strengths and limitations. Currently, there are few datasets with limited data available to train machine learning models. There are very few commercial applications of machine learning in medical practice to date, mostly represented by mobile applications, which include questionnaires and psychometric assessments with limited machine learning data processing. SUMMARY Application of machine learning technologies in detection and prediction of dementia may provide an advantage to psychiatry and neurology by promoting a better understanding of the nature of the disease and more accurate evidence-based processes that are reproducible and standardized.

Background: Longitudinal neuroimaging provides spatiotemporal brain data (STBD) measurement that can be utilised to understand dynamic changes in brain structure and/or function underpinning cognitive activities. Making sense of such highly interactive information is challenging, given that the features manifest intricate temporal, causal relations between the spatially distributed neural sources in the brain.\ud \ud Methods: The current paper argues for the advancement of deep learning algorithms in brain-inspired spiking neural networks (SNN), capable of modelling structural data across time (longitudinal measurement) and space (anatomical components). The paper proposes a methodology and a computational architecture based on SNN for building personalised predictive models from longitudinal brain data to accurately detect, understand, and predict the dynamics of an individual’s functional brain state. The methodology includes finding clusters of similar data to each individual, data interpolation, deep learning in a 3-dimensional brain-template structured SNN model, classification and prediction of individual outcome, visualisation of structural brain changes related to the predicted outcomes, interpretation of results, and individual and group predictive marker discovery. \ud \ud Results: To demonstrate the functionality of the proposed methodology, the paper presents experimental results on a longitudinal magnetic resonance imaging (MRI) dataset derived from 175 older adults of the internationally recognised community-based cohort Sydney Memory and Ageing Study (MAS) spanning 6 years of follow-up.\ud \ud Significance: The models were able to accurately classify and predict 2 years ahead of cognitive decline, such as mild cognitive impairment (MCI) and dementia with 95% and 91% accuracy, respectively. The proposed methodology also offers a 3-dimensional visualisation of the MRI models reflecting the dynamic patterns of regional changes in white matter hyperintensity (WMH) and brain volume over 6 years.\ud \ud Conclusion: The method is efficient for personalised predictive modelling on a wide range of neuroimaging longitudinal data, including also demographic, genetic, and clinical data. As a case study, it resulted in finding predictive markers for MCI and dementia as dynamic brain patterns using MRI data.

Molecular hydrogen (H

Leeches are amazing animals that can be classified as conditionally poisonous animals since the salivary cocktail they produce is injected directly into the victim, and its components have strictly defined biological purposes, such as preventing blood clot formation. Thrombolytic drugs are mainly aimed at treating newly formed blood clots. Aged clots are stabilized by a large number of isopeptide bonds that prevent the action of thrombolytics. These bonds are destroyed by destabilase, an enzyme of the leech's salivary glands. Here, we conducted a pilot study to evaluate the feasibility and effectiveness of the use of destabilase in relation to blood clots formed during real pathological processes. We evaluated the isopeptidase activity of destabilase during the formation of a stabilized fibrin clot. We showed that destabilase does not affect the internal and external coagulation cascades. We calculated the dose-response curve and tested the ability of destabilase to destroy isopeptide bonds in natural blood clots. The effect of aged and fresh clots dissolving ability after treatment with destabilase coincided with the morphological characteristics of clots during surgery. Thus, recombinant destabilase can be considered as a potential drug for the treatment of aged clots, which are difficult to treat with known thrombolytics.

Environmental chemical (EC) exposures and our interactions with them has significantly increased in the recent decades. Toxicity associated biological characterization of these chemicals is challenging and inefficient, even with available high-throughput technologies. In this report, we describe a novel computational method for characterizing toxicity, associated biological perturbations and disease outcome, called the Chemo-Phenotypic Based Toxicity Measurement (CPTM). CPTM is used to quantify the EC "toxicity score" (Z

The Stroke Riskometer mobile application is a novel, validated way to provide personalized stroke risk assessment for individuals and motivate them to reduce their risks. Although this app is being used worldwide, its reliability across different countries has not yet been rigorously investigated using appropriate methodology. The Generalizability Theory (G-Theory) is an advanced statistical method suitable for examining reliability and generalizability of assessment scores across different samples, cultural and other contexts and for evaluating sources of measurement errors. G-Theory was applied to the Stroke Riskometer data sampled from 1300 participants in 13 countries using two-facet nested observational design (person by item nested in the country). The Stroke Riskometer demonstrated strong reliability in measuring stroke risks across the countries with coefficients G relative and absolute of 0.84, 95%CI [0.79; 0.89] and 0.82, 95%CI [0.76; 0.88] respectively. D-study analyses revealed that the Stroke Riskometer has optimal reliability in its current form in measuring stroke risk for each country and no modifications are required. These results suggest that the Stroke Riskometer's scores are generalizable across sample population and countries permitting cross-cultural comparisons. Further studies investigating reliability of the Stroke Riskometer over time in longitudinal study design are warranted.

Response inhibition is typically considered a brain mechanism selectively triggered by particular “inhibitory” stimuli or events. Based on recent research, an alternative non-selective mechanism was proposed by several authors. Presumably, the inhibitory brain activity may be triggered not only by the presentation of “inhibitory” stimuli but also by any imperative stimuli, including Go stimuli, when the context is uncertain. Earlier support for this notion was mainly based on the absence of a significant difference between neural activity evoked by equiprobable Go and NoGo stimuli. Equiprobable Go/NoGo design with a simple response time task limits potential confounds between response inhibition and accompanying cognitive processes while not preventing prepotent automaticity. However, previous neuroimaging studies used classical null hypothesis significance testing, making it impossible to accept the null hypothesis. Therefore, the current research aimed to provide evidence for the practical equivalence of neuronal activity in the Go and NoGo trials using Bayesian analysis of functional magnetic resonance imaging (fMRI) data. Thirty-four healthy participants performed a cued Go/NoGo task with an equiprobable presentation of Go and NoGo stimuli. To independently localize brain areas associated with response inhibition in similar experimental conditions, we performed a meta-analysis of fMRI studies using equal-probability Go/NoGo tasks. As a result, we observed overlap between response inhibition areas and areas that demonstrate the practical equivalence of neuronal activity located in the right dorsolateral prefrontal cortex, parietal cortex, premotor cortex, and left inferior frontal gyrus. Thus, obtained results favour the existence of non-selective response inhibition, which can act in settings of contextual uncertainty induced by the equal probability of Go and NoGo stimuli.

BACKGROUND A major issue in evaluating the cognitive status of ageing populations is a clear distinction between enduring and dynamic aspects of global cognition necessary for evaluating risks of dementia and effectiveness of preventive interventions. MATERIALS AND METHODS Generalizability Theory was applied to investigate dynamic and enduring aspects of global cognition using longitudinal data over 10 years of follow-up. Measures included the Mini-Mental Status Examination (MMSE) and the Telephone Interview for Cognitive Status-modified (TICS-M). The sample (N = 238) included 154 females, mean age = 76.54 years, SD = 3.94 from the Sydney Memory and Ageing Study. RESULTS The MMSE measured dynamic and enduring aspects of cognition to a comparable degree with 56% of variance explained by enduring aspects and 44% by dynamic aspects and showed low sensitivity/high specificity in detecting dementia. A shortened version of the MMSE (MMSE-D8) better captured dynamic aspects of cognition after removing three items less sensitive to change. The TICS-M predominantly measured enduring aspects of cognition (72%) with the remaining 28% due to dynamic aspects and displayed high sensitivity/high specificity for dementia screening. CONCLUSIONS The MMSE measures both dynamic and enduring cognitive aspects and is suitable for general clinical assessments, while the MMSE-D8 can be used to monitor transitory changes of global cognition over time. The TICS-M is more useful for measuring enduring features of cognition and screening for dementia. Our findings highlight the value of generalizability theory to distinguish dynamic and enduring features of cognition, which may contribute to preventive interventions and monitoring cognitive ability over time.

Motivation Intrinsically disordered proteins (IDPs) are involved in numerous processes crucial for living organisms. Bias in amino acid composition of these proteins determines their unique biophysical and functional features. Distinct intrinsically disordered regions (IDRs) with compositional bias play different important roles in various biological processes. IDRs enriched in particular amino acids in human proteome have not been described consistently. Results We developed DisEnrich—the database of human proteome IDRs that are significantly enriched in particular amino acids. Each human protein is described using Gene Ontology (GO) function terms, disorder prediction for the full-length sequence using three methods, enriched IDR composition and ranks of human proteins with similar enriched IDRs. Distribution analysis of enriched IDRs among broad functional categories revealed significant overrepresentation of R- and Y-enriched IDRs in metabolic and enzymatic activities and F-enriched IDRs in transport. About 75% of functional categories contain IDPs with IDRs significantly enriched in hydrophobic residues that are important for protein–protein interactions. Availability and implementation The database is available at http://prodata.swmed.edu/DisEnrichDB/. Supplementary information Supplementary data are available at Bioinformatics Advances online.

Since the WHO declared the COVID-19 outbreak a pandemic, the most actual problem has been a change in the lifestyle of the population of Russia and the rest of the world. Fear of illness, self-isolation/quarantine, and decreased quality of life have dramatically increased the level of stress-related disorders in the population. The main mental disorders arising from stress refer to anxiety disorders (post-traumatic stress disorder (PTSD), panic disorder, agoraphobia, social phobia, generalized anxiety disorder), obsessive-compulsive disorder, depressions of varying severity and conversion reactions. The symptoms and early warning signs of stress-related disorders may be chronic or episodic. Stress-related disorders are corrected with psychotropic therapy, which aims to restore the balance of neurotransmitters. Current first choice agents for the treatment of both pathological anxiety and depression are selective serotonin reuptake inhibitors (SSRIs). During the pandemic, the SSRI fluvoxamine is of special interest. Its mechanisms of action are recognized as potentially useful for treating COVID-19 infection. Two studies confirming the efficacy and safety of fluvoxamine in the treatment of coronavirus infection are described.Как только Всемирная организация здравоохранения (ВОЗ) объявила вспышку COVID-19 пандемией, самой актуальной проблемой стало изменение образа жизни жителей России и всего мира. Страх перед болезнью, самоизоляция/карантин, снижение качества жизни резко повысили уровень стресс-связанных расстройств. К основным психическим нарушениям, возникающим при стрессе, относят тревожные расстройства, включая посттравматическое стрессовое расстройство, паническое расстройство, агорафобию, социальную фобию, обсессивно-компульсивное расстройство и генерализованное тревожное расстройство, депрессии различной степени выраженности, конверсионные реакции. Симптомы и ранние предупреждающие сигналы стресс-связанных расстройств по своей природе могут быть хроническими либо эпизодическими. Стресс-связанные расстройства корректируются при помощи психотропной терапии, которая направлена на восстановление баланса нейромедиаторов. К современным средствам первого выбора для лечения как патологической тревоги, так и депрессии относятся селективные ингибиторы обратного захвата серотонина (СИОЗС). В период пандемии необходимо особо отметить СИОЗС флувоксамин. Он обладает механизмами действия, которые признаются потенциально полезными для лечения инфекции COVID-19. Описываются два исследования, подтверждающие эффективность и безопасность флувоксамина в лечении коронавирусной инфекции.

Accurate distinction between state and trait anxiety is necessary for assessment and monitoring of individual anxiety levels over time and developing effective interventions to reduce anxiety. Generalizability theory (G-theory) is a suitable method to distinguish between state and trait and to evaluate reliability of test scores and sources of measurement error in the assessment of affective conditions. We applied G-theory to the widely used 40-item State and Trait Anxiety Inventory (STAI) completed by 139 participants on three occasions separated by 2-week intervals. The results show that both subscales of the STAI demonstrated excellent reliability for test scores in measuring trait anxiety with high generalizability of scores across occasions and persons (G = 0.84-0.92). The most dynamic aspects of state anxiety were identified in both subscales including satisfaction, nervousness, feelings of pleasure, perceived failure, calmness, feeling inadequate, and sensitivity to disappointments and this informed the development of a more sensitive state anxiety scale presented here. The STAI trait subscale and the proposed sensitive state subscale can be used to more accurately distinguish between state and trait anxiety. The most dynamic aspects of anxiety identified using G-theory are more amenable and need to be considered as the primary target of interventions aiming at reducing anxiety. More comprehensive assessment of state anxiety may benefit from the development of a longer scale informed by G-theory. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

(1) Background: The purpose of this review is to analyze domestic and foreign studies on the role of collagen-encoding genes polymorphism in the development of intervertebral discs (IVDs) degeneration in humans. (2) Methods: We have carried out a search for full-text articles published in e-Library, PubMed, Oxford Press, Clinical Case, Springer, Elsevier and Google Scholar databases. The search was carried out using keywords and their combinations. The search depth was 5 years (2016–2021). In addition, this review includes articles of historical interest. Despite an extensive search, it is possible that we might have missed some studies published in recent years. (3) Results: According to the data of genome-wide and associative genetic studies, the following candidate genes that play a role in the biology of IVDs and the genetic basis of the processes of collagen degeneration of the annulus fibrosus and nucleus pulposus of IVDs in humans are of the greatest interest to researchers: COL1A1, COL2A1, COL9A2, COL9A3, COL11A1 and COL11A2. In addition, the role of genes COL1A2, COL9A1 and others is being actively studied. (4) Conclusions: In our review, we summarized and systematized the available information on the role of genetic factors in IVD collagen fibers turnover and also focused on the functions of different types of collagen present in the IVD. Understanding the etiology of impaired collagen formation can allow doctors to prescribe pathogenetically-based treatment, achieving the most effective results.

A high serum vitamin B12 level (hypercobalaminemia) is a underestimated anomaly. Clinically, it can be paradoxically accompanied by signs of deficiency, which are related to defects in tissue uptake of vitamin B12. The increase in the level of serum cobalamin occurs mainly in serious diseases that require early diagnosis: hemoblastosis, liver and kidney diseases, etc. This review presents data on the metabolism of vitamin B12 and the potential significance of increasing its level as a marker for the early diagnosis of these diseases.Гиперкобаламинемия - синдром повышения уровня витамина B12 в сыворотке крови, значение которого в клинической практике часто недооценивается. Это явление может сопровождаться парадоксальными с клинической точки зрения признаками гиповитаминоза витамина В12, отражающими наличие функционального дефицита, обусловленного дефектами потребления витамина тканями. Этиологическими факторами повышения уровня кобаламина в сыворотке крови являются преимущественно тяжелые заболевания, при которых особое значение для прогноза имеет ранняя диагностика: солидные опухоли, злокачественные гематологические новообразования, а также заболевания печени и почек с признаками их недостаточности. В настоящем обзоре представлены данные об обмене витамина В12 и потенциальной значимости повышения его уровня как маркера ранней диагностики этих заболеваний.

The WHOQOL tools are widely used, multi-faceted, patient-rated, quality of life (QoL) measures, developed by the World Health Organization. The WHOQOL questionnaires are used to assess generic quality of life issues affected by all health problems. This study developed a module to use with the WHOQOL tools to improve their sensitivity to Health Related QoL issues relevant to mental health recovery. Using a sequential mixed-methods approach, two research stages occurred. A qualitative stage invited 88 participants with experience of mental health recovery, into focus groups and importance rating activities, to identify candidate items for the new module. Following this, a quantitative stage involved 667 participants with, and without, mental health/addiction issues completing online or paper-based questionnaires to analyze which candidate items differentiated between those with and without mental health/addiction issues. Classical test theory and iterative Partial Credit Rasch Analysis were used to identify the most suitable candidate items for a reliable and valid mental health recovery module to be used with the WHOQOL tools. Seventeen candidate items captured important HRQoL facets relevant to mental health recovery. Rasch analysis removed 10 misfitting items. The final 7-item module, which demonstrated the best Rasch model fit, enquires about recovery beliefs, identifying strengths, self-awareness, acceptance, capacity to relate, feeling understood, and recovery progress. Ordinal-to-interval conversion tables have been developed to optimize measurement precision when using the module. Important HRQoL issues central to mental health recovery can be reliably evaluated by using the recovery module with the WHOQOL tools.

It becomes increasingly clear that ubiquitination of cellular proteins is not an indispensable prerequisite of their degradation in proteasomes. There are a number of proteins to be eliminated which are not pre-ubiquitinated for their recognition by regulatory subcomplex of 26S proteasome, but which directly interact with the 20S proteasome core particle (20S proteasome). The obligatory precondition for such interaction consists in existence of disordered (hydrophobic) fragments in the target protein. In this study we have investigated the interaction of a number of multifunctional (moonlighting) proteins (glyceraldehyde-3-phosphate dehydrogenase (GAPDH), aldolase, pyruvate kinase) and neurodegeneration-related proteins (a-synuclein, myelin basic protein) with 20S proteasome immobilized on the SPR-biosensor chip and stabilized by means of a bifunctional agent dimethyl pimelimidate (in order to prevent possible dissociation of this subcomplex). Only two of all investigated proteins (aldolase and pyruvate kinase) interacted with the immobilized 20S proteasome (Kd of 8.17´10-7 M and 5.56´10-7 M, respectively). In addition to earlier detected GAPDH ubiquitination, mass spectrometric analysis of the studied proteins revealed the presence of the ubiquitin signature (Lys-e-Gly-Gly) only in aldolase. Oxidation of aldolase and pyruvate kinase, which promotes elimination of proteins via their direct interaction with 20S proteasome, caused a 2-3-fold decrease in their Kd values as comparison with this parameter obtained for the intact proteins. The results of this study provide further evidence for direct interaction of both ubiquitinated proteins (aldolase), and non-ubiquitinated proteins (pyruvate kinase) with the 20S proteasome core particle (20S proteasome). The effectiveness of this interaction is basically equal for the ubiquitinated proteins and non-ubiquitinated proteins.Stanovitsia vse bolee ochevidnym, chto ubikvitinirovanie vnutrikletochnykh belkov ne iavliaetsia obiazatel'nym étapom, neobkhodimym dlia ikh degradatsii v proteasomakh. Izvestno nemalo podlezhashchikh éliminatsii belkov, kotorye ne podvergaiutsia predvaritel'nomu ubikvitinirovaniiu dlia uznavaniia reguliatornymi subchastitsami 26S proteasomy, a postupaiut neposredstvenno v ee korovuiu (proteoliticheskuiu) chast' – 20S proteasomu. Neobkhodimym usloviem dlia étogo iavliaetsia nalichie v belke nestrukturirovannykh uchastkov. V dannoĭ rabote issledovali sviazyvanie riada polifunktsional'nykh belkov (glitseral'degid-3-fosfatdegidrogenaza (GAFD), al'dolaza, piruvatkinaza), a takzhe belkov, uchastvuiushchikh v protsessakh neĭrodegeneratsii (a-sinuklein, osnovnoĭ belok mielina), s immobilizovannoĭ na chipe SPR-biosensora Biacore 20S proteasomoĭ. Dlia predotvrashcheniia vozmozhnoĭ dissotsiatsii 20S proteasomu v khode immobilizatsii stabilizirovali pri pomoshchi bifunktsional'nogo sshivaiushchego reagenta – dimetilpimelimidata. Iz vsekh issledovannykh belkov tol'ko al'dolaza i piruvatkinaza vzaimodeĭstvovali s 20S proteasomoĭ (Kd sootvetstvenno 8,17´10-7 M i 5,56´10-7 M). V dopolnenie k ranee obnaruzhennomu ubikvitinirovaniiu GAFD, mass-spektrometricheskiĭ analiz preparatov étikh belkov vyiavil nalichie tak nazyvaemoĭ ubikvitinovoĭ signatury Lys-e-Gly-Gly tol'ko v preparate al'dolazy. Okislenie piruvatkinazy i al'dolazy, sposobstvuiushchee éliminatsii belkov v rezul'tate ikh neposredstvennogo vzaimodeĭstviia s 20S proteasomoĭ, privodilo k snizheniiu Kd v 2-3 raza po sravneniiu s intaktnymi belkami. Poluchennye rezul'taty svidetel'stvuiut v pol'zu togo, chto s 20S proteasomoĭ odinakovo éffektivno sviazyvaiutsia kak ubikvitinirovannye (al'dolaza), tak i neubikvitinirovannye (piruvatkinaza) belki.

Long noncoding RNAs (lncRNAs) are key molecules that regulate gene expression in a variety of organisms. LncRNAs can drive different transcriptional and post-transcriptional events that impact cellular functions. Recent studies have identified many lncRNAs associated with immune cell development and activation; however, an understanding of their functional role in host immunity to infection is just emerging. Here, we provide a detailed and updated review of the functional roles of lncRNAs in regulating mammalian immune responses during host-pathogen interactions, because these functions may be either beneficial or detrimental to the host. With increased mechanistic insight into the roles of lncRNAs, it may be possible to design and/or improve lncRNA-based therapies to treat a variety of infectious and inflammatory diseases.

The manual classification of protein domains is approaching its 20th anniversary. ECOD is our mixed manual-automatic domain classification. Over time, the types of proteins which require manual curation has changed. Depositions with complex multidomain and multichain arrangements are commonplace. Transmembrane domains are regularly classified. Repeatedly, domains which are initially believed to be novel are found to have homologous links to existing classified domains. Here we present a brief summary of recent manual curation efforts in ECOD generally combined with specific case studies of transmembrane and multidomain proteins wherein manual curation was useful for discovering new homologous relationships. We present a new taxonomy for the classification of ABC transporter transmembrane domains. We examine alternate topologies of the leucine-specific (LS) domain of Leucine tRNA-synthetase. Finally, we elaborate on a distant homologous links between two helical dimerization domains.

Purpose Currently, there is no reliable instrument to measure naming abilities in bilingual speakers of English and French. The Boston Naming Test (BNT; Kaplan, Goodglass, & Weintraub, 1983 )is a widely used scale for clinical assessments of language function, but it is not suitable to assess bilinguals. Rasch analysis provides a unique and powerful method to establish measurement invariance across language groups that improves reliability of measurement. Method Rasch analysis was applied to a sample ( n = 215) of English or French monolingual and bilingual speakers completing the BNT in either language. Participants included English–French bilinguals ( n = 83), English monolinguals ( n = 72), and French monolinguals ( n = 60). Results The best overall Rasch model fit was obtained after the removal of 22 misfitting items, resulting in a 38-item BNT solution (BNT-38), with a modification of 7 items that showed differential item functioning by language factor. To increase the clinical utility of the BNT-38 in French speakers and bilinguals, we generated ordinal-to-interval conversion tables for monolinguals and bilinguals in English and French. Conclusions Use of the BNT-38 and the associated conversion tables will allow valid comparisons of naming abilities across bilingual and monolingual English and French speakers of different age groups. Applying these tools increases accuracy in measurement of naming ability and higher diagnostic precision in French and English monolinguals and bilinguals.

Generation of patient-specific induced pluripotent stem cells (iPSCs) and their subsequent differentiation into cardiomyocytes opened new opportunities for studying pathogenesis of inherited cardiovascular diseases. One of these diseases is hypertrophic cardiomyopathy (HCM) for which no efficient therapy methods have been developed so far. In this study, the approach based on patient-specific iPSCs was applied to create a model of the disease. Genetic analysis of a hypertrophic cardiomyopathy patient revealed R326Q mutation in the MYBPC3 gene. iPSCs of the patient were generated and characterized. The cells were differentiated into cardiomyocytes together with the control iPSCs from a healthy donor. The patient's iPSC-derived cardiomyocytes exhibited early HCM features, such as abnormal calcium handling and increased intracellular calcium concentration. Therefore, cardiomyocytes obtained by directed differentiation of iPSCs from the HCM patient can be used as a model system to study HCM pathogenesis.