Transdiagnostic risk of mental disorders in offspring of affected parents: a meta-analysis of family high-risk and registry studies

The offspring of parents with mental disorders are at increased risk for developing mental disorders themselves. The risk to offspring may extend transdiagnostically to disorders other than those present in the parents. The literature on this topic is vast but mixed. To inform targeted prevention and genetic counseling, we performed a comprehensive, PRISMA 2020-compliant meta-analysis. We systematically searched the literature published up to September 2022 to retrieve original family high-risk and registry studies reporting on the risk of mental disorders in offspring of parents with any type of mental disorder. We performed random-effects meta-analyses of the relative risk (risk ratio, RR) and absolute risk (lifetime, up to the age at assessment) of mental disorders, defined according to the ICD or DSM. Cumulative incidence by offspring age was determined using meta-analytic Kaplan-Meier curves. We measured heterogeneity with the I² statistic, and risk of bias with the Quality In Prognosis Studies (QUIPS) tool. Sensitivity analyses addressed the impact of study design (family high-risk vs. registry) and specific vs. transdiagnostic risks. Transdiagnosticity was appraised with the TRANSD criteria. We identified 211 independent studies that reported data on 3,172,115 offspring of parents with psychotic, bipolar, depressive, disruptive, attention-deficit/hyperactivity, anxiety, substance use, eating, obsessive-compulsive, and borderline personality disorders, and 20,428,575 control offspring. The RR and lifetime risk of developing any mental disorder were 3.0 and 55% in offspring of parents with anxiety disorders; 2.6 and 17% in offspring of those with psychosis; 2.1 and 55% in offspring of those with bipolar disorder; 1.9 and 51% in offspring of those with depressive disorders; and 1.5 and 38% in offspring of those with substance use disorders. The offspring's RR and lifetime risk of developing the same mental disorder diagnosed in their parent were 8.4 and 32% for attention-deficit/hyperactivity disorder; 5.8 and 8% for psychosis; 5.1 and 5% for bipolar disorder; 2.8 and 9% for substance use disorders; 2.3 and 14% for depressive disorders; 2.3 and 1% for eating disorders; and 2.2 and 31% for anxiety disorders. There were 37 significant transdiagnostic associations between parental mental disorders and the RR of developing a different mental disorder in the offspring. In offspring of parents with psychosis, bipolar and depressive disorder, the risk of the same disorder onset emerged at 16, 5 and 6 years, and cumulated to 3%, 19% and 24% by age 18; and to 8%, 36% and 46% by age 28. Heterogeneity ranged from 0 to 0.98, and 96% of studies were at high risk of bias. Sensitivity analyses restricted to prospective family high-risk studies confirmed the pattern of findings with similar RR, but with greater absolute risks compared to analyses of all study types. This study demonstrates at a global, meta-analytic level that offspring of affected parents have strongly elevated RR and lifetime risk of developing any mental disorder as well as the same mental disorder diagnosed in the parent. The transdiagnostic risks suggest that offspring of parents with a range of mental disorders should be considered as candidates for targeted primary prevention.     

Temperature change as a driver of spatial patterns and long‐term trends in chironomid (Insecta: Diptera) diversity

Anthropogenic activities have led to a global decline in biodiversity, and monitoring studies indicate that both insect communities and wetland ecosystems are particularly affected. However, there is a need for long‐term data (over centennial or millennial timescales) to better understand natural community dynamics and the processes that govern the observed trends. Chironomids (Insecta: Diptera: Chironomidae) are often the most abundant insects in lake ecosystems, sensitive to environmental change, and, because their larval exoskeleton head capsules preserve well in lake sediments, they provide a unique record of insect community dynamics through time. Here, we provide the results of a metadata analysis of chironomid diversity across a range of spatial and temporal scales. First, we analyse spatial trends in chironomid diversity using Northern Hemispheric data sets overall consisting of 837 lakes. Our results indicate that in most of our data sets, summer temperature (T_jul) is strongly associated with spatial trends in modern‐day chironomid diversity. We observe a strong increase in chironomid alpha diversity with increasing T_jul in regions with present‐day T_jul between 2.5 and 14°C. In some areas with T_jul > 14°C, chironomid diversity stabilizes or declines. Second, we demonstrate that the direction and amplitude of change in alpha diversity in a compilation of subfossil chironomid records spanning the last glacial–interglacial transition (~15,000–11,000 years ago) are similar to those observed in our modern data. A compilation of Holocene records shows that during phases when the amplitude of temperature change was small, site‐specific factors had a greater influence on the chironomid fauna obscuring the chironomid diversity–temperature relationship. Our results imply expected overall chironomid diversity increases in colder regions such as the Arctic under sustained global warming, but with complex and not necessarily predictable responses for individual sites.     

FLCN,a novel autophagy component,interacts with GABARAP and is regulated by ULK1 phosphorylation

Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant condition caused by mutations in the FLCN gene and characterized by benign hair follicle tumors, pneumothorax, and renal cancer. Folliculin (FLCN), the protein product of the FLCN gene, is a poorly characterized tumor suppressor protein, currently linked to multiple cellular pathways. Autophagy maintains cellular homeostasis by removing damaged organelles and macromolecules. Although the autophagy kinase ULK1 drives autophagy, the underlying mechanisms are still being unraveled and few ULK1 substrates have been identified to date. Here, we identify that loss of FLCN moderately impairs basal autophagic flux, while re-expression of FLCN rescues autophagy. We reveal that the FLCN complex is regulated by ULK1 and elucidate 3 novel phosphorylation sites (Ser406, Ser537, and Ser542) within FLCN, which are induced by ULK1 overexpression. In addition, our findings demonstrate that FLCN interacts with a second integral component of the autophagy machinery, GABA(A) receptor-associated protein (GABARAP). The FLCN-GABARAP association is modulated by the presence of either folliculin-interacting protein (FNIP)-1 or FNIP2 and further regulated by ULK1. As observed by elevation of GABARAP, sequestome 1 (SQSTM1) and microtubule-associated protein 1 light chain 3 (MAP1LC3B) in chromophobe and clear cell tumors from a BHD patient, we found that autophagy is impaired in BHD-associated renal tumors. Consequently, this work reveals a novel facet of autophagy regulation by ULK1 and substantially contributes to our understanding of FLCN function by linking it directly to autophagy through GABARAP and ULK1.     

The effect of low temperatures on fatty acid composition of crops with different cold resistance

The study was focused on fatty acid (FA) composition of lipids from the seedlings and roots of crops having different cold resistance and grown at 27°C or 4°C. Biosynthesis of FA in the lipids of seedlings and roots of cold-susceptible maize (Zea mays L.) at both growth temperatures was controlled by chloroplast ω6 desaturase and microsomal ω6 desaturase, respectively. The content of linoleic acid was 56.2% and 43.3% in the coleoptiles of maize seedlings grown at 4 and 27°C, respectively, and in the roots it was 52.2% and 38.5%, respectively. The content of α-linolenoic acid in the coleoptiles was 6.7–6.8% at both temperatures, while in the root lipids it was higher at low temperature (3.15% at 27°C vs. 4.7% at 4°C). FA biosynthesis in the seedling coleoptiles of wheat (Triticum aestivum L.) and Siberian wild rye (Elymus sibiricus L.) grown at low temperature was controlled by the chloroplast ω3 desaturase. A minor increase in the content of α-linolenoic acid was observed at low temperature: 29.7% to 30.2% in wheat and 22.8% to 25.8% in wild rye. In the root tissues of these species, the biosynthesis of α-linolenoic acid was controlled by the microsomal ω3 desaturase. The content of α-linolenoic acid was higher at low temperature: in wheat it was 6.1% at 27°C and 17.1%, and 4°C, while in Siberian wild rye, 7.1% and 12.0% at 4 and 27°C, respectively.     

Perceived wellbeing of patients one year post stroke in general practice - <Emphasis Type="Italic">recommendations for quality aftercare</Emphasis>

Background  

Annually, 41,000 people in the Netherlands have strokes. This has multiple physical and psychosocial consequences. Most patients return home after discharge from hospital. Quality aftercare by general practitioners is important to support patients at home. The purpose of this study is to examine the wellbeing of patients who returned home immediately after discharge from hospital, one year post stroke, in comparison with the general Dutch population of the same age and to determine factors that could influence wellbeing.     

The effect of habitat hydrology on intraspecific competition,settlement structure,and reproduction in the water vole (<Emphasis Type="Italic">Arvicola terrestris</Emphasis>)

Analysis of long-term monitoring of the water vole population in Northern Baraba Lowland (Ubinskii raion, Novosibirsk oblast) has revealed correlation between flow intensity of the Om’ River in the study area and population numbers and population dynamics (estimated May through August), average number of live embryos in overwintered females, and percentage of mature young-of-the-year females in different years of study.     

Metal cofactors play a dual role in Mycobacterium tuberculosis inorganic pyrophosphatase

Inorganic pyrophosphatase from Mycobacterium tuberculosis (Mt-PPase) is one of the possible targets for the rational design of anti-tuberculosis agents. In this paper, functional properties of this enzyme are characterized in the presence of the most effective activators--Mg2+ and Mn2+. Dissociation constants of Mt-PPase complexed with Mg2+ or Mn2+ are essentially similar to those of Escherichia coli PPase. Stability of a hexameric form of Mt-PPase has been characterized as a function of pH both for the metal-free enzyme and for Mg2+- or Mn2+-enzyme. Hexameric metal-free Mt-PPase has been shown to dissociate, forming monomers at pH below 4 or trimers at pH from 8 to 10. Mg2+ or Mn2+ shift the hexamer-trimer equilibrium found for the apo-Mt-PPase at pH 8-10 toward the hexameric form by stabilizing intertrimeric contacts. The pK(a) values have been determined for groups that control the observed hexamer-monomer (pK(a) 5.4), hexamer-trimer (pK(a) 7.5), and trimer-monomer (pK(a) 9.8) transitions. Our results demonstrate that due to the non-conservative amino acid residues His21 and His86 in the active site of Mt-PPase, substrate specificity of this enzyme, in contrast to other typical PPases, does not depend on the nature of the metal cofactor.     

DNA complexes with polycations used for delivery of DNA into cells

The formation and physicochemical properties of high-molecular thymus and plasmid DNA complexes with synthetic polymers based on (dimethyl-amino)ethyl methacrylate (DMAEM), (diethyl-amino)ethyl methacrylate (DEAEM), and polyvinyl amine (PVA) were investigated in solutions of different ionic strength by low-gradient viscometry, electrophoresis, circular dichroism, spectrophotometry, and dynamic light scattering. The toxicity of complexes in T98G cells was studied. It was shown that, when the ratio of polycations to DNA charged groups concentration (N+/P) reaches values > 1, DNA condensation occurs. It is accompanied by increasing optical density of solutions. Changes in DNA size after condensation were estimated. Phase diagrams of systems DNA/polycation in the presence of NaCl were obtained. It was shown by MTT-analysis that DNA complexes with polycations in the range of concentrations used have low toxicity.     

Reconstruction of palaeoecological and palaeoclimatic conditions of the Holocene in the south of the Taimyr according to an analysis of lake sediments

A sediment core from Khatanga-12 Lake (Taimyr Peninsula, Krasnoyarsk krai) has been studied. The 131.5-cm-long core covers ca. 7100 years of sedimentation. Chironomid analysis, a qualitative reconstruction of the paleoenvironment in the region, and a quantitative reconstruction of variations of the mean July air temperature and in the water depth of the lake have been performed using Northern Russia chironomid-inferred mean July temperature models (Nazarova et al., 2008, 2011, 2015). Khatanga-12 Lake was formed during the Middle Holocene warming as a result of thermokarst processes. The development of the lake ecosystem at different stages of its development was influenced by climatic and cryolithogenic factors. The Middle Holocene warming, which occurred around 7100–6250 cal. years BP, activated thermokarst processes and resulted in the formation of the lake basin. Later, between 6250 and 4500 cal. years BP, a period of cooling took place, as is proved by chironomid analysis. The bottom sediments of the lake during this period were formed by erosion processes on the lake shores. The reconstructed conditions were close to the modern after 2500 cal. years BP.