Mountains of our future Earth: Defining priorities for mountain research

The Perth conferences, held every 5 years in Perth, Scotland, bring together people who identify as mountain researchers and who are interested in issues related to global change in mountain social-ecological systems. These conferences provide an opportunity to evaluate the evolution of research directions within the mountain research community, as well as to identify research priorities. The Future Earth Strategic Research Agenda provides a useful framework for evaluating the mountain research community\u27s progress toward addressing global change and sustainability challenges. Using a process originally set up to analyze contributions to the 2010 conference, the abstracts accepted for the 2015 conference in the context of the Future Earth framework were analyzed. This revealed a continued geographic underrepresentation in mountain research of Africa, Latin America, and South and Southeast Asia but a more even treatment of biophysical and social science themes than in 2010. It also showed that the Perth conference research community strongly focused on understanding system processes (the Dynamic Planet theme of the Future Earth research agenda). Despite the continued bias of conference contributions toward traditional observation- and conservation-oriented research, survey results indicate that conference participants clearly believe that transdisciplinary, transformative research is relevant to mountains. Of the 8 Future Earth focal challenges, those related to safeguarding natural assets, promoting sustainable land use, increasing resilience and understanding the water-energy-food nexus received considerable attention. The challenges related to sustainable consumption, decarbonizing socioeconomic systems, cities, and health were considerably less well represented, despite their relevance to mountain socioeconomic systems. Based on these findings, we outline a proposal for the future directions of mountain research

SARS-CoV-2-specific immune responses and clinical outcomes after COVID-19 vaccination in patients with immune-suppressive disease

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune responses and infection outcomes were evaluated in 2,686 patients with varying immune-suppressive disease states after administration of two Coronavirus Disease 2019 (COVID-19) vaccines. Overall, 255 of 2,204 (12%) patients failed to develop anti-spike antibodies, with an additional 600 of 2,204 (27%) patients generating low levels (<380 AU ml−1). Vaccine failure rates were highest in ANCA-associated vasculitis on rituximab (21/29, 72%), hemodialysis on immunosuppressive therapy (6/30, 20%) and solid organ transplant recipients (20/81, 25% and 141/458, 31%). SARS-CoV-2-specific T cell responses were detected in 513 of 580 (88%) patients, with lower T cell magnitude or proportion in hemodialysis, allogeneic hematopoietic stem cell transplantation and liver transplant recipients (versus healthy controls). Humoral responses against Omicron (BA.1) were reduced, although cross-reactive T cell responses were sustained in all participants for whom these data were available. BNT162b2 was associated with higher antibody but lower cellular responses compared to ChAdOx1 nCoV-19 vaccination. We report 474 SARS-CoV-2 infection episodes, including 48 individuals with hospitalization or death from COVID-19. Decreased magnitude of both the serological and the T cell response was associated with severe COVID-19. Overall, we identified clinical phenotypes that may benefit from targeted COVID-19 therapeutic strategies

Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)—present in some but not all cells—remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk

Mountains of Our Future Earth: Defining Priorities for Mountain Research: A Synthesis From the 2015 Perth III Conference

The Perth conferences, held every 5 years in Perth, Scotland, bring together people who identify as mountain researchers and who are interested in issues related to global change in mountain social-ecological systems. These conferences provide an opportunity to evaluate the evolution of research directions within the mountain research community, as well as to identify research priorities. The Future Earth Strategic Research Agenda provides a useful framework for evaluating the mountain research community's progress toward addressing global change and sustainability challenges. Using a process originally set up to analyze contributions to the 2010 conference, the abstracts accepted for the 2015 conference in the context of the Future Earth framework were analyzed. This revealed a continued geographic underrepresentation in mountain research of Africa, Latin America, and South and Southeast Asia but a more even treatment of biophysical and social science themes than in 2010. It also showed that the Perth conference research community strongly focused on understanding system processes (the Dynamic Planet theme of the Future Earth research agenda). Despite the continued bias of conference contributions toward traditional observation- and conservation-oriented research, survey results indicate that conference participants clearly believe that transdisciplinary, transformative research is relevant to mountains. Of the 8 Future Earth focal challenges, those related to safeguarding natural assets, promoting sustainable land use, increasing resilience and understanding the water-energy-food nexus received considerable attention. The challenges related to sustainable consumption, decarbonizing socioeconomic systems, cities, and health were considerably less well represented, despite their relevance to mountain socioeconomic systems. Based on these findings, we outline a proposal for the future directions of mountain research

Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia

Abstract Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0–49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2–5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1–46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an ‘AP-4 deficiency syndrome’. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.</jats:p