3DLigandSite: structure-based prediction of protein-ligand binding sites.

3DLigandSite is a web tool for the prediction of ligand-binding sites in proteins. Here, we report a significant update since the first release of 3DLigandSite in 2010. The overall methodology remains the same, with candidate binding sites in proteins inferred using known binding sites in related protein structures as templates. However, the initial structural modelling step now uses the newly available structures from the AlphaFold database or alternatively Phyre2 when AlphaFold structures are not available. Further, a sequence-based search using HHSearch has been introduced to identify template structures with bound ligands that are used to infer the ligand-binding residues in the query protein. Finally, we introduced a machine learning element as the final prediction step, which improves the accuracy of predictions and provides a confidence score for each residue predicted to be part of a binding site. Validation of 3DLigandSite on a set of 6416 binding sites obtained 92% recall at 75% precision for non-metal binding sites and 52% recall at 75% precision for metal binding sites. 3DLigandSite is available at https://www.wass-michaelislab.org/3dligandsite. Users submit either a protein sequence or structure. Results are displayed in multiple formats including an interactive Mol* molecular visualization of the protein and the predicted binding sites.

Prognostic accuracy and clinical utility of psychometric instruments for individuals at clinical high-risk of psychosis: a systematic review and meta-analysis.

Accurate prognostication of individuals at clinical high-risk for psychosis (CHR-P) is an essential initial step for effective primary indicated prevention. We aimed to summarise the prognostic accuracy and clinical utility of CHR-P assessments for primary indicated psychosis prevention. Web of Knowledge databases were searched until 1st January 2022 for longitudinal studies following-up individuals undergoing a psychometric or diagnostic CHR-P assessment, reporting transition to psychotic disorders in both those who meet CHR-P criteria (CHR-P + ) or not (CHR-P-). Prognostic accuracy meta-analysis was conducted following relevant guidelines. Primary outcome was prognostic accuracy, indexed by area-under-the-curve (AUC), sensitivity and specificity, estimated by the number of true positives, false positives, false negatives and true negatives at the longest available follow-up time. Clinical utility analyses included: likelihood ratios, Fagan's nomogram, and population-level preventive capacity (Population Attributable Fraction, PAF). A total of 22 studies (n = 4 966, 47.5% female, age range 12-40) were included. There were not enough meta-analysable studies on CHR-P diagnostic criteria (DSM-5 Attenuated Psychosis Syndrome) or non-clinical samples. Prognostic accuracy of CHR-P psychometric instruments in clinical samples (individuals referred to CHR-P services or diagnosed with 22q.11.2 deletion syndrome) was excellent: AUC = 0.85 (95% CI: 0.81-0.88) at a mean follow-up time of 34 months. This result was driven by outstanding sensitivity (0.93, 95% CI: 0.87-0.96) and poor specificity (0.58, 95% CI: 0.50-0.66). Being CHR-P + was associated with a small likelihood ratio LR + (2.17, 95% CI: 1.81-2.60) for developing psychosis. Being CHR-P- was associated with a large LR- (0.11, 95%CI: 0.06-0.21) for developing psychosis. Fagan's nomogram indicated a low positive (0.0017%) and negative (0.0001%) post-test risk in non-clinical general population samples. The PAF of the CHR-P state is 10.9% (95% CI: 4.1-25.5%). These findings consolidate the use of psychometric instruments for CHR-P in clinical samples for primary indicated prevention of psychosis. Future research should improve the ability to rule in psychosis risk.

Differentially conserved amino acid positions may reflect differences in SARS-CoV-2 and SARS-CoV behaviour.

MOTIVATION: SARS-CoV-2 is a novel coronavirus currently causing a pandemic. Here, we performed a combined in-silico and cell culture comparison of SARS-CoV-2 and the closely related SARS-CoV. RESULTS: Many amino acid positions are differentially conserved between SARS-CoV-2 and SARS-CoV, which reflects the discrepancies in virus behaviour, i.e. more effective human-to-human transmission of SARS-CoV-2 and higher mortality associated with SARS-CoV. Variations in the S protein (mediates virus entry) were associated with differences in its interaction with ACE2 (cellular S receptor) and sensitivity to TMPRSS2 (enables virus entry via S cleavage) inhibition. Anti-ACE2 antibodies more strongly inhibited SARS-CoV than SARS-CoV-2 infection, probably due to a stronger SARS-CoV-2 S-ACE2 affinity relative to SARS-CoV S. Moreover, SARS-CoV-2 and SARS-CoV displayed differences in cell tropism. Cellular ACE2 and TMPRSS2 levels did not indicate susceptibility to SARS-CoV-2. In conclusion, we identified genomic variation between SARS-CoV-2 and SARS-CoV that may reflect the differences in their clinical and biological behaviour. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Serum levels of neuropeptide Y in patients with chronic schizophrenia during treatment augmentation with sarcosine (results of the double-blind randomized controlled PULSAR study).

OBJECTIVE: Modulation of glutamatergic neurotransmission in schizophrenia by sarcosine leads to a reduction in primary negative symptoms, while its metabolic profile is safe. In order to extend research in the area, we assessed serum levels of neuropeptide Y (NPY), a hypothalamic hormone related to anxiety and depression, also involved in mechanisms inducing weight gain. Additionally, we analyzed associations between NPY concentrations and its changes with severity of symptoms and metabolic parameters. METHODS: A prospective 6-month, randomized, double-blind placebo-controlled trial was completed by 57 subjects with chronic schizophrenia with predominant negative symptoms and stable antipsychotic treatment. The participants received 2 g of sarcosine (n = 28) or placebo (n = 29) daily. We assessed serum NPY concentrations and severity of symptoms (with the Positive and Negative Syndrome Scale [PANSS] and Calgary Depression Scale for Schizophrenia) at the beginning of the study, after 6 weeks and 6 months. RESULTS: Sarcosine did not affect NPY levels in all time points. The highest decrease in NPY concentrations was observed in the subjects who were initially depressed, who became euthymic at the last visit. We noticed an improvement in the total PANSS score, and negative symptom and general psychopathology subscales in the sarcosine group, however, without any correlation with NPY levels. CONCLUSION: The use of sarcosine does not change NPY levels. Peripheral NPY concentrations may be related to depressive symptoms in schizophrenia.

Plasma ß-Endorphin Concentration and Antipsychotic Treatment Outcome in Schizophrenia: 1-Year Follow-Up.

BACKGROUND Increased levels of endogenous opioids have been observed in patients with schizophrenia; however, the influence of these endogenous opioids on the biology of schizophrenia remains unclear. The aim of this study was to evaluate the impact of beta-endorphin (BE) on the course of schizophrenia and risk of relapse. MATERIAL AND METHODS The study included 25 patients hospitalized with schizophrenia and 47 controls. Their symptoms were evaluated using Positive and Negative Syndrome Scale (PANSS) and composite index at five points: at the onset of hospitalization; after 4, 6 and 10 weeks of treatment; and after 12 months. ß-endorphin plasma concentrations were assessed in patients at study enrollment and after 6 weeks of treatment. Data regarding rehospitalization during follow-up were also collected. RESULTS Patients had higher BE concentration than controls at study enrollment (P=0.002) and after 6 weeks (P=0.000). BE levels increased during treatment (mean 0.538ng/mL vs. mean 0.624 ng/mL; P=0.007). No correlation was found between BE concentration and PANSS subscale score at any stage of the study. A higher BE level at study enrollment was related to a predominance of negative symptoms after 1 year, measured with composite index (R=-0.404; P=0.045). Patients who were later hospitalized again were significantly more likely to demonstrate an increase in BE levels over 6 weeks (P=0.001). CONCLUSIONS Individuals with schizophrenia demonstrated higher BE concentrations than healthy controls; this tendency was particularly apparent in those affected by negative symptoms. The imbalance in the endogenous opioid system might adversely alter the course of disease and predispose patients to persistence of negative symptoms, despite antipsychotic treatment.

A developmentally-stable pattern of premorbid schizoid-schizotypal features predicts psychotic transition from the clinical high-risk for psychosis state.

BACKGROUND: Despite the extensive research performed on prediction of psychosis from a Clinical High Risk for Psychosis state (CHR-P), the positive predictive value of the CHR-P designation remains unsatisfactory and further models including additional clinical and biological variables are required. Existing studies indicate that schizotypy assessed at baseline in "at-risk" individuals may be considered a predictor of transition from CHR-P to psychosis. This approach, however, is burdened with bias resulting from a possible overlap between current psychopathology and schizotypal features. No studies so far have assessed schizotypy in CHR-P from a developmental perspective. AIM: The aim of the study was to identify associations between a long-standing, parent-reported premorbid level of schizoid-schizotypal traits and the probability of psychotic transition in individuals with CHR-P. METHODS: The mothers of 107 individuals diagnosed as presenting CHR-P with the use of Comprehensive Assessment of At Risk Mental States12/2006 were interviewed with the Scale for the Assessment of Premorbid Schizoid-Schizotypal Traits (PSST). RESULTS: A high level of enduring schizotypy was found to be significantly associated with psychotic transition from CHR-P (HR: 1.78, 95% CI: 1.40-2.27, p < 0.0001), as indicated by the proportional hazards model, adjusted for age, sex and clinical covariates potentially related to the outcome. PSST items comprising negative schizotypy appeared to be the strongest predictors of transition. CONCLUSIONS: The assessment of parent-reported, present early in the development premorbid schizoid-schizotypal traits, which can be easily performed in clinical settings, may be of value in estimating the probability of transition from an "at risk" state to psychotic disorder.

Omega-3 fatty acids in first-episode schizophrenia - a randomized controlled study of efficacy and relapse prevention (OFFER): rationale, design, and methods.

BACKGROUND: Polyunsaturated fatty acid (PUFA) metabolism abnormalities have been long implicated in the etiology of schizophrenia. Although several randomized clinical trials have been carried out to assess the efficacy of omega-3 PUFA as add-on therapy in reducing psychopathology in populations of chronic patients with schizophrenia, only a few concern first-episode schizophrenia. The majority of these studies used a 12-week intervention based on ethyl-eicosapentaenoic acid (ethyl-EPA), however, with conflicting results. An intervention based on docosahexaenoic acid plus EPA has not been used in first-episode schizophrenia studies so far. No add-on supplementation studies have been carried out in medicated first-episode schizophrenia patients to assess the efficacy of omega-3 PUFA in preventing relapses. METHODS: A randomized placebo-controlled one-center trial will be used to compare the efficacy of 26-week intervention, composed of either 1320 mg/day of EPA and 880 mg/day of DHA, or olive oil placebo with regard to symptom severity and relapse rate in first-episode schizophrenia patients. Eighty-two patients (aged 16-35) will be recruited for the study. Eligible patients will be randomly allocated to one of two intervention arms: an active arm or a placebo arm (olive oil). The primary outcome measure of the clinical evaluation is schizophrenia symptom severity measured by the Positive and Negative Syndrome Scale (PANSS). Other outcomes include depressive symptoms, patient functioning and the level of insight. Correlates of change measured during the study will include structural brain changes, oxidative stress and defense, as well as neuroplasticity indicators. Metabolic syndrome components will also be assessed throughout the study. DISCUSSION: By comparing 26-week administration of EPA + DHA or (placebo) olive oil as add-on therapy in reducing symptom severity and one-year relapse rate in patients with first episode schizophrenia, it is intended to provide new insights into the efficacy of omega-3 PUFA and correlates of change, and contribute to the improvement of mental health care for individuals suffering from schizophrenia. TRIAL REGISTRATION: This study has been registered at Clinical Trials.gov with the following number: NCT02210962 .

Comparison of Metabolite Concentrations in the Left Dorsolateral Prefrontal Cortex, the Left Frontal White Matter, and the Left Hippocampus in Patients in Stable Schizophrenia Treated with Antipsychotics with or without Antidepressants. ¹H-NMR Spectroscopy Study.

Managing affective, negative, and cognitive symptoms remains the most difficult therapeutic problem in stable phase of schizophrenia. Efforts include administration of antidepressants. Drugs effects on brain metabolic parameters can be evaluated by means of proton nuclear magnetic resonance (¹H-NMR) spectroscopy. We compared spectroscopic parameters in the left prefrontal cortex (DLPFC), the left frontal white matter (WM) and the left hippocampus and assessed the relationship between treatment and the spectroscopic parameters in both groups. We recruited 25 patients diagnosed with schizophrenia (DSM-IV-TR), with dominant negative symptoms and in stable clinical condition, who were treated with antipsychotic and antidepressive medication for minimum of three months. A group of 25 patients with schizophrenia, who were taking antipsychotic drugs but not antidepressants, was matched. We compared metabolic parameters (N-acetylaspartate (NAA), myo-inositol (mI), glutamatergic parameters (Glx), choline (Cho), and creatine (Cr)) between the two groups. All patients were also assessed with the Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS). In patients receiving antidepressants we observed significantly higher NAA/Cr and NAA/Cho ratios within the DLPFC, as well as significantly higher mI/Cr within the frontal WM. Moreover, we noted significantly lower values of parameters associated with the glutamatergic transmission--Glx/Cr and Glx/Cho in the hippocampus. Doses of antipsychotic drugs in the group treated with antidepressants were also significantly lower in the patients showing similar severity of psychopathology.

Adding Sarcosine to Antipsychotic Treatment in Patients with Stable Schizophrenia Changes the Concentrations of Neuronal and Glial Metabolites in the Left Dorsolateral Prefrontal Cortex.

The glutamatergic system is a key point in pathogenesis of schizophrenia. Sarcosine (N-methylglycine) is an exogenous amino acid that acts as a glycine transporter inhibitor. It modulates glutamatergic transmission by increasing glycine concentration around NMDA (N-methyl-d-aspartate) receptors. In patients with schizophrenia, the function of the glutamatergic system in the prefrontal cortex is impaired, which may promote negative and cognitive symptoms. Proton nuclear magnetic resonance (¹H-NMR) spectroscopy is a non-invasive imaging method enabling the evaluation of brain metabolite concentration, which can be applied to assess pharmacologically induced changes. The aim of the study was to evaluate the influence of a six-month course of sarcosine therapy on the concentration of metabolites (NAA, N-acetylaspartate; Glx, complex of glutamate, glutamine and γ-aminobutyric acid (GABA); mI, myo-inositol; Cr, creatine; Cho, choline) in the left dorso-lateral prefrontal cortex (DLPFC) in patients with stable schizophrenia. Fifty patients with schizophrenia, treated with constant antipsychotics doses, in stable clinical condition were randomly assigned to administration of sarcosine (25 patients) or placebo (25 patients) for six months. Metabolite concentrations in DLPFC were assessed with 1.5 Tesla ¹H-NMR spectroscopy. Clinical symptoms were evaluated with the Positive and Negative Syndrome Scale (PANSS). The first spectroscopy revealed no differences in metabolite concentrations between groups. After six months, NAA/Cho, mI/Cr and mI/Cho ratios in the left DLPFC were significantly higher in the sarcosine than the placebo group. In the sarcosine group, NAA/Cr, NAA/Cho, mI/Cr, mI/Cho ratios also significantly increased compared to baseline values. In the placebo group, only the NAA/Cr ratio increased. The addition of sarcosine to antipsychotic therapy for six months increased markers of neurons viability (NAA) and neurogilal activity (mI) with simultaneous improvement of clinical symptoms. Sarcosine, two grams administered daily, seems to be an effective adjuvant in the pharmacotherapy of schizophrenia.

Temperament traits and preference for surgical or nonsurgical specialties in year 6 medical students.

BACKGROUND: Personality traits may also be associated with preference for a particular specialty. However, little is known about the relationship between the surgical career preferences of medical students and their temperament traits. PURPOSES: The aim of the study was to explore the relationship between surgical or nonsurgical specialties and temperament in 6th-year medical students. METHODS: The study included 409 students (283 women, 126 men) of the 6th year at the Medical University of Lodz. The subjects fulfilled a career preference and demographic questionnaire as well as the Formal Characteristics of Behaviour-Temperament Inventory by Zawadzki and Stelau. RESULTS: The surgical specialty was preferred by 30.1% of the students and by 64.5% of the nonsurgical; 5.4% were undecided. The specialty preference of the medical students was associated with temperament traits. An analysis of variance showed differences in Emotional Reactivity, F(1, 380)=3.888, p=049, η2=01; Endurance, F(1, 380)=10.973, p=001, η2=028; and Briskness, F(1, 380)=10.252, p=001, η2=026. Students preferring surgical specialty scored significantly higher on Endurance (M=11.21, SD=4.8) and Briskness (M=16.54, SD=2.82) scales than students choosing a nonsurgical specialty (M=9.12, SD=4.51) and (M=15.19, SD=3.21), respectively. Those preferring a surgical specialty scored lower on the Emotional Reactivity (M=8.91, SD=4.55) scale than students choosing nonsurgical specialty (M=10.53, SD=4.22). CONCLUSIONS: The findings suggest that certain temperament traits may be related to preference of surgical or nonsurgical specialties. This knowledge of temperament traits could be a useful tool in helping graduates choose a fulfilling career best suited to their psychological well-being and diagnosing work related issues in the medical profession.

Evaluation of COVID-19 Effect on Mental Health, Self-Harm, and Suicidal Behaviors in Children and Adolescents Population.

OBJECTIVES: The impact of the COVID-19 pandemic on the psychological state of the under-18 population includes an increased risk of psychopathological symptoms development and exacerbation of already present psychiatric disorders. This study aimed to assess the prevalence of mental health problems in Polish children and adolescents with a focus on suicidal and self-harm behavior with the impact of the pandemic. METHODS: The questionnaire collected demographic data, information regarding mental states and psychopathological symptoms, history of self-harm and suicidal behaviors, as well as the experience of psychological, and physical violence, and suicidal self-harm behaviors before and during the COVID-19 pandemic. RESULTS: In the final analysis, 782 responses were included. Self-evaluation of general and mental health scores was significantly lower during the pandemic among children (both p < 0.001) and adolescents (both p < 0.001). Moreover, general and mental health scores were lower among adolescents compared to children before (both p < 0.001) and during (both p < 0.001) the pandemic. The frequency of seeking help because of mental health problems increased during the pandemic among children and adolescents, while no changes were observed in the prevalence of psychiatric hospitalizations in either of the populations (p = 0.317 and p = 1.00, respectively). Out of autoregressive behaviors among children during the pandemic period, only the frequency of thinking about death increased (p = 0.038). No suicidal attempts were undertaken by children in either of the evaluated time periods. The presence of all autoaggressive behaviors was greater among adolescents compared to children both before and during the COVID-19 pandemic (all p<0.05). CONCLUSIONS: A subjective decrease in psychophysical well-being, an increase in the frequency of seeking mental health help during the pandemic, as well as an increased prevalence of depressive and anxiety symptoms were observed in the under-18 population as a potential consequence of the COVID-19 pandemic and related socioeconomic changes. The marked increase in self-harm behavior in the adolescent population (age > 12) and the marked increase in the frequency of death thinking in children (age ≤ 12) suggests the need for greater awareness and easier access to professional help from mental health specialists, particularly in a time of unprecedented stress and social isolation.

Intensity of Psychoactive Substance Use Affects the Occurrence of Prodromal Symptoms of Psychosis.

BACKGROUND: Psychosis is defined as a series of symptoms that impair the mind and lead to a kind of loss of reference to reality. Development of psychosis is usually preceded by the appearance of prodromal symptoms. Numerous attempts have been made to find out how psychoactive substances can influence the onset and development of psychotic disorders, but to date there are no studies that show a link between the onset of prodromal symptoms and the use of psychoactive substances. METHODS: A survey consisting of epidemiological and demographic questions, the Drug Use Disorders Identification Test (DUDIT), and the Prodromal Questionnaire Brief Version (PQ-B) was conducted on social media among users of illegal psychoactive substances, covering 703 study participants. RESULTS: A total of 39.8% of the respondents had been treated by a psychiatrist, and the most popular drugs used by respondents in their lifetime were tetrahydrocannabinol-containing products, MDMA, amphetamines, and LSD. A significant correlation was found between the DUDIT and the PQ-B values. CONCLUSIONS: Intensity of psychoactive substance use correlated positively with the risk of appearance and intensity of prodromal symptoms of psychosis. Early exposure to psychoactive substances increased the risk of heavy substance use in adulthood and led to more frequent prodromal states.

Affiliation to a Social Group as a Preventive Factor in Suicidal Behaviors in Children and Adolescents during the COVID-19 Pandemic.

Suicide is one of the most common causes of death in the population of children and adolescents. Available data show the continuous growth of this phenomenon and the ineffectiveness of prevention programs. Additionally, the COVID-19 pandemic significantly affected young people's mental health, including an increased risk of suicidal behaviors due to limited direct contact with the school and peer groups in favor of the home environment. Therefore, the aim of this narrative review was to consider the risk factors and protective factors for suicidal behavior in the under-18 population, with a particular focus on the importance of belonging to a social group and building identification with it as a phenomenon protecting against suicidal behavior. Additionally, in this review, we evaluate how the COVID-19 pandemic affected these relationships. The PubMed database was used in the search with the following keywords: suicide, suicide behaviors, child and adolescent suicide behaviors, group affiliation, family affiliation, ethnicity, religious affiliation, and the COVID-19 pandemic, with articles published between 2002 and 2022 analyzed. Research conducted to date indicates that both sustained and stable family and peer relationships, as well as a sense of identification and belonging, noticeably reduce the risk of suicidal behavior. Ethnic or cultural affiliation seems to have been particularly important during the isolation in the home environment caused by the COVID-19 pandemic. Additionally, it has been shown that while in lockdown, contact through social media with individuals' identification groups was associated with a reduced chance of emotional crises. Furthermore, regardless of cultural background, attachment to a particular group correlates with enhanced psychiatric state of children and adolescents. Thus, available data highlight the need for building and maintaining affiliations with suitable groups as a protective factor against suicidal behaviors.

Evaluation of Psychological and Physical Violence towards Children and Adolescents before and during the COVID-19 Pandemic in the Lodz Voivodship.

BACKGROUND: It has been shown that the course of COVID-19 infection in the under-18 population was in many cases sparsely symptomatic. In contrast, the impact of the pandemic on the psychological state is quite different. The risk of psychopathological symptoms in children and adolescents increased and the course of already present psychiatric disorders has often been exacerbated. OBJECTIVES: Thus, this study aimed to evaluate the prevalence of psychological and physical violence among children and adolescents and its change during the COVID-19 pandemic, as well as to investigate various factors that might affect violence. METHODS: In this survey study, 782 responses were included, with 480 collected during the second and 302 during the fourth wave of COVID-19. In this cross-sectional study, an anonymous questionnaire was used to collect demographic data, medical history, mental state, psychopathological symptoms, as well as the presence of psychological, physical violence, and suicidal self-harm behaviors before (retrospectively) and during the COVID-19 pandemic in the under-18 population of the Lodz Voivodship. The survey was prepared using Google Forms. RESULTS: A decrease in the prevalence of physical violence during both waves of the pandemic has been observed (6.39% vs. 3.45%; p < 0.001), with only a similar trend present for psychological violence 16.75% vs. 14.71%; p = 0.081). No difference between physical and psychological violence was present in different pandemic waves, type of flat or house individuals lived in, availability of one's room, number of people living in the house, number of siblings, and type of school classes (p > 0.050). Older children (>15 years old) were more likely to be victims of psychological violence before and during the pandemic (both p < 0.001). A statistically significant model was obtained for psychological violence before (p < 0.001, R2 = 0.011) and during the pandemic (p = 0.007, R2 = 0.032). Risk factors for psychological violence before the pandemic included male gender (B = 0.531, p = 0.009, OR = 1.700), older age (B = 0.869, p = 0.001, OR = 2.385), and smaller city size (B = -0.187, p = 0.004, OR = 0.829), while for psychological violence during the pandemic, the risk factors were only male gender (B = 0.482, p = 0.022, OR = 1.620) and older age (B = 0.555, p = 0.046, OR = 1.742). No statistically significant models were created for physical violence (p > 0.050). CONCLUSIONS: The observed decrease in physical violence during the COVID-19 pandemic suggests that in the studied group, home environment was not the main source of physical violence. Yet, we did not find any predicting factors for this form of violence. Violence, both physical and psychological, is a dangerous phenomenon in the under-18 population both in the pre-pandemic period and in crisis situations such as the pandemic.

Evolution of γ chain cytokines: Mechanisms, methods and applications.

The common γ chain family of cytokines and their receptors play fundamental roles in the immune system. Evolutionary studies of γ chain cytokines have elegantly illustrated how the immune system adapts to ever-changing environmental conditions. Indeed, these studies have revealed the uniqueness of cytokine evolution, which exhibits strong positive selection pressure needed to adapt to rapidly evolving threats whilst still conserving their receptor binding capabilities. In this review, we summarise the evolutionary mechanisms that gave rise to the characteristically diverse family of γ chain cytokines. We also speculate on the benefits of studying cytokine evolution, which may provide alternative ways to design novel cytokine therapeutic strategies. Additionally, we discuss current evolutionary models that elucidate the emergence of distinct cytokines (IL-4 and IL-13) and cytokine receptors (IL-2Rα and IL-15Rα). Finally, we address and reflect on the difficulties associated with evolutionary studies of rapidly evolving genes and describe a variety of computational methods that have revealed numerous aspects of cytokine evolution.

The Orphan Response Regulator Rv3143 Modulates the Activity of the NADH Dehydrogenase Complex (Nuo) in Mycobacterium tuberculosis via Protein-Protein Interactions.

Two-component signal transduction systems enable mycobacterial cells to quickly adapt and adequately respond to adverse environmental conditions encountered at various stages of host infection. We attempted to determine the role of the Rv3143 "orphan" response regulator in the physiology of Mycobacterium tuberculosis and its orthologue Msmeg_2064 in Mycobacterium smegmatis. We identified the Rv3143 protein as an interaction partner for NuoD, a member of the type I NADH dehydrogenase complex involved in oxidative phosphorylation. The mutants Δrv3143 and Δmsmeg_2064 were engineered in M. tuberculosis and M. smegmatis cells, respectively. The Δmsmeg_2064 strain exhibited a significant reduction in growth and viability in the presence of reactive nitrogen species. The Rv3143-deficient strain was sensitive to valinomycin, which is known to reduce the electrochemical potential of the cell and overexpressed genes required for nitrate respiration. An increased level of reduction of the 2,3,5-triphenyltetrazolium chloride (TTC) electron acceptor in Δrv3143 and Δmsmeg_2064 cells was also evident. The silencing of ndh expression using CRISPRi/dCas9 affected cell survival under limited oxygen conditions. Oxygen consumption during entry to hypoxia was most severely affected in the double-mutant Δmsmeg_2064 ndhCRISPRi/dCas9 . We propose that the regulatory protein Rv3143 is a component of the Nuo complex and modulates its activity.

Major Depression and Onset of Frontotemporal Dementia.

Purpose: Frontotemporal dementia (FTD) is still a clinical challenge with the highest rate of misdiagnosis and poor outcome. The pathogenetic relationship between depression and neurodegeneration remains unclear. This study evaluated depression prevalence before FTD diagnosis. Patients and Methods: The aim was to assess the prevalence and impact of depression on FTD diagnostic process. The clinical characteristics of 72 patients hospitalized in Department of Affective and Psychotic Disorders Medical University of Lodz between 2010 and 2020 with final diagnosis FTD were analyzed. The data referring to first psychiatric diagnosis, time from first psychopathological symptoms to clarification of FTD diagnosis were collected. The patients who did not undergo full neuropsychiatric verification were excluded from the analysis. Results: About 69% of patients had other concomitant diagnosis of mental disorders which was made prior to FTD diagnosis. Among this subsample, 71% revealed depression diagnosis with at least moderate severity. The patients whose first diagnosis was psychotic depression revealed the longest period from the appearance of the first psychopathological symptoms to the diagnosis of FTD in comparison to the subsample with other psychiatric diagnosis (p=0.034; mean 4.33±3.28 years vs mean 2.68±1.39 years). Conclusion: The severe depressive symptoms in older age may reflect the development of neurodegeneration before full-blown frontotemporal dementia symptomatology. We hypothesized that psychotic depression is a predictor of FTD. Further investigations in this field are required.

Are Children Harmed by Being Locked up at Home? The Impact of Isolation during the COVID-19 Pandemic on the Phenomenon of Domestic Violence.

The phenomenon of violence against children is a very complex one. There are many types of child abuse, and they are culturally dependent to a significant degree. Although studies show that children generally only suffer from mild COVID-19 infection, some social restrictions introduced during the pandemic, such as home isolation, may have many severe consequences on the population's mental health. Studies on this topic suggest that violence against children increased during lockdown due to the COVID-10 pandemic. This narrative review summarizes this available literature on the subject and discusses the different forms of violence against children, their cultural aspects, the impact of the COVID-19 pandemic on the phenomenon of violence, the long-term consequences of the above, and forms of assistance for abused minors.

Higher order language impairments can predict the transition of ultrahigh risk state to psychosis-An empirical study.

AIM: Higher order language skills, for example, non-literal language, humour, prosody deal with 'what is meant' and they are necessary for communicative exchange and relationships; No study has investigated their link with conversion to psychosis. The purpose of this study was to determine whether such skills could act as predictors of the onset of psychosis, and compare those of individuals converting and non-converting to psychosis with control of cognitive functions. METHODS: Seventy-three patients, aged 15 to 32 years, fulfilling ultrahigh risk criteria took part: 14% of whom were receiving antipsychotic drugs. The study was observational, prospective and longitudinal in nature, and scheduled for 60 months. Pragmatic language skills were evaluated using the Polish version of the right hemisphere language battery. The ultrahigh risk (UHR) criteria were evaluated with Comprehensive Assessment of At-Risk Mental States; attention, intelligence and verbal fluency were controlled. RESULTS: The conversion rate was 25%; converters demonstrated impaired humour comprehension and metaphor explanation abilities; composite score of pragmatic language was associated with a hazard ratio of 6.0 (95% CI 1.8-20.5) and AUC of .73. Verbal fluency was an independent predictor of conversion, but attention and intelligence were not; pragmatic language skills were associated with social function but not with prodromal symptoms. CONCLUSIONS: The results suggest that deficits in humour comprehension and metaphor explanation could predict conversion to psychosis. These findings could improve diagnosis and create implications for speech and language therapy in UHR groups. Further studies on the mechanisms of pragmatic skills should analyze their relationship with abstract measures and semantic coherence.

The Relationship Between Antipsychotic Treatment and Plasma ß-Endorphin Concentration in Patients with Schizophrenia.

OBJECTIVE: Some studies indicate the presence of elevated opioid levels in cases of schizophrenia and their relationship with negative symptoms. The pathogenesis of schizophrenia may be associated with an imbalance in the modulatory effect of opioids on the dopaminergic system. The aim of the study was to identify the association between ß-endorphin (BE) concentration and the outcome of short-term schizophrenia treatment. METHODS: We examined 49 patients hospitalized due to exacerbation of schizophrenia symptoms and 47 controls without schizophrenia. The severity of psychopathological symptoms was evaluated using Positive and Negative Syndrome Scale (PANSS) at the onset of hospitalization, and after four, six and ten weeks of treatment. Patients were classified into negative (NEG) and mixed (M) psychopathological subtypes according to the PANSS composite index. Β-endorphin (BE) plasma concentrations were assessed in all participants; in patients on inclusion to the study and after six weeks of treatment. RESULTS: The patients with schizophrenia demonstrated higher BE levels than controls. During six-week antipsychotic treatment, BE concentration significantly increased in both NEG (p=0.000) and M (p=0.007), and positive symptoms were effectively reduced. In the NEG group, the prevalence of negative symptoms decreased only transiently and returned to approximately baseline values after 10 weeks (p=0.268). In the M patients, the prevalence of negative symptoms increased gradually (p=0.001), with more severe positive and, notably, negative symptoms correlating with higher BE2 concentrations at the 10-week assessment (R= 0.47, p= 0.0135 vs R= 0.74, p=0.0000). In both NEG and M, a greater rise in BE2 level correlated with a lower composite index during treatment. CONCLUSION: Patients with schizophrenia demonstrate higher BE levels compared to controls. These changes in BE concentration during antipsychotic treatment could reflect the interaction between dopaminergic transmission and endogenous opioids. A rise in BE level following effective antipsychotic therapy could be a potential predictor of persisting negative symptoms.