Exposing T Cell Secrets Inside and Outside the Thymus.

I've had serious misgivings about writing this article, because from living the experience day by day, it's hard to believe my accomplishments merit the attention. To skirt this roadblock, I forced myself to pretend I was in a conversation with my trainees, trying to distill the central driving forces of my career in science. The below chronicles my evolution from would-be astronaut/ballerina to budding developmental biologist to devoted T cell immunologist. It traces my work from a focus on intrathymic events that mold developing T cells into self-major histocompatibility complex (MHC)-restricted lymphocytes to extrathymic events that fine-tune the T cell receptor (TCR) repertoire and impose the finishing touches on T cell maturation. It is a story of a few personal attributes multiplied by generous mentors, good luck, hard work, perseverance, and knowing when to step down.

Plasmacytoid Dendritic Cells: Development, Regulation, and Function.

Plasmacytoid dendritic cells (pDCs) are a unique sentinel cell type that can detect pathogen-derived nucleic acids and respond with rapid and massive production of type I interferon. This review summarizes our current understanding of pDC biology, including transcriptional regulation, heterogeneity, role in antiviral immune responses, and involvement in immune pathology, particularly in autoimmune diseases, immunodeficiency, and cancer. We also highlight the remaining gaps in our knowledge and important questions for the field, such as the molecular basis of unique interferon-producing capacity of pDCs. A better understanding of cell type-specific positive and negative control of pDC function should pave the way for translational applications focused on this immune cell type.

GWAS on birth year infant mortality rates provides evidence of recent natural selection.

Following more than a century of phenotypic measurement of natural selection processes, much recent work explores relationships between molecular genetic measurements and realized fitness in the next generation. We take an innovative approach to the study of contemporary selective pressure by examining which genetic variants are "sustained" in populations as mortality exposure increases. Specifically, we deploy a so-called "regional GWAS" (genome-wide association study) that links the infant mortality rate (IMR) by place and year in the United Kingdom with common genetic variants among birth cohorts in the UK Biobank. These cohorts (born between 1936 and 1970) saw a decline in IMR from above 65 to under 20 deaths per 1,000 live births, with substantial subnational variations and spikes alongside wartime exposures. Our results show several genome-wide significant loci, including LCT and TLR10/1/6, related to area-level cohort IMR exposure during gestation and infancy. Genetic correlations are found across multiple domains, including fertility, cognition, health behaviors, and health outcomes, suggesting an important role for cohort selection in modern populations.

Thymic Atrophy and Immune Dysregulation in Infants with Complex Congenital Heart Disease.

Congenital heart disease (CHD) is the most common birth defect, and up to 50% of infants with CHD require cardiovascular surgery early in life. Current clinical practice often involves thymus resection during cardiac surgery, detrimentally affecting T-cell immunity. However, epidemiological data indicate that CHD patients face an elevated risk for infections and immune-mediated diseases, independent of thymectomy. Hence, we examined whether the cardiac defect impacts thymus function in individuals with CHD. We investigated thymocyte development in 58 infants categorized by CHD complexity. To assess the relationship between CHD complexity and thymic function, we analyzed T-cell development, thymic output, and biomarkers linked to cardiac defects, stress, or inflammation. Patients with highly complex CHD exhibit thymic atrophy, resulting in low frequencies of recent thymic emigrants in peripheral blood, even prior to thymectomy. Elevated plasma cortisol levels were detected in all CHD patients, while high NT-proBNP and IL-6 levels were associated with thymic atrophy. Our findings reveal an association between complex CHD and thymic atrophy, resulting in reduced thymic output. Consequently, thymus preservation during cardiovascular surgery could significantly enhance immune function and the long-term health of CHD patients.

Spatio-temporal plant hormonomics: From tissue to subcellular resolution.

Due to technological advances in mass spectrometry, significant progress has been achieved recently in plant hormone research. Nowadays, plant hormonomics is well established as a fully integrated scientific field focused on the analysis of phytohormones, mainly on their isolation, identification and spatiotemporal quantification in plants. This review represents a comprehensive meta-study of the advances in the phytohormone analysis by mass spectrometry over the past decade. To address current trends and future perspectives, Web of Science data were systematically collected and key features such as mass spectrometry-based analyses were evaluated using multivariate data analysis methods. Our findings showed that plant hormonomics is currently divided into targeted and untargeted approaches. Both aim to miniaturize the sample, allowing high-resolution quantification to be covered in plant organs as well as subcellular compartments. Therefore, we can study plant hormone biosynthesis, metabolism and signalling at a spatio-temporal resolution. Moreover, this trend has recently been accelerated by technological advances such as fluorescence-activated cell sorting or mass spectrometry imaging.

Cost-effectiveness of romosozumab for the treatment of postmenopausal women with osteoporosis at high risk of fracture in Belgium.

This study evaluated the cost-effectiveness of sequential treatment with romosozumab-to-alendronate compared to alendronate monotherapy and teriparatide-to-alendronate, in postmenopausal osteoporotic women from a Belgian healthcare perspective. Romosozumab-to-alendronate was found to be cost-effective compared to alendronate monotherapy and dominant compared to teriparatide-to-alendronate for osteoporotic women at high risk of fracture in Belgium. PURPOSE: This study aimed to evaluate the cost-effectiveness of sequential treatment with romosozumab followed by alendronate compared to alendronate monotherapy and teriparatide followed by alendronate, in postmenopausal osteoporotic women at high risk of fracture, from a Belgian healthcare perspective. Romosozumab is reimbursed in Belgium since December 2021. METHODS: A Markov microsimulation model was used to evaluate the cost-effectiveness of romosozumab-to-alendronate compared to alendronate monotherapy and to teriparatide-to-alendronate over a lifetime horizon. Patients transition between five different health states every 6 months based on fracture risks or death. The model was populated with Belgium-specific epidemiological and cost data, where available. The fracture risk reduction of romosozumab treatment was collated from the ARCH study, and from a published network meta-analysis. Costs were included from a healthcare perspective (NIHDI). Cost-effectiveness was reported in terms of costs per quality-adjusted life year (QALY), reported in Euro (€) 2022. Deterministic (DSA) and probabilistic sensitivity analyses (PSA) were performed. RESULTS: Romosozumab-to-alendronate was associated with 0.12 additional QALYs at an additional cost of €2314 compared to alendronate monotherapy, resulting in an ICER of €19,978. Compared to teriparatide-to-alendronate, romosozumab-to-alendronate was found to be dominant, with higher QALYs and lower costs. The base-case results were robust to uncertainty in the input parameters when conducting the sensitivity analysis. CONCLUSION: Sequential treatment with romosozumab followed by alendronate was found to be cost-effective compared to alendronate monotherapy and dominant compared to teriparatide followed by alendronate for postmenopausal women with osteoporosis at high risk of fracture in Belgium.

Trade-off in the partitioning of recent photosynthate carbon under global change.

There may be trade-offs in the allocation patterns of recent photosynthetic carbon (RPC) allocation in response to environmental changes, with a greater proportion of RPC being directed towards compartments experiencing limited resource availability. Alternatively, the allocation of RPC could shift from sources to sinks as plants processing excess photosynthates. It prompts the question: Does the pattern of RPC allocation vary under global changes? If so, is this variation driven by optimal or by residual C allocation strategies? We conducted a meta-analysis by complicating 273 pairwise observations from 55 articles with 13 C or 14 C pulse or continuous labeling to assess the partitioning of RPC in biomass (leaf, stem, shoot, and root), soil pools (soil organic C, rhizosphere, and microbial biomass C) and CO2 fluxes under elevated CO2 (eCO2 ), warming, drought and nitrogen (N) addition. We propose that the increased allocation of RPC to belowground under sufficient CO2 results from the excretion of excess photosynthates. Warming led to a significant reduction in the percentage of RPC allocated to shoots, alongside an increase in roots allocation, although this was not statistically significant. This pattern is due to the reduced water availability resulting from warming. In conditions of drought, there was a notable increase in the partitioning of RPC to stems (+7.25%) and roots (+36.38%), indicative of a greater investment of RPC in roots for accessing water from deeper soil. Additionally, N addition led to a heightened allocation of RPC in leaves (+10.18%) and shoots (+5.78%), while reducing its partitioning in soil organic C (-8.92%). Contrary to the residual C partitioning observed under eCO2 , the alterations in RPC partitioning in response to warming, drought, and N supplementation are more comprehensively explained through the lens of optimal partitioning theory, showing a trade-off in the partitioning of RPC under global change.

Immune recovery and the role of recent thymic emigrated T lymphocytes after pediatric hematopoietic stem cell transplantation.

BACKGROUND AIMS: Adequate re-establishment of thymopoiesis is critical for long-term immune reconstitution after hematopoietic cell transplantation (HCT), potentially impacting patient survival rates. This study aimed to evaluate immune reconstitution in pediatric HCT recipients by quantifying recent thymic emigrants (RTEs), specifically CD3+CD31+CD45RA+ cells. METHODS: We conducted a retrospective analysis of 186 pediatric patients transplanted between 2013 and 2020, undergoing their first allogeneic HCT, who were alive in the first 100 days after transplantation with immune recovery evaluation at three time points: day 100, day 180 and day 360 after HCT. We analyzed the distribution of peripheral blood subsets of T, B and natural killer lymphocytes and assessed the impact of underlying disease, HCT type, stem cell source, recipient age, conditioning regimen, graft-versus-host disease (GVHD) occurrence and cytomegalovirus (CMV) reactivation on immune recovery. RESULTS: At day 100, patients under 10 years exhibited higher RTE CD4+ and CD8+CD31+CD45RA+ counts compared with older patients (5.3 versus 2.2 cells/µL, P = 0.022 and 48 versus 72.8 cells/µL, P = 0.049, respectively). Patients with haploidentical HCT had lower RTE CD4+ counts compared with those with unrelated or related donors (2.4 versus 4.4 versus 7.9 cells/µL, P = 0.024). Administration of rabbit anti-thymocyte globulin negatively impacted RTE CD4+ production (median, 6.5 versus 2.4 cells/µL, P = 0.007). At day 180, the presence of GVHD had a negative influence on RTE production (11.7 versus 56.8 cells/µL, P < 0.001), particularly higher-grade acute GVHD (without, 56.8 cells/µL, grade 1-2, 28.1 cells/µL, grade 3-4, 6.0 cells/µL, P < 0.001). Patients with CMV reactivation had higher CD8+CD31+CD45RA+ compared with those without reactivation (median, 204.6 versus 100.2 cells/µL, P = 0.022). At day 360, no variables significantly affected RTE recovery. Overall survival at 5-year follow-up was 87.7%, with a median of 1170 days (range, 122-3316). Multivariate analysis showed that age >10 years (P = 0.038), negative CMV donor serology (P = 0.0029) and acute GVHD (P = 0.0026) had a negative impact on survival. CONCLUSIONS: This study highlights variations in RTE production based on patient age, donor type and immunosuppression regimen employed.

Differential decline of SARS-CoV-2-specific antibody levels, innate and adaptive immune cells, and shift of Th1/inflammatory to Th2 serum cytokine levels long after first COVID-19.

BACKGROUND: SARS-CoV-2 has triggered a pandemic and contributes to long-lasting morbidity. Several studies have investigated immediate cellular and humoral immune responses during acute infection. However, little is known about long-term effects of COVID-19 on the immune system. METHODS: We performed a longitudinal investigation of cellular and humoral immune parameters in 106 non-vaccinated subjects ten weeks (10 w) and ten months (10 m) after their first SARS-CoV-2 infection. Peripheral blood immune cells were analyzed by multiparametric flow cytometry, serum cytokines were examined by multiplex technology. Antibodies specific for the Spike protein (S), the receptor-binding domain (RBD) and the nucleocapsid protein (NC) were determined. All parameters measured 10 w and 10 m after infection were compared with those of a matched, noninfected control group (n = 98). RESULTS: Whole blood flow cytometric analyses revealed that 10 m after COVID-19, convalescent patients compared to controls had reduced absolute granulocyte, monocyte, and lymphocyte counts, involving T, B, and NK cells, in particular CD3+CD45RA+CD62L+CD31+ recent thymic emigrant T cells and non-class-switched CD19+IgD+CD27+ memory B cells. Cellular changes were associated with a reversal from Th1- to Th2-dominated serum cytokine patterns. Strong declines of NC- and S-specific antibody levels were associated with younger age (by 10.3 years, p < .01) and fewer CD3-CD56+ NK and CD19+CD27+ B memory cells. Changes of T-cell subsets at 10 m such as normalization of effector and Treg numbers, decline of RTE, and increase of central memory T cell numbers were independent of antibody decline pattern. CONCLUSIONS: COVID-19 causes long-term reduction of innate and adaptive immune cells which is associated with a Th2 serum cytokine profile. This may provide an immunological mechanism for long-term sequelae after COVID-19.

A mismatch between early and recent life stress predicts better response inhibition, but not cognitive inhibition.

A growing body of work has found that a mismatch between early and recent life stress, more than a cumulative influence of stress, contributes to detrimental stress-related health outcomes. To date, however, no work has examined how such a mismatch might relate to stress-related cognitive outcomes. We addressed this gap in the current study by assessing participants' (N = 154, Mage = 18.7, 104 female) early and recent life stress using the same inventory, and subsequently assessing their inhibitory control in a hybrid stop-signal/flanker task. Surprisingly, we found that a greater degree of stressor mismatch was associated with better response inhibition (i.e. smaller stop-signal reaction time) across a number of analytic approaches. Cognitive inhibition (i.e. the flanker interference effect) was not associated with stressor mismatch. These results thus show that a greater degree of mismatch between early and recent life stress is related to response inhibition in the same way as acute stress affects response inhibition, suggesting that response inhibition may be an important cognitive process for navigating both acute stress and general environmental conditions that do not match the conditions in which expected stress occurrence was established.

The inhibitory effect of a recent distractor: singleton vs. multiple distractors.

In the complex interplay between sensory and cognitive processes, the brain must sift through a flood of sensory data to pinpoint relevant signals. This selective mechanism is crucial for the effective control of behaviour, by allowing organisms to focus on important tasks and blocking out distractions. The Inhibition of a Recent Distractor (IRD) Task examines this selection process by exploring how inhibiting distractors influences subsequent eye movements towards an object in the visual environment. In a series of experiments, research by Crawford et al. (2005a) demonstrated a delayed response to a target appearing at the location that was previously occupied by a distractor, demonstrating a legacy inhibition exerted by the distractor on the spatial location of the upcoming target. This study aimed to replicate this effect and to investigate any potential constraints when multiple distractors are presented. Exploring whether the effect is observed in more ecologically relevant scenarios with multiple distractors is crucial for assessing the extent to which it can be applied to a broader range of environments. Experiment 1 successfully replicated the effect, showing a significant IRD effect only with a single distractor. Experiments 2-5 explored a number of possible explanations for this phenomenon.

Recent HIV infection and associated factors among newly diagnosed HIV cases in the Southwest Ethiopia Regional State: HIV case-based surveillance analysis (2019-2022).

BACKGROUND: Globally, there were an estimated 39 million people living with HIV with 1.3 million new HIV infections by the end of 2023. The Sub-Saharan Africa accounted 51% of new HIV infections. HIV case-based Surveillance collects data on newly diagnosed HIV cases, recent HIV infections, and other sentinel events, aiding evidence-based decision making. There is limited evidence on these in Ethiopia. The objective of this study is to determine the incidence proportion of recent infections and associated factors among newly diagnosed HIV cases and their distribution by person, place, and time in the Southwest Ethiopia Regional State. METHODS: A retrospective analysis was conducted on HIV case-based surveillance dataset (July 2019 to June 2022) from the Southwest Ethiopia Regional State. Recent HIV infection is an infection that acquired within the last 12 months as diagnosed by Asante recency test kits. Data were analyzed using SPSS version 26. ArcGIS version 10.8 was used for mapping recent infections. Logistic regression was employed to identify factors associated with recent infections. In multivariable logistic regression analysis, variables with p-value < 0.05 and an adjusted odds ratio with 95% confidence interval were considered to declare significant association. RESULTS: A total of 1,167 newly diagnosed HIV cases (eligible cases) were identified. Among these, 786 (67.3%) recency tests were performed. The mean age of individuals with recent infection was 28.4 years. The proportion of recent infection is 89 (11.3%, 95% CI: 11.2, 11.5%). The highest proportion of recent infection is reported from the West Omo zone (42.9%), whereas 13.2% in Bench Sheko zone. Recent infection is significantly associated with age 15-24 years [AOR = 7.14, 95%CI: 2.89,17.57], age 25-34 years [AOR = 5.34, 95%CI: 2.20,12.94], females [AOR = 2.03, 95%CI: 1.26,3.25], and contact history with the index case [AOR = 0.48, 95%CI: 0.28, 0.83]. The incidence of recent infection increased from 86 (in 2019/20) to 132 (in 2022) recent infections per 1,000 newly diagnosed cases. CONCLUSIONS: Recent HIV infection is a public health concern in the Southwest Ethiopia Regional State with an increasing incidence. Targeted prevention efforts are necessary, especially for females and younger people.

Safety and Effectiveness of Antidysrhythmic Drugs for Pharmacologic Cardioversion of Recent-Onset Atrial Fibrillation: a Systematic Review and Bayesian Network Meta-analysis.

PURPOSE: The available evidence to determine which antidysrhythmic drug is superior for pharmacologic cardioversion of recent-onset (onset within 48 h) atrial fibrillation (AF) is uncertain. We aimed to identify the safest and most effective agent for pharmacologic cardioversion of recent-onset AF in the emergency department. METHODS: We searched MEDLINE, Embase, and Web of Science from inception to February 21, 2023 (PROSPERO: CRD42018083781). Eligible studies were randomized controlled trials that enrolled adult participants with AF ≤ 48 h, compared a guideline-recommended antidysrhythmic drug with another antidysrhythmic drug or a different formulation of the same drug or placebo and reported specific adverse events. The primary outcome was immediate, serious adverse event - cardiac arrest, sustained ventricular tachydysrhythmia, atrial flutter 1:1 atrioventricular conduction, hypotension, and bradycardia. Additional analyses included the outcomes of conversion to sinus rhythm within 4 h and 24 h. We extracted data according to PRISMA-NMA and appraised trials using Cochrane RoB 2. We performed Bayesian network meta-analysis (NMA) using a Markov Chain Monte Carlo method with random-effect model and vague prior distribution to calculate odds ratios with 95% credible intervals. We assessed confidence using CINeMA. We used surface under the cumulative ranking curve (SUCRA) to rank agent(s). RESULTS: The systematic review initially identified 5545 studies. Twenty-five studies met eligibility criteria, and 22 studies (n = 3082) provided data for NMA, which demonstrated that vernakalant (SUCRA = 70.9%) is most likely to be safest. Additional effectiveness NMA demonstrated that flecainide (SUCRA = 89.0%) is most likely to be superior for conversion within 4 h (27 studies; n = 2681), and ranolazine-amiodarone IV (SUCRA 93.7%) is most likely to be superior for conversion within 24 h (24 studies; n = 3213). Confidence in the NMA estimates is variable and limited mostly by within-study bias and imprecision. CONCLUSIONS: Among guideline-recommended antidysrhythmic drugs, the combination of digoxin IV and amiodarone IV is definitely among the least safe for cardioversion of recent onset AF; flecainide, vernakalant, ibutilide, propafenone, and amiodarone IV are definitely among the most effective for cardioversion within 4 h; flecainide is definitely among the most effective for cardioversion within 24 h. Further, randomized controlled trials with predetermined and strictly defined, hemodynamic adverse event outcomes are recommended.

Between-hospital care referrals for severe alcohol-related liver disease during the COVID-19 pandemic, 2020 to 2022.

Increased alcohol consumption during the coronavirus disease 2019 pandemic is projected to impact alcohol-related liver disease (ALD) morbidity and mortality. Inter-hospital escalation-of-care referral requests to our tertiary-care hepatology unit were analyzed from January 2020 through December 2022. Most requests to our center were for ALD with an increase in requests from intermediate care units, suggestive of higher acuity illness.

The Relationship Between Parent Fear of Hypoglycemia and Youth Glycemic Control Across the Recent-Onset Period in Families of Youth with Type 1 Diabetes.

BACKGROUND: This study aims to examine the relationship between parents' fear of hypoglycemia (FH) over a 1-year period and child glucose metrics in 126 families of youth recently diagnosed with type 1 diabetes (T1D). METHODS: Parents completed the Hypoglycemia Fear Survey for Parents (HFS-P) and uploaded 14 days of glucose data at a baseline, 6-month, and 12-month assessment. RESULTS: Parents' HFS-P total and worry scores increased to a clinically meaningful degree from baseline to 6-month assessment, while multilevel models revealed within- and between-person variability in parents' HFS-P worry and behavior scores over time associated with child glycemia. Specifically, a significant negative relationship for within-person worry scores suggested that when parents reported higher than their average worry scores, their children recorded fewer glucose values in the target range, while within-person behavior scores suggested that when parents reported lower than their average behavior scores, their children recorded more values above the target range. There was also a negative relationship for between-person behavior scores with child glycated hemoglobin and a positive relationship for between-person behavior scores with child glucose values in the target range. CONCLUSIONS: In the recent-onset period of T1D, parental FH worry and behavior associated with child glycemia possibly due to changes in parents' perceptions of their child's hypoglycemia risk. The clinically meaningful increases in parent FH in the recent-onset period and the negative association for between-person behavior scores with child glycated hemoglobin suggest that clinics should consider screening parents for FH, especially among parents of children with lower glycemic levels.

Are recent health, welfare and care graduates part of a rural and remote workforce solution? Evidence from Tasmania, Australia.

BACKGROUND: Strong growth in graduate supply from health, welfare and care courses across Australia may bode well for easing rural workforce shortages. However, little is known about the employment opportunities available for recent graduates in non-metropolitan areas. This study aimed to quantify and describe advertised job vacancies for health, welfare and care professions in Tasmania, a largely rural and geographically isolated island state of Australia. Further, it aimed to examine those job vacancies specifying that recent graduates were suitable to apply. METHODS: Job advertisements for health, welfare and care professionals were collected weekly throughout 2018 from six online job vacancy websites. Data were extracted on 25 variables pertaining to type of profession, number of positions, location, and graduate suitability. Location of positions were recoded into a Modified Monash Model (MM) category, the Australian geographic standard used to classify rurality. Positions advertised in MM2 areas were considered regional and MM3-7 areas rural to very remote. Data were analysed using descriptive and inferential statistics. RESULTS: Over the twelve-month period, 3967 advertisements were identified, recruiting for more than 4700 positions across 49 different health, welfare and care professions in Tasmania. Most vacancies were in the non-government sector (58.5%) and located in regional areas (71.7%) of the state. Professions most frequently advertised were registered nurse (24.4%) and welfare worker (11.4%). Eleven professions, including physiotherapist and occupational therapist, recorded a disproportionate number of advertisements relative to workforce size, suggesting discipline specific workforce shortages. Only 4.6% of collected advertisements specified that a recent graduate would be suitable to apply. Of these, most were for the non-government sector (70.1%) and located in regional areas (73.4%). The professions of physiotherapist (26.6%) and occupational therapist (11.4%) were most frequently represented in advertised graduate suitable positions. CONCLUSIONS: Despite a range of advertised employment opportunities for health, welfare and care professionals across Tasmania, few specified vacancies as suitable for recent graduates and most were located in regional areas of the state. Health, welfare and care services in non-metropolitan locations may need to develop more employment opportunities for recent graduates and explicitly advertise these to job-seeking graduates to help grow and sustain the rural and remote health workforce into the future.

Poxvirus Vaccines: Past, Present, and Future.

Smallpox was a significant cause of mortality for over three thousand years, amounting to 10% of deaths yearly. Edward Jenner discovered smallpox vaccination in 1796, which rapidly became a smallpox infection preventive practice throughout the world and eradicated smallpox infection by 1980. After smallpox eradication, monkeypox vaccines have been used primarily in research and in outbreaks in Africa, where the disease is endemic. In the present, the vaccines are being used for people who work with animals or in high-risk areas, as well as for healthcare workers treating patients with monkeypox. Among all orthopoxviruses (OPXV), monkeypox viral (MPXV) infection occurs mainly in cynomolgus monkeys, natural reservoirs, and occasionally causes severe multi-organ infection in humans, who were the incidental hosts. The first case of the present epidemic of MXPV was identified on May 7, 2022, and rapidly increased the number of cases. In this regard, the WHO declared the outbreak, an international public health emergency on July 23, 2022. The first monkeypox vaccine was developed in the 1960s by the US Army and was based on the vaccinia virus, which is also used in smallpox vaccines. In recent years, newer monkeypox vaccines have been developed based on other viruses such as Modified Vaccinia Ankara (MVA). These newer vaccines are safer and can provide longer-lasting immunity with fewer side effects. For the future, there is ongoing research to improve the current vaccines and to develop new ones. One notable advance has been the development of a recombinant vaccine that uses a genetically modified vaccinia virus to express monkeypox antigens. This vaccine has shown promising results in pre-clinical trials and is currently undergoing further testing in clinical trials. Another recent development has been the use of a DNA vaccine, which delivers genetic material encoding monkeypox antigens directly into cells. This type of vaccine has shown effectiveness in animal studies and is also undergoing clinical testing in humans. Overall, these recent advances in monkeypox vaccine development hold promise for protecting individuals against this potentially serious disease.

Embers of the Past: Early Childhood Traumas Interact with Variation in P2RX7 Gene Implicated in Neuroinflammation on Markers of Current Suicide Risk.

Both early childhood traumatic experiences and current stress increase the risk of suicidal behaviour, in which immune activation might play a role. Previous research suggests an association between mood disorders and P2RX7 gene encoding P2X7 receptors, which stimulate neuroinflammation. We investigated the effect of P2RX7 variation in interaction with early childhood adversities and traumas and recent stressors on lifetime suicide attempts and current suicide risk markers. Overall, 1644 participants completed questionnaires assessing childhood adversities, recent negative life events, and provided information about previous suicide attempts and current suicide risk-related markers, including thoughts of ending their life, death, and hopelessness. Subjects were genotyped for 681 SNPs in the P2RX7 gene, 335 of which passed quality control and were entered into logistic and linear regression models, followed by a clumping procedure to identify clumps of SNPs with a significant main and interaction effect. We identified two significant clumps with a main effect on current suicidal ideation with top SNPs rs641940 and rs1653613. In interaction with childhood trauma, we identified a clump with top SNP psy_rs11615992 and another clump on hopelessness containing rs78473339 as index SNP. Our results suggest that P2RX7 variation may mediate the effect of early childhood adversities and traumas on later emergence of suicide risk.

Structure, Evolution, and Mitochondrial Genome Analysis of Mussel Species (Bivalvia, Mytilidae).

Based on the nucleotide sequences of the mitochondrial genome (mitogenome) of specimens taken from two mussel species (Arcuatula senhousia and Mytilus coruscus), an investigation was performed by means of the complex approaches of the genomics, molecular phylogenetics, and evolutionary genetics. The mitogenome structure of studied mussels, like in many other invertebrates, appears to be much more variable than in vertebrates and includes changing gene order, duplications, and deletions, which were most frequent for tRNA genes; the mussel species' mitogenomes also have variable sizes. The results demonstrate some of the very important properties of protein polypeptides, such as hydrophobicity and its determination by the purine and pyrimidine nucleotide ratio. This fact might indirectly indicate the necessity of purifying natural selection for the support of polypeptide functionality. However, in accordance with the widely accepted and logical concept of natural cutoff selection for organisms living in nature, which explains its action against deleterious nucleotide substitutions in the nonsynonymous codons (mutations) and its holding of the active (effective) macromolecules of the polypeptides in a population, we were unable to get unambiguous evidence in favor of this concept in the current paper. Here, the phylogeny and systematics of mussel species from one of the largest taxons of bivalve mollusks are studied, the family known as Mytilidae. The phylogeny for Mytilidae (order Mytilida), which currently has no consensus in terms of systematics, is reconstructed using a data matrix of 26-27 mitogenomes. Initially, a set of 100 sequences from GenBank were downloaded and checked for their gender: whether they were female (F) or male (M) in origin. Our analysis of the new data confirms the known drastic differences between the F/M mitogenome lines in mussels. Phylogenetic reconstructions of the F-lines were performed using the combined set of genetic markers, reconstructing only protein-coding genes (PCGs), only rRNA + tRNA genes, and all genes. Additionally, the analysis includes the usage of nucleotide sequences composed of other data matrices, such as 20-68 mitogenome sequences. The time of divergence from MRCA, estimated via BEAST2, for Mytilidae is close to 293 Mya, suggesting that they originate in the Silurian Period. From all these data, a consensus for the phylogeny of the subfamily of Mytilinae and its systematics is suggested. In particular, the long-debated argument on mussel systematics was resolved as to whether Mytilidae, and the subfamily of Mytilinae, are monophyletic. The topology signal, which was strongly resolved in this paper and in the literature, has refuted the theory regarding the monophyly of Mytilinae.

The relationship between patterns of negative life experiences and clinical presentation in a psychiatric sample.

BACKGROUND: Attempts have been made to classify the patterns of polytraumatization using a person-centered approach. However, most studies have only focused on maltreatment and interpersonal trauma and have been unable to examine various clinical symptoms. OBJECTIVES: This study aimed to explore patterns of negative life experiences, including maltreatment, lifetime trauma, and recent stressful life events, and compare diverse dimensions of the clinical manifestations among the subtypes in a clinical sample. METHOD: We investigated childhood maltreatment, lifetime trauma, and recent stressful events using a self-report method in 1410 psychiatric patients; we classified the patterns of lifelong negative life experiences using latent profile analysis (LPA). We used the rates of psychiatric diagnosis, the Beck Depression Inventory, the Impact of Event Scale-Revised (IES-R-K), and the Multiphasic Minnesota Personality Inventory-2-Restructured Form to compare various symptom dimensions among the derived subtypes. RESULTS: LPA indicated a four-class solution: mild, recent stress, maltreatment, and multiple adversity group. The multiple adversity group experiencing both lifetime trauma and recent stressful life events, in addition to maltreatment, including sexual abuse, had a high rate of severe mental illness and more symptom dimensions of thought and behavior problems. However, the rates of depressive disorders and emotional/internalizing symptoms were not more than those in the other two groups (recent stress and maltreatment groups) experiencing moderate levels of lifetime trauma. There was no significant difference between the recent stress and maltreatment groups for most symptom dimensions. CONCLUSIONS: The findings indicate that distinct symptom profiles may be associated with the pattern of negative experiences, suggesting that negative experiences need multidimensional investigation in clinical settings.