Evolution of immune genes is associated with the Black Death.

Infectious diseases are among the strongest selective pressures driving human evolution1,2. This includes the single greatest mortality event in recorded history, the first outbreak of the second pandemic of plague, commonly called the Black Death, which was caused by the bacterium Yersinia pestis3. This pandemic devastated Afro-Eurasia, killing up to 30-50% of the population4. To identify loci that may have been under selection during the Black Death, we characterized genetic variation around immune-related genes from 206 ancient DNA extracts, stemming from two different European populations before, during and after the Black Death. Immune loci are strongly enriched for highly differentiated sites relative to a set of non-immune loci, suggesting positive selection. We identify 245 variants that are highly differentiated within the London dataset, four of which were replicated in an independent cohort from Denmark, and represent the strongest candidates for positive selection. The selected allele for one of these variants, rs2549794, is associated with the production of a full-length (versus truncated) ERAP2 transcript, variation in cytokine response to Y. pestis and increased ability to control intracellular Y. pestis in macrophages. Finally, we show that protective variants overlap with alleles that are today associated with increased susceptibility to autoimmune diseases, providing empirical evidence for the role played by past pandemics in shaping present-day susceptibility to disease.

OPA1 mutation affects autophagy and triggers senescence in autosomal dominant optic atrophy plus fibroblasts.

In several cases of mitochondrial diseases, the underlying genetic and bioenergetic causes of reduced oxidative phosphorylation (OxPhos) in mitochondrial dysfunction are well understood. However, there is still limited knowledge about the specific cellular outcomes and factors involved for each gene and mutation, which contributes to the lack of effective treatments for these disorders. This study focused on fibroblasts from a patient with Autosomal Dominant Optic Atrophy (ADOA) plus syndrome harboring a mutation in the Optic Atrophy 1 (OPA1) gene. By combining functional and transcriptomic approaches, we investigated the mitochondrial function and identified cellular phenotypes associated with the disease. Our findings revealed that fibroblasts with the OPA1 mutation exhibited a disrupted mitochondrial network and function, leading to altered mitochondrial dynamics and reduced autophagic response. Additionally, we observed a premature senescence phenotype in these cells, suggesting a previously unexplored role of the OPA1 gene in inducing senescence in ADOA plus patients. This study provides novel insights into the mechanisms underlying mitochondrial dysfunction in ADOA plus and highlights the potential importance of senescence in disease progression.

Frailty and survival in the 1918 influenza pandemic.

One of the most well-known yet least understood aspects of the 1918 influenza pandemic is the disproportionately high mortality among young adults. Contemporary accounts further describe the victims as healthy young adults, which is contrary to the understanding of selective mortality, which posits that individuals with the highest frailty within a group are at the greatest risk of death. We use a bioarchaeological approach, combining individual-level information on health and stress gleaned from the skeletal remains of individuals who died in 1918 to determine whether healthy individuals were dying during the 1918 pandemic or whether underlying frailty contributed to an increased risk of mortality. Skeletal data on tibial periosteal new bone formation were obtained from 369 individuals from the Hamann-Todd documented osteological collection in Cleveland, Ohio. Skeletal data were analyzed alongside known age at death using Kaplan-Meier survival and Cox proportional hazards analysis. The results suggest that frail or unhealthy individuals were more likely to die during the pandemic than those who were not frail. During the flu, the estimated hazards for individuals with periosteal lesions that were active at the time of death were over two times higher compared to the control group. The results contradict prior assumptions about selective mortality during the 1918 influenza pandemic. Even among young adults, not everyone was equally likely to die-those with evidence of systemic stress suffered greater mortality. These findings provide time depth to our understanding of how variation in life experiences can impact morbidity and mortality even during a pandemic caused by a novel pathogen.

Ancient pathogens provide a window into health and well-being.

This perspective draws on the record of ancient pathogen genomes and microbiomes illuminating patterns of infectious disease over the course of the Holocene in order to address the following question. How did major changes in living circumstances involving the transition to and intensification of farming alter pathogens and their distributions? Answers to this question via ancient DNA research provide a rapidly expanding picture of pathogen evolution and in concert with archaeological and historical data, give a temporal and behavioral context for heath in the past that is relevant for challenges facing the world today, including the rise of novel pathogens.

Climate change, human health, and resilience in the Holocene.

Climate change is an indisputable threat to human health, especially for societies already confronted with rising social inequality, political and economic uncertainty, and a cascade of concurrent environmental challenges. Archaeological data about past climate and environment provide an important source of evidence about the potential challenges humans face and the long-term outcomes of alternative short-term adaptive strategies. Evidence from well-dated archaeological human skeletons and mummified remains speaks directly to patterns of human health over time through changing circumstances. Here, we describe variation in human epidemiological patterns in the context of past rapid climate change (RCC) events and other periods of past environmental change. Case studies confirm that human communities responded to environmental changes in diverse ways depending on historical, sociocultural, and biological contingencies. Certain factors, such as social inequality and disproportionate access to resources in large, complex societies may influence the probability of major sociopolitical disruptions and reorganizations-commonly known as "collapse." This survey of Holocene human-environmental relations demonstrates how flexibility, variation, and maintenance of Indigenous knowledge can be mitigating factors in the face of environmental challenges. Although contemporary climate change is more rapid and of greater magnitude than the RCC events and other environmental changes we discuss here, these lessons from the past provide clarity about potential priorities for equitable, sustainable development and the constraints of modernity we must address.

Mitofusin 2 mutation drives cell proliferation in Charcot-Marie-Tooth 2A fibroblasts.

Dominant mutations in ubiquitously expressed mitofusin 2 gene (MFN2) cause Charcot-Marie-Tooth type 2A (CMT2A; OMIM 609260), an inherited sensory-motor neuropathy that affects peripheral nerve axons. Mitofusin 2 protein has been found to take part in mitochondrial fusion, mitochondria-endoplasmic reticulum tethering, mitochondrial trafficking along axons, mitochondrial quality control and various types of cancer, in which MFN2 has been indicated as a tumor suppressor gene. Discordant data on the mitochondrial altered phenotypes in patient-derived fibroblasts harboring MFN2 mutations and in animal models have been reported. We addressed some of these issues by focusing on mitochondria behavior during autophagy and mitophagy in fibroblasts derived from a CMT2AMFN2 patient with an MFN2650G > T/C217F mutation in the GTPase domain. This study investigated mitochondrial dynamics, respiratory capacity and autophagy/mitophagy, to tackle the multifaceted MFN2 contribution to CMT2A pathogenesis. We found that MFN2 mutated fibroblasts showed impairment of mitochondrial morphology, bioenergetics capacity, and impairment of the early stages of autophagy, but not mitophagy. Unexpectedly, transcriptomic analysis of mutated fibroblasts highlighted marked differentially expressed pathways related to cell population proliferation and extracellular matrix organization. We consistently found the activation of mTORC2/AKT signaling and accelerated proliferation in the CMT2AMFN2 fibroblasts. In conclusion, our evidence indicates that MFN2 mutation can positively drive cell proliferation in CMT2AMFN2 fibroblasts.

Medieval monastic health: Variation in skeletal signs of inflammation and developmental stress between religious orders in London.

OBJECTIVES: Previous bioarchaeological analyses of medieval monastic and nonmonastic cemeteries in London revealed evidence of lower risks of mortality, and thus better health, in the monastic settings. However, comparison of the two monastic communities, Bermondsey Abbey and Merton Priory, which adhered to different religious ideals, suggested lower risks of mortality in the former. This study examines patterns of skeletal biomarkers, which reflect developmental stress or inflammation, in an attempt to clarify the possible underlying mechanisms producing apparent health differences in these monastic communities. MATERIALS AND METHODS: This study uses skeletal data on age-at-death, periosteal new bone formation (PNBF), and cribra orbitalia from 558 adults (18 years of age and older) estimated to be male from Bermondsey Abbey and Merton Priory. Biomarker age patterns are assessed via Kaplan-Meier survival analysis and binary logistic regression. Differences in frequencies of biomarkers between the monastic sites are evaluated using Chi-square and hierarchical log-linear analyses. RESULTS: In general, PNBF is positively associated with age, and cribra orbitalia is negatively associated with age. The frequency of PNBF formation is significantly higher and that of cribra orbitalia is significantly lower in Bermondsey Abbey compared with Merton Priory. CONCLUSIONS: The differences in frequencies of these skeletal biomarkers support previous findings suggesting that health conditions were better in Bermondsey Abbey than in Merton Priory. The age patterns of cribra orbitalia suggest that these differences reflect conditions and the greater health-promoting effects of religiosity or isolation from the lay community in Bermondsey Abbey rather than differences in selective admissions processes.

The challenges and lessons from a formative process and value-based evaluation of the wave 1 roll-out of the all Wales Diabetes Prevention Programme.

BACKGROUND: The All Wales Diabetes Prevention Programme (AWDPP) is a Wales wide, public health initiative designed to systematically identify adults at risk of developing type 2 diabetes and offer a 30-minute person-centred lifestyle conversation focused on diet and physical activity. An independent formative process and value-based evaluation was commissioned to examine the implementation of this programme in 14 primary care cluster areas across Wales during the initial roll-out. METHODS: This evaluation was undertaken to ascertain the views on early implementation of the programme from service users, health care professionals and key stakeholders. The evaluation was informed by the Medical Research Council Framework for Process Evaluation and Wales Prudent Healthcare principles. As part of the value-based assessment, a preliminary cost-consequence analysis was conducted to understand the short-term economic impact of the implementation of the programme. RESULTS: Service users who took part in the evaluation highly valued the programme and nearly half had been previously unaware that they were at risk of developing type 2 diabetes. Delivering the programme presented challenges but there was significant enthusiasm and support from all stakeholders. Overall, the programme was being delivered as intended albeit with evidence of some variation in the application of the programme eligibility criteria. CONCLUSIONS: In Wave 1 of the AWDPP roll-out, the intent to deliver the programme in line with Prudent Healthcare was successful and promising in terms of demonstrating value. Opinions expressed by service users suggest the AWDPP matters to them; raising awareness, promoting knowledge and capacity to change behaviours and motivate and raise confidence.

Lumbopelvic fixation in the treatment of spinopelvic dissociation: union, complications, and neurologic outcomes of a multicenter case series.

PURPOSE: To review outcomes of spinopelvic dissociation treated with open lumbopelvic fixation. METHODS: We reviewed all cases of spinopelvic dissociation treated at three Level-I trauma centers with open lumbopelvic fixation, including those with adjunctive percutaneous fixation. We collected demographic data, associated injuries, pre- and postoperative neurologic status, pre- and postoperative kyphosis, and Roy-Camille classification. Outcomes included presence of union, reoperation rates, and complications involving hardware or wound. RESULTS: From an initial cohort of 260 patients with spinopelvic dissociation, forty patients fulfilled inclusion criteria with a median follow-up of 351 days. Ten patients (25%) had a combination of percutaneous iliosacral and open lumbopelvic repair. Average pre- and postoperative kyphosis was 30 degrees and 26 degrees, respectively. Twenty patients (50%) had neurologic deficit preoperatively, and eight (20%) were unknown or unable to be assessed. All patients presenting with bowel or bladder dysfunction (n = 12) underwent laminectomy at time of surgery, with 3 patients (25%) having continued dysfunction at final follow-up. Surgical site infection occurred in four cases (10%) and wound complications in two (5%). All cases (100%) went on to union and five patients (13%) required hardware removal. CONCLUSION: Open lumbopelvic fixation resulted in a high union rate in the treatment of spinopelvic dissociation. Approximately 1 in 6 patients had a wound complication, the majority of which were surgical site infections. Bowel and bladder dysfunction at presentation were common with the majority of cases resolving by final follow-up when spinopelvic dissociation had been treated with decompression and stable fixation.

Replication Protein A Enhances Kinetics of Uracil DNA Glycosylase on ssDNA and Across DNA Junctions: Explored with a DNA Repair Complex Produced with SpyCatcher/SpyTag Ligation.

DNA repair proteins participate in extensive protein-protein interactions that promote the formation of DNA repair complexes. To understand how complex formation affects protein function during base excision repair, we used SpyCatcher/SpyTag ligation to produce a covalent complex between human uracil DNA glycosylase (UNG2) and replication protein A (RPA). Our covalent "RPA-Spy-UNG2" complex could identify and excise uracil bases in duplex areas next to ssDNA-dsDNA junctions slightly faster than the wild-type proteins, but this was highly dependent on DNA structure, as the turnover of the RPA-Spy-UNG2 complex slowed at DNA junctions where RPA tightly engaged long ssDNA sections. Conversely, the enzymes preferred uracil sites in ssDNA where RPA strongly enhanced uracil excision by UNG2 regardless of ssDNA length. Finally, RPA was found to promote UNG2 excision of two uracil sites positioned across a ssDNA-dsDNA junction, and dissociation of UNG2 from RPA enhanced this process. Our approach of ligating together RPA and UNG2 to reveal how complex formation affects enzyme function could be applied to examine other assemblies of DNA repair proteins.