Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations.

Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that is most prevalent in Northern Europe. Although it is known that inherited risk for MS is located within or in close proximity to immune-related genes, it is unknown when, where and how this genetic risk originated1. Here, by using a large ancient genome dataset from the Mesolithic period to the Bronze Age2, along with new Medieval and post-Medieval genomes, we show that the genetic risk for MS rose among pastoralists from the Pontic steppe and was brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the steppe population and later in Europe, probably driven by pathogenic challenges coinciding with changes in diet, lifestyle and population density. This study highlights the critical importance of the Neolithic period and Bronze Age as determinants of modern immune responses and their subsequent effect on the risk of developing MS in a changing environment.

The selection landscape and genetic legacy of ancient Eurasians.

The Holocene (beginning around 12,000 years ago) encompassed some of the most significant changes in human evolution, with far-reaching consequences for the dietary, physical and mental health of present-day populations. Using a dataset of more than 1,600 imputed ancient genomes1, we modelled the selection landscape during the transition from hunting and gathering, to farming and pastoralism across West Eurasia. We identify key selection signals related to metabolism, including that selection at the FADS cluster began earlier than previously reported and that selection near the LCT locus predates the emergence of the lactase persistence allele by thousands of years. We also find strong selection in the HLA region, possibly due to increased exposure to pathogens during the Bronze Age. Using ancient individuals to infer local ancestry tracts in over 400,000 samples from the UK Biobank, we identify widespread differences in the distribution of Mesolithic, Neolithic and Bronze Age ancestries across Eurasia. By calculating ancestry-specific polygenic risk scores, we show that height differences between Northern and Southern Europe are associated with differential Steppe ancestry, rather than selection, and that risk alleles for mood-related phenotypes are enriched for Neolithic farmer ancestry, whereas risk alleles for diabetes and Alzheimer's disease are enriched for Western hunter-gatherer ancestry. Our results indicate that ancient selection and migration were large contributors to the distribution of phenotypic diversity in present-day Europeans.

100 ancient genomes show repeated population turnovers in Neolithic Denmark.

Major migration events in Holocene Eurasia have been characterized genetically at broad regional scales1-4. However, insights into the population dynamics in the contact zones are hampered by a lack of ancient genomic data sampled at high spatiotemporal resolution5-7. Here, to address this, we analysed shotgun-sequenced genomes from 100 skeletons spanning 7,300 years of the Mesolithic period, Neolithic period and Early Bronze Age in Denmark and integrated these with proxies for diet (13C and 15N content), mobility (87Sr/86Sr ratio) and vegetation cover (pollen). We observe that Danish Mesolithic individuals of the Maglemose, Kongemose and Ertebølle cultures form a distinct genetic cluster related to other Western European hunter-gatherers. Despite shifts in material culture they displayed genetic homogeneity from around 10,500 to 5,900 calibrated years before present, when Neolithic farmers with Anatolian-derived ancestry arrived. Although the Neolithic transition was delayed by more than a millennium relative to Central Europe, it was very abrupt and resulted in a population turnover with limited genetic contribution from local hunter-gatherers. The succeeding Neolithic population, associated with the Funnel Beaker culture, persisted for only about 1,000 years before immigrants with eastern Steppe-derived ancestry arrived. This second and equally rapid population replacement gave rise to the Single Grave culture with an ancestry profile more similar to present-day Danes. In our multiproxy dataset, these major demographic events are manifested as parallel shifts in genotype, phenotype, diet and land use.

Population genomics of post-glacial western Eurasia.

Western Eurasia witnessed several large-scale human migrations during the Holocene1-5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes-mainly from the Mesolithic and Neolithic periods-from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a 'great divide' genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 BP, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 BP, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a 'Neolithic steppe' cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.

A human genome editing-based MLL::AF4 ALL model recapitulates key cellular and molecular leukemogenic features.

Cellular ontogeny and MLL breakpoint site influence the capacity of MLL-edited CD34+ hematopoietic cells to initiate and recapitulate infant patients' features in pro-B-cell acute lymphoblastic leukemia (B-ALL). We provide key insights into the leukemogenic determinants of MLL-AF4+ infant B-ALL.

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-ß are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.

Synthesis of Metal-Organic Cages via Orthogonal Bond Cleavage in 3D Metal-Organic Frameworks.

Herein we address the question of whether a supramolecular finite metal-organic structure such as a cage or metal-organic polyhedron (MOP) can be synthesized via controlled cleavage of a three-dimensional (3D) metal-organic structure. To demonstrate this, we report the synthesis of a Cu(II)-based cuboctahedral MOP through orthogonal olefinic bond cleavage of the cavities of a 3D, Cu(II)-based, metal-organic framework (MOF). Additionally, we demonstrate that controlling the ozonolysis conditions used for the cleavage enables Clip-off Chemistry synthesis of two cuboctahedral MOPs that differ by their external functionalization: one in which all 24 external groups represent a mixture of aldehydes, carboxylic acids, acetals and esters, and one in which all are aldehydes.

Isolation of the Secondary Building Unit of a 3D Metal-Organic Framework through Clip-Off Chemistry, and Its Reuse To Synthesize New Frameworks by Dynamic Covalent Chemistry.

Herein, we present a novel methodology for synthesizing metal clusters or secondary building units (SBUs) that are subsequently employed to construct innovative metal-organic frameworks (MOFs) via dynamic covalent chemistry. Our approach entails extraction of SBUs from preformed MOFs through complete disassembly by clip-off chemistry. The initial MOF precursor is designed to incorporate the desired SBU, connected exclusively by cleavable linkers (in this study, with olefinic bonds). Cleavage of all the organic linkers (in this study, via ozonolysis under reductive conditions) liberates the SBUs functionalized with aldehyde groups. Once synthesized, these SBUs can be further reacted with amines in dynamic covalent chemistry to build new, rationally designed MOFs.

Role of Skewed X-Chromosome Inactivation in Common Variable Immunodeficiency.

The term common variable immunodeficiency (CVID) encompasses a clinically diverse group of disorders, mainly characterized by hypogammaglobulinemia, insufficient specific antibody production, and recurrent infections. The genetics of CVID is complex, and monogenic defects account for only a portion of cases, typically <30%. Other proposed mechanisms include digenic, oligogenic, or polygenic inheritance and epigenetic dysregulation. In this study, we aimed to assess the role of skewed X-chromosome inactivation (XCI) in CVID. Within our cohort of 131 genetically analyzed CVID patients, we selected female patients with rare variants in CVID-associated genes located on the X-chromosome. Four patients harboring heterozygous variants in BTK (n = 2), CD40LG (n = 1), and IKBKG (n = 1) were included in the study. We assessed XCI status using the HUMARA assay and an NGS-based method to quantify the expression of the 2 alleles in mRNA. Three of the 4 patients (75%) exhibited skewed XCI, and the mutated allele was predominantly expressed in all cases. Patient 1 harbored a hypomorphic variant in BTK (p.Tyr418His), patient 3 had a pathogenic variant in CD40LG (c.288+1G>A), and patient 4 had a hypomorphic variant in IKBKG (p.Glu57Lys) and a heterozygous splice variant in TNFRSF13B (TACI) (c.61+2T>A). Overall, the analysis of our cohort suggests that CVID in a small proportion of females (1.6% in our cohort) is caused by skewed XCI and highly penetrant gene variants on the X-chromosome. Additionally, skewed XCI may contribute to polygenic effects (3.3% in our cohort). These results indicate that skewed XCI may represent another piece in the complex puzzle of CVID genetics.

Development, validation, and prognostic evaluation of a risk score for long-term liver-related outcomes in the general population: a multicohort study.

BACKGROUND: Liver cirrhosis is a major cause of death worldwide. Cirrhosis develops after a long asymptomatic period of fibrosis progression, with the diagnosis frequently occurring late, when major complications or cancer develop. Few reliable tools exist for timely identification of individuals at risk of cirrhosis to allow for early intervention. We aimed to develop a novel score to identify individuals at risk for future liver-related outcomes. METHODS: We derived the LiverRisk score from an international prospective cohort of individuals from six countries without known liver disease from the general population, who underwent liver fibrosis assessment by transient elastography. The score included age, sex, and six standard laboratory variables. We created four groups: minimal risk, low risk, medium risk, and high risk according to selected cutoff values of the LiverRisk score (6, 10, and 15). The model's discriminatory accuracy and calibration were externally validated in two prospective cohorts from the general population. Moreover, we ascertained the prognostic value of the score in the prediction of liver-related outcomes in participants without known liver disease with median follow-up of 12 years (UK Biobank cohort). FINDINGS: We included 14 726 participants: 6357 (43·2%) in the derivation cohort, 4370 (29·7%) in the first external validation cohort, and 3999 (27·2%) in the second external validation cohort. The score accurately predicted liver stiffness in the development and external validation cohorts, and was superior to conventional serum biomarkers of fibrosis, as measured by area under the receiver-operating characteristics curve (AUC; 0·83 [95% CI [0·78-0·89]) versus the fibrosis-4 index (FIB-4; 0·68 [0·61-0·75] at 10 kPa). The score was effective in identifying individuals at risk of liver-related mortality, liver-related hospitalisation, and liver cancer, thereby allowing stratification to different risk groups for liver-related outcomes. The hazard ratio for liver-related mortality in the high-risk group was 471 (95% CI 347-641) compared with the minimal risk group, and the overall AUC of the score in predicting 10-year liver-related mortality was 0·90 (0·88-0·91) versus 0.84 (0·82-0·86) for FIB-4. INTERPRETATION: The LiverRisk score, based on simple parameters, predicted liver fibrosis and future development of liver-related outcomes in the general population. The score might allow for stratification of individuals according to liver risk and thus guide preventive care. FUNDING: European Commission under the H20/20 programme; Fondo de Investigación Sanitaria de Salud; Instituto de Salud Carlos III; Spanish Ministry of Economy, Industry, and Competitiveness; the European Regional Development Fund; and the German Ministry of Education and Research (BMBF).

Exploring predictors of dysphagia in survivors of head and neck cancer: A cross-sectional study.

PURPOSE: To evaluate the prevalence of dysphagia in survivors of head and neck cancer (sHNC) and to identify the predictors contributing to the development of dysphagia. METHODS: We enrolled 62 sHNC in a cross-sectional study to check the prevalence of dysphagia in sHNC and to evaluate which factors were influencing the presence of this side effect. Besides dysphagia, sociodemographic and clinical characteristics, oral symptoms, maximal mouth opening (MMO), sleep quality and physical condition were evaluated, and a linear regression analysis was performed to verify which of these outcomes impact dysphagia. RESULTS: Among all the sHNC, 85.5% presented dysphagia. The linear regression analysis confirmed that 44.9% of the variance in dysphagia was determined by coughing, MMO and sleep quality, being MMO the most powerful predictor, followed by coughing and sleep quality. CONCLUSION: Dysphagia affected the great majority of sHNC. Moreover, symptoms as coughing, reduced MMO and sleep disorders may act as predictors contributing to the development of dysphagia. Our results emphasize the importance of an early and proper identification of the symptoms as well as an adequate treatment strategy to address the cluster of symptoms that sHNC undergo.

Skin cancer prevention in extreme sports: Intervention in a 24-h race.

INTRODUCTION: Excessive sun exposure and sunburns are the main preventable causes of skin cancer. The growing popularity of outdoor sports in developed countries has motivated the objective of this work to study the risk of photoexposure and the skin cancer prevention needs of athletes in an extreme race and evaluate an intervention targeted at this population. METHODS: An observational study was conducted during the XXIII edition of the 101 km de Ronda race, which consisted of trail running and mountain biking categories. Environmental and personal dosimetry, monitoring of meteorological conditions, evaluation of the athletes' photoprotection and skin examination habits, a dermatological checkup, and a satisfaction questionnaire were performed. RESULTS: The ultra-endurance race was carried out under adverse conditions (maximum ultraviolet index (UVI) = 9.2, temperatures above 30°C, and relative humidity >35%). The mean effective erythema dose received by race athletes (n = 11) was 2959.2 ± 404.2 J/m2 , equivalent to 29.6 standard erythema doses (SED). The CHACES questionnaire (n = 1145) showed a sunburn rate of 58% and poor protective habits: 62.9% of athletes do not usually use sunscreen and 67.2% do not self-examine their skin. Actinic keratoses (4.7%) and suspicious skin cancer lesions (4.2%) were found in dermatologic screening exams (n = 170). On the satisfaction questionnaire (n = 111), this intervention was rated as excellent (95.5%). CONCLUSION: This research highlights the extreme risk of photoexposure that athletes are subjected to during ultra-endurance competitions. In the same way, it shows the need to carry out interventions aimed at the acquisition of healthy photoprotection habits and skin surveillance in this target group.

Sex and Equipment Impact on Lifting Velocity and the Maximum Repetitions in Bench Press.

This study investigated how equipment and sex affect the prediction accuracy of the maximum number of repetitions performed to failure (RTF) using the fastest mean velocity of the set (MVfastest). Sixteen men and twelve women completed four sessions (two using free-weight equipment and two sessions using the Smith machine). Each session involved three sets of repetitions to failure against the 65%, 75%, and 85% of the one-repetition maximum, interspersed by 10-min of rest. The goodness-of-fit of the individualized RTF-MVfastest relationships was comparable between both equipment types and sexes (P≥0.510). Moreover, there were not significant differences in the MVfastest associated with RTF between equipment types (P≥0.258). However, the MVfastest associated with RTF was higher for men than for women in repetitions 6 to 15 (P≤0.043; ES≥0.69). In addition, the absolute errors when predicting RTF showed no significant differences between equipment types and loads (P<0.444). Specifically, these RTF estimates were within an acceptable range for men (<2 repetitions), but not for women (≥2 repetitions) (main effect of sex: P≤0.018; ES≥0.58). These findings suggest that individualized RTF-MVfastest equations estimate the RTF with an acceptable precision in men during bench press exercises in both equipment types but exhibit lower precision for women.

High Amplitude Spike Generator in Au Nanodot-Incorporated NbOx Mott Memristor.

NbOx-based Mott memristors exhibit fast threshold switching behaviors, making them suitable for spike generators in neuromorphic computing and stochastic clock generators in security devices. In these applications, a high output spike amplitude is necessary for threshold level control and accurate signal detection. Here, we propose a materialwise solution to obtain the high amplitude spikes by inserting Au nanodots into the NbOx device. The Au nanodots enable increasing the threshold voltage by modulating the oxygen contents at the electrode-oxide interface, providing a higher ON current compared to nanodot-free NbOx devices. Also, the reduction of the local switching region volume decreases the thermal capacitance of the system, allowing the maximum spike amplitude generation. Consequently, the Au nanodot incorporation increases the spike amplitude of the NbOx device by 6 times, without any additional external circuit elements. The results are systematically supported by both a numerical model and a finite-element-method-based multiphysics model.

Genetic Characterization of Extensively Drug-Resistant Shigella sonnei Infections, Spain, 2021-2022.

In 2022, the United Kingdom reported an increase in drug resistance in Shigella sonnei isolates. We report 33 cases in Spain genetically related to the UK cases and 4 cases with similar antimicrobial resistance profiles infected with genetically distant strains. Our results suggest circulation of multiple genetic clusters of multidrug-resistant S. sonnei in Spain.

Molecular Challenges in the Diagnosis of X-Linked Chronic Granulomatous Disease: CNVs, Intronic Variants, Skewed X-Chromosome Inactivation, and Gonosomal Mosaicism.

Chronic granulomatous disease (CGD) is a prototypical inborn error of immunity affecting phagocytes, in which these cells are unable to produce reactive oxygen species. CGD is caused by defects in genes encoding subunits of the NADPH oxidase enzyme complex (CYBA, CYBB, CYBC1, NCF1, NCF2, NCF4); inflammatory responses are dysregulated, and patients are highly susceptible to recurrent severe bacterial and fungal infections. X-linked CGD (XL-CGD), caused by mutations in the CYBB gene, is the most common and severe form of CGD. In this study, we describe the analytical processes undertaken in 3 families affected with XL-CGD to illustrate several molecular challenges in the genetic diagnosis of this condition: in family 1, a girl with a heterozygous deletion of CYBB exon 13 and skewed X-chromosome inactivation (XCI); in family 2, a boy with a hemizygous deletion of CYBB exon 7, defining its consequences at the mRNA level; and in family 3, 2 boys with the same novel intronic variant in CYBB (c.1151 + 6 T > A). The variant affected the splicing process, although a small fraction of wild-type mRNA was produced. Their mother was a heterozygous carrier, while their maternal grandmother was a carrier in form of gonosomal mosaicism. In summary, using a variety of techniques, including an NGS-based targeted gene panel and deep amplicon sequencing, copy number variation calling strategies, microarray-based comparative genomic hybridization, and cDNA analysis to define splicing defects and skewed XCI, we show how to face and solve some uncommon genetic mechanisms in the diagnosis of XL-CGD.

(Bio)Functionalisation of Metal-Organic Polyhedra by Using Click Chemistry.

The surface chemistry of Metal-Organic Polyhedra (MOPs) is crucial to their physicochemical properties because it governs how they interact with external substances such as solvents, synthetic organic molecules, metal ions, and even biomolecules. Consequently, the advancement of synthetic methods that facilitate the incorporation of diverse functional groups onto MOP surfaces will significantly broaden the range of properties and potential applications for MOPs. This study describes the use of copper(I)-catalysed, azide-alkyne cycloaddition (CuAAC) click reactions to post-synthetically modify the surface of alkyne-functionalised cuboctahedral MOPs. To this end, a novel Rh(II)-based MOP with 24 available surface alkyne groups was synthesised. Each of the 24 alkyne groups on the surface of the "clickable" Rh-MOP can react with azide-containing molecules at room temperature, without compromising the integrity of the MOP. The wide substrate catalogue and orthogonal nature of CuAAC click chemistry was exploited to densely functionalise MOPs with diverse functional groups, including polymers, carboxylic and phosphonic acids, and even biotin moieties, which retained their recognition capabilities once anchored onto the surface of the MOP.

Ultraviolet sun exposure and sun protection behaviors in outdoor rock climbers.

BACKGROUND: Overexposure to sunlight and sunburn are the main preventable causes of skin cancer. Outdoor sports are associated with significant levels of sunlight exposure. AIMS: We sought to quantify the sun radiation exposure received by outdoor rock climbers and assess their sun exposure habits, sun protection behaviors, attitudes, and knowledge regarding skin cancer. METHODS: From April to June 2021, outdoor rock climbers contacted via email completed an online validated self-reported questionnaire on sun related habits, behaviors, attitudes and knowledge. As a pilot trial, ten participants wore a personal dosimeter during two outdoor climbing weekends in May and November 2021. Ambient ultraviolet radiation (UVR) was also recorded. RESULTS: A total of 217 outdoor rock climbers (103 women), mean age 36.8 ± 8.8 years (range 20-70 years) and median climbing practice per week of 8 h (IQR 7.5) were studied. Two in three (65.9%) participants reported at least one sunburn event during the previous rock climbing season. Of the survey respondents, 49.3% reported using sunscreen with SPF ≥ 15, 47% wore sunglasses, and 14.3% indicated they reapplied sunscreen every two hours. The median personal UVR dose measured during the two outdoor climbing weekends analyzed was 5.2 (IQR 1.8) and 8.8 (IQR 1.1) standard erythemal doses, respectively. CONCLUSIONS: The high rates of sunburn, the elevated personal UVR measured and the clearly insufficient sun protection practices followed during rock climbing together with unsatisfactory attitudes towards tanning reveal the need to develop explicit sun protection campaigns and educational strategies to reduce the risk of skin cancer among the athletes studied.

Risk assessment of occupational skin cancer among outdoor workers in southern Spain: local pilot study.

OBJECTIVE: Overexposure to ultraviolet (UV) radiation is the main preventable cause of skin cancer. Outdoor workers, exposed to the sun for many hours throughout their working lives, are at special risk. The aim of this study is to determine occupational photoexposure and photoprotection among outdoor workers employed by a municipality in southern Spain. METHODS: Cross-sectional descriptive study focusing on outdoor workers employed by the municipality of Fuengirola (in areas such as construction, gardening, urban cleaning and beach maintenance). The participants were monitored by personal dosimetry, participated in a dermatological check-up and answered a validated questionnaire (CHACES) on their habits, attitudes and knowledge related to sun exposure. RESULTS: The median effective erythema dose of exposure to solar UV radiation during the working day (n=20) was 379.4 J/m2, equivalent to 3.8 standard erythema doses, almost 3 times higher than the recommended limits for an 8-hour workday. Skin examination (n=128) revealed the presence of actinic lentigines (79.7%), actinic keratoses (8.6%) and skin cancer (3.9%). The CHACES questionnaire (n=128) revealed a sunburn rate of 50.0%. Photoprotection practices were markedly deficient: only 16.7% of the survey respondents sought protection in the shade, 20.3% avoided exposure during the peak exposure hours and 33.1% applied sunscreen. CONCLUSIONS: This is the first study to evaluate UV radiation exposure, occupational sun protection practices, sunburn and actinic injuries of different outdoor workers in one of the sunniest regions of Spain and underlines the need for effective interventions to protect outdoor workers' health.