Novel integrative elements and genomic plasticity in ocean ecosystems.

Horizontal gene transfer accelerates microbial evolution. The marine picocyanobacterium Prochlorococcus exhibits high genomic plasticity, yet the underlying mechanisms are elusive. Here, we report a novel family of DNA transposons-"tycheposons"-some of which are viral satellites while others carry cargo, such as nutrient-acquisition genes, which shape the genetic variability in this globally abundant genus. Tycheposons share distinctive mobile-lifecycle-linked hallmark genes, including a deep-branching site-specific tyrosine recombinase. Their excision and integration at tRNA genes appear to drive the remodeling of genomic islands-key reservoirs for flexible genes in bacteria. In a selection experiment, tycheposons harboring a nitrate assimilation cassette were dynamically gained and lost, thereby promoting chromosomal rearrangements and host adaptation. Vesicles and phage particles harvested from seawater are enriched in tycheposons, providing a means for their dispersal in the wild. Similar elements are found in microbes co-occurring with Prochlorococcus, suggesting a common mechanism for microbial diversification in the vast oligotrophic oceans.

The brain microvasculature is a primary mediator of interferon-α neurotoxicity in human cerebral interferonopathies.

Aicardi-Goutières syndrome (AGS) is an autoinflammatory disease characterized by aberrant interferon (IFN)-α production. The major cause of morbidity in AGS is brain disease, yet the primary source and target of neurotoxic IFN-α remain unclear. Here, we demonstrated that the brain was the primary source of neurotoxic IFN-α in AGS and confirmed the neurotoxicity of intracerebral IFN-α using astrocyte-driven Ifna1 misexpression in mice. Using single-cell RNA sequencing, we demonstrated that intracerebral IFN-α-activated receptor (IFNAR) signaling within cerebral endothelial cells caused a distinctive cerebral small vessel disease similar to that observed in individuals with AGS. Magnetic resonance imaging (MRI) and single-molecule ELISA revealed that central and not peripheral IFN-α was the primary determinant of microvascular disease in humans. Ablation of endothelial Ifnar1 in mice rescued microvascular disease, stopped the development of diffuse brain disease, and prolonged lifespan. These results identify the cerebral microvasculature as a primary mediator of IFN-α neurotoxicity in AGS, representing an accessible target for therapeutic intervention.

Genome sequencing and analysis of the Tasmanian devil and its transmissible cancer.

The Tasmanian devil (Sarcophilus harrisii), the largest marsupial carnivore, is endangered due to a transmissible facial cancer spread by direct transfer of living cancer cells through biting. Here we describe the sequencing, assembly, and annotation of the Tasmanian devil genome and whole-genome sequences for two geographically distant subclones of the cancer. Genomic analysis suggests that the cancer first arose from a female Tasmanian devil and that the clone has subsequently genetically diverged during its spread across Tasmania. The devil cancer genome contains more than 17,000 somatic base substitution mutations and bears the imprint of a distinct mutational process. Genotyping of somatic mutations in 104 geographically and temporally distributed Tasmanian devil tumors reveals the pattern of evolution and spread of this parasitic clonal lineage, with evidence of a selective sweep in one geographical area and persistence of parallel lineages in other populations.

Modeling and design of heterogeneous hierarchical bioinspired spider web structures using deep learning and additive manufacturing.

Spider webs are incredible biological structures, comprising thin but strong silk filament and arranged into complex hierarchical architectures with striking mechanical properties (e.g., lightweight but high strength, achieving diverse mechanical responses). While simple 2D orb webs can easily be mimicked, the modeling and synthesis of 3D-based web structures remain challenging, partly due to the rich set of design features. Here, we provide a detailed analysis of the heterogeneous graph structures of spider webs and use deep learning as a way to model and then synthesize artificial, bioinspired 3D web structures. The generative models are conditioned based on key geometric parameters (including average edge length, number of nodes, average node degree, and others). To identify graph construction principles, we use inductive representation sampling of large experimentally determined spider web graphs, to yield a dataset that is used to train three conditional generative models: 1) an analog diffusion model inspired by nonequilibrium thermodynamics, with sparse neighbor representation; 2) a discrete diffusion model with full neighbor representation; and 3) an autoregressive transformer architecture with full neighbor representation. All three models are scalable, produce complex, de novo bioinspired spider web mimics, and successfully construct graphs that meet the design objectives. We further propose an algorithm that assembles web samples produced by the generative models into larger-scale structures based on a series of geometric design targets, including helical and parametric shapes, mimicking, and extending natural design principles toward integration with diverging engineering objectives. Several webs are manufactured using 3D printing and tested to assess mechanical properties.

Molecular understanding of Ni2+-nitrogen family metal-coordinated hydrogel relaxation times using free energy landscapes.

Incorporating dynamic metal-coordination bonds as cross-links into synthetic materials has become attractive not only to improve self-healing and toughness, but also due to the tunability of metal-coordination bonds. However, a priori determination of bond lifetime of metal-coordination complexes, especially important in the rational design of metal-coordinated materials with prescribed properties, is missing. We report an empirical relationship between the energy landscape of metal-coordination bonds, simulated via metadynamics, and the resulting macroscopic relaxation time in ideal metal-coordinated hydrogels. Importantly, we expand the Arrhenius relationship between the macroscopic hydrogel relaxation time and metal-coordinate bond activation energy to include width and landscape ruggedness identified in the simulated energy landscapes. Using biologically relevant Ni2+-nitrogen coordination complexes as a model case, we demonstrate that the quantitative relationship developed from histidine-Ni2+ and imidazole-Ni2+ complexes can predict the average relaxation times of other Ni2+-nitrogen coordinated networks. We anticipate the quantitative relationship presented here to be a starting point for the development of more sophisticated models that can predict relaxation timescales of materials with programmable viscoelastic properties.

Computational Design and Manufacturing of Sustainable Materials through First-Principles and Materiomics.

Engineered materials are ubiquitous throughout society and are critical to the development of modern technology, yet many current material systems are inexorably tied to widespread deterioration of ecological processes. Next-generation material systems can address goals of environmental sustainability by providing alternatives to fossil fuel-based materials and by reducing destructive extraction processes, energy costs, and accumulation of solid waste. However, development of sustainable materials faces several key challenges including investigation, processing, and architecting of new feedstocks that are often relatively mechanically weak, complex, and difficult to characterize or standardize. In this review paper, we outline a framework for examining sustainability in material systems and discuss how recent developments in modeling, machine learning, and other computational tools can aid the discovery of novel sustainable materials. We consider these through the lens of materiomics, an approach that considers material systems holistically by incorporating perspectives of all relevant scales, beginning with first-principles approaches and extending through the macroscale to consider sustainable material design from the bottom-up. We follow with an examination of how computational methods are currently applied to select examples of sustainable material development, with particular emphasis on bioinspired and biobased materials, and conclude with perspectives on opportunities and open challenges.

Discovering design principles of collagen molecular stability using a genetic algorithm, deep learning, and experimental validation.

Collagen is the most abundant structural protein in humans, providing crucial mechanical properties, including high strength and toughness, in tissues. Collagen-based biomaterials are, therefore, used for tissue repair and regeneration. Utilizing collagen effectively during materials processing ex vivo and subsequent function in vivo requires stability over wide temperature ranges to avoid denaturation and loss of structure, measured as melting temperature (Tm). Although significant research has been conducted on understanding how collagen primary amino acid sequences correspond to Tm values, a robust framework to facilitate the design of collagen sequences with specific Tm remains a challenge. Here, we develop a general model using a genetic algorithm within a deep learning framework to design collagen sequences with specific Tm values. We report 1,000 de novo collagen sequences, and we show that we can efficiently use this model to generate collagen sequences and verify their Tm values using both experimental and computational methods. We find that the model accurately predicts Tm values within a few degrees centigrade. Further, using this model, we conduct a high-throughput study to identify the most frequently occurring collagen triplets that can be directly incorporated into collagen. We further discovered that the number of hydrogen bonds within collagen calculated with molecular dynamics (MD) is directly correlated to the experimental measurement of triple-helical quality. Ultimately, we see this work as a critical step to helping researchers develop collagen sequences with specific Tm values for intended materials manufacturing methods and biomedical applications, realizing a mechanistic materials by design paradigm.

Extra-pair paternity explains cooperation in a bird species.

In many social animals, females mate with multiple males, but the adaptive value of female extra-pair mating is not fully understood. Here, we tested whether male pied flycatchers (Ficedula hypoleuca) engaging in extra-pair copulations with neighboring females were more likely to assist their neighbors in antipredator defense. We found that extra-pair sires joined predator-mobbing more often, approached predators more closely, and attacked predators more aggressively than males without extra-pair offspring in the neighboring nest. Extra-pair mating may incentivize males to assist in nest defense because of the benefits that this cooperative behavior has on their total offspring production. For females, this mating strategy may help recruit more males to join in antipredator defense, offering better protection and ultimately improving reproductive success. Our results suggest a simple mechanism by which extra-pair mating can improve reproductive success in breeding birds. In summary, males siring extra-pair offspring in neighboring nests assist neighbors in antipredator defense more often than males without extra-pair offspring.

Long-term Elevation of Complement Factors in Cerebrospinal Fluid of Patients With Borna Disease Virus 1 Encephalitis.

BACKGROUND: Borna disease virus 1 (BoDV-1) causes rare but severe zoonotic infections in humans, presenting as encephalitis. The case-fatality risk is very high and no effective countermeasures have been established so far. An immunopathology is presumed, while data on immune responses in humans are limited. Evidence of a role of the complement system in various neurological disorders and in viral infections of the central nervous system is increasing and specific inhibitors are available as therapeutic options. METHODS: In this study, we investigated factors of the complement system in the cerebrospinal fluid (CSF) of patients with BoDV-1 infections (n = 17) in comparison to noninflammatory control CSF samples (n = 11), using a bead-based multiplex assay. In addition, immunohistochemistry was performed using postmortem brain tissue samples. RESULTS: We found an intrathecal elevation of complement factors of all complement pathways and an active cascade during human BoDV-1 infections. The increase of certain complement factors such as C1q was persistent, and C3 complement deposits were detected in postmortem brain sections. Intrathecal complement levels were negatively correlated with survival. CONCLUSIONS: Further investigations are warranted to clarify whether targeting the complement cascade by specific inhibitors might be beneficial for patients suffering from severe BoDV-1 encephalitis.

Irinotecan and temozolomide in combination with dasatinib and rapamycin versus irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma (RIST-rNB-2011): a multicentre, open-label, randomised, controlled, phase 2 trial.

BACKGROUND: Neuroblastoma is the most common extracranial solid tumour in children. Relapsed or refractory neuroblastoma is associated with a poor outcome. We assessed the combination of irinotecan-temozolomide and dasatinib-rapamycin (RIST) in patients with relapsed or refractory neuroblastoma. METHODS: The multicentre, open-label, randomised, controlled, phase 2, RIST-rNB-2011 trial recruited from 40 paediatric oncology centres in Germany and Austria. Patients aged 1-25 years with high-risk relapsed (defined as recurrence of all stage IV and MYCN amplification stages, after response to treatment) or refractory (progressive disease during primary treatment) neuroblastoma, with Lansky and Karnofsky performance status at least 50%, were assigned (1:1) to RIST (RIST group) or irinotecan-temozolomide (control group) by block randomisation, stratified by MYCN status. We compared RIST (oral rapamycin [loading 3 mg/m2 on day 1, maintenance 1 mg/m2 on days 2-4] and oral dasatinib [2 mg/kg per day] for 4 days with 3 days off, followed by intravenous irinotecan [50 mg/m2 per day] and oral temozolomide [150 mg/m2 per day] for 5 days with 2 days off; one course each of rapamycin-dasatinib and irinotecan-temozolomide for four cycles over 8 weeks, then two courses of rapamycin-dasatinib followed by one course of irinotecan-temozolomide for 12 weeks) with irinotecan-temozolomide alone (with identical dosing as experimental group). The primary endpoint of progression-free survival was analysed in all eligible patients who received at least one course of therapy. The safety population consisted of all patients who received at least one course of therapy and had at least one post-baseline safety assessment. This trial is registered at ClinicalTrials.gov, NCT01467986, and is closed to accrual. FINDINGS: Between Aug 26, 2013, and Sept 21, 2020, 129 patients were randomly assigned to the RIST group (n=63) or control group (n=66). Median age was 5·4 years (IQR 3·7-8·1). 124 patients (78 [63%] male and 46 [37%] female) were included in the efficacy analysis. At a median follow-up of 72 months (IQR 31-88), the median progression-free survival was 11 months (95% CI 7-17) in the RIST group and 5 months (2-8) in the control group (hazard ratio 0·62, one-sided 90% CI 0·81; p=0·019). Median progression-free survival in patients with amplified MYCN (n=48) was 6 months (95% CI 4-24) in the RIST group versus 2 months (2-5) in the control group (HR 0·45 [95% CI 0·24-0·84], p=0·012); median progression-free survival in patients without amplified MYCN (n=76) was 14 months (95% CI 9-7) in the RIST group versus 8 months (4-15) in the control group (HR 0·84 [95% CI 0·51-1·38], p=0·49). The most common grade 3 or worse adverse events were neutropenia (54 [81%] of 67 patients given RIST vs 49 [82%] of 60 patients given control), thrombocytopenia (45 [67%] vs 41 [68%]), and anaemia (39 [58%] vs 38 [63%]). Nine serious treatment-related adverse events were reported (five patients given control and four patients given RIST). There were no treatment-related deaths in the control group and one in the RIST group (multiorgan failure). INTERPRETATION: RIST-rNB-2011 demonstrated that targeting of MYCN-amplified relapsed or refractory neuroblastoma with a pathway-directed metronomic combination of a multkinase inhibitor and an mTOR inhibitor can improve progression-free survival and overall survival. This exclusive efficacy in MYCN-amplified, relapsed neuroblastoma warrants further investigation in the first-line setting. FUNDING: Deutsche Krebshilfe.

Atypical (non-V600E) BRAF mutations in metastatic colorectal cancer in population and real-world cohorts.

BRAF-V600E mutation (mt) is a strong negative prognostic and predictive biomarker in metastatic colorectal cancer (mCRC). Non-V600Emt, designated atypical BRAFmt (aBRAFmt) are rare, and little is known about their frequency, co-mutations and prognostic and predictive role. These were compared between mutational groups of mCRC patients collected from three Nordic population-based or real-world cohorts. Pathology of aBRAFmt was studied. The study included 1449 mCRC patients with 51 (3%) aBRAFmt, 182 (13%) BRAF-V600Emt, 456 (31%) RAS&BRAF wild-type (wt) and 760 (52%) RASmt tumours. aBRAFmt were seen in 2% of real-world and 4% of population-based cohorts. Twenty-six different aBRAFmt were detected, 11 (22%) class 2 (serrated adenocarcinoma in 2/9 tested), 32 (64%) class 3 (serrated in 15/25) and 4 (8%) unclassified. aBRAFmt patients were predominantly male, had more rectal primaries, less peritoneal metastases, deficient mismatch repair in one (2%), and better survival after metastasectomy (89% 5-year overall survival [OS]-rate) compared with BRAF-V600Emt. aBRAFmt and BRAF-V600Emt had poorer performance status and received fewer treatment lines than RAS&BRAFwt and RASmt. OS among aBRAFmt (median 14.4 months) was longer than for BRAF-V600Emt (11.2 months), but shorter than for RAS&BRAFwt (30.5 months) and RASmt (23.4 months). Addition of bevacizumab trended for better OS for the aBRAFmt. Nine patients with aBRAFmt received cetuximab/panitumumab without response. aBRAFmt represents a distinct subgroup differing from other RAS/BRAF groups, with serrated adenocarcinoma in only half. OS for patients with aBRAFmt tumours was slightly better than for BRAF-V600Emt, but worse than for RASmt and RAS&BRAFwt. aBRAFmt should not be a contraindication for metastasectomy.

The use of extracorporeal photopheresis in solid organ transplantation-current status and future directions.

Prevention and management of allograft rejection urgently require more effective therapeutic solutions. Current immunosuppressive therapies used in solid organ transplantation, while effective in reducing the risk of acute rejection, are associated with substantial adverse effects. There is, therefore, a need for agents that can provide immunomodulation, supporting graft tolerance, while minimizing the need for immunosuppression. Extracorporeal photopheresis (ECP) is an immunomodulatory therapy currently recommended in international guidelines as an adjunctive treatment for the prevention and management of organ rejection in heart and lung transplantations. This article reviews clinical experience and ongoing research with ECP for organ rejection in heart and lung transplantations, as well as emerging findings in kidney and liver transplantation. ECP, due to its immunomodulatory and immunosuppressive-sparing effects, offers a potential therapeutic option in these settings, particularly in high-risk patients with comorbidities, infectious complications, or malignancies.

Cell-free fetal DNA for genetic evaluation in Copenhagen Pregnancy Loss Study (COPL): a prospective cohort study.

BACKGROUND: One in four pregnancies end in a pregnancy loss. Although the effect on couples is well documented, evidence-based treatments and prediction models are absent. Fetal aneuploidy is associated with a higher chance of a next successful pregnancy compared with euploid pregnancy loss in which underlying maternal conditions might be causal. Ploidy diagnostics are therefore advantageous but challenging as they require collection of the pregnancy tissue. Cell-free fetal DNA (cffDNA) from maternal blood has the potential for evaluation of fetal ploidy status, but no large-scale validation of the method has been done. METHODS: In this prospective cohort study, women with a pregnancy loss were recruited as a part of the Copenhagen Pregnancy Loss (COPL) study from three gynaecological clinics at public hospitals in Denmark. Women were eligible for inclusion if older than 18 years with a pregnancy loss before gestational age 22 weeks (ie, 154 days) and with an intrauterine pregnancy confirmed by ultrasound (including anembryonic sac), and women with pregnancies of unknown location or molar pregnancies were excluded. Maternal blood was collected while pregnancy tissue was still in situ or within 24 h after pregnancy tissue had passed and was analysed by genome-wide sequencing of cffDNA. Direct sequencing of the pregnancy tissue was done as reference. FINDINGS: We included 1000 consecutive women, at the time of a pregnancy loss diagnosis, between Nov 12, 2020, and May 1, 2022. Results from the first 333 women with a pregnancy loss (recruited between Nov 12, 2020, and Aug 14, 2021) were used to evaluate the validity of cffDNA-based testing. Results from the other 667 women were included to evaluate cffDNA performance and result distribution in a larger cohort of 1000 women in total. Gestational age of fetus ranged from 35-149 days (mean of 70·5 days [SD 16·5], or 10 weeks plus 1 day). The cffDNA-based test had a sensitivity for aneuploidy detection of 85% (95% CI 79-90) and a specificity of 93% (95% CI 88-96) compared with direct sequencing of the pregnancy tissue. Among 1000 cffDNA-based test results, 446 (45%) were euploid, 405 (41%) aneuploid, 37 (4%) had multiple aneuploidies, and 112 (11%) were inconclusive. 105 (32%) of 333 women either did not manage to collect the pregnancy tissue or collected a sample classified as unknown tissue giving a high risk of being maternal. INTERPRETATION: This validation of cffDNA-based testing in pregnancy loss shows the potential and feasibility of the method to distinguish euploid and aneuploid pregnancy loss for improved clinical management and benefit of future reproductive medicine and women's health research. FUNDING: Ole Kirks Foundation, BioInnovation Institute Foundation, and the Novo Nordisk Foundation.

FURIN regulates cytotoxic T-lymphocyte effector function and memory cell transition in mice.

The proprotein convertase subtilisin/kexins (PCSKs) regulate biological actions by cleaving immature substrate proteins. The archetype PCSK, FURIN, promotes the pathogenicity of viruses by proteolytically processing viral proteins. FURIN has also important regulatory functions in both innate and adaptive immune responses but its role in the CD8+ CTLs remains enigmatic. We used a T-cell-specific FURIN deletion in vivo to demonstrate that FURIN promotes host response against the CTL-dependent lymphocytic choriomeningitis virus by virtue of restricting viral burden and augmenting interferon gamma (IFNG) production. We also characterized Furin KO CD8+ T cells ex vivo, including after their activation with FURIN regulating cytokines IL12 or TGFB1. Furin KO CD8+ T cells show an inherently activated phenotype characterized by the upregulation of effector genes and increased frequencies of CD44+ , TNF+ , and IFNG+ cells. In the activated CTLs, FURIN regulates the productions of IL2, TNF, and GZMB and the genes associated with the TGFBR-signaling pathway. FURIN also controls the expression of Eomes, Foxo1, and Bcl6 and the levels of ITGAE and CD62L, which implies a role in the development of CTL memory. Collectively, our data suggest that the T-cell expressed FURIN is important for host responses in viral infections, CTL homeostasis/activation, and memory development.

Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget's disease of bone.

INTRODUCTION: Paget's disease of bone (PDB) frequently presents at an advanced stage with irreversible skeletal damage. Clinical outcomes might be improved by earlier diagnosis and prophylactic treatment. METHODS: We randomised 222 individuals at increased risk of PDB because of pathogenic SQSTM1 variants to receive 5 mg zoledronic acid (ZA) or placebo. The primary outcome was new bone lesions assessed by radionuclide bone scan. Secondary outcomes included change in existing lesions, biochemical markers of bone turnover and skeletal events related to PDB. RESULTS: The median duration of follow-up was 84 months (range 0-127) and 180 participants (81%) completed the study. At baseline, 9 (8.1%) of the ZA group had PDB lesions vs 12 (10.8%) of the placebo group. Two of the placebo group developed new lesions versus none in the ZA group (OR 0.41, 95% CI 0.00 to 3.43, p=0.25). Eight of the placebo group had a poor outcome (lesions which were new, unchanged or progressing) compared with none of the ZA group (OR 0.08, 95% CI 0.00 to 0.42, p=0.003). At the study end, 1 participant in the ZA group had lesions compared with 11 in the placebo group. Biochemical markers of bone turnover were significantly reduced in the ZA group. One participant allocated to placebo required rescue therapy with ZA because of symptomatic disease. The number and severity of adverse events did not differ between groups. CONCLUSIONS: Genetic testing for pathogenic SQSTM1 variants coupled with intervention with ZA is well tolerated and has favourable effects on the progression of early PDB. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

Hierarchically structured bioinspired nanocomposites.

Next-generation structural materials are expected to be lightweight, high-strength and tough composites with embedded functionalities to sense, adapt, self-repair, morph and restore. This Review highlights recent developments and concepts in bioinspired nanocomposites, emphasizing tailoring of the architecture, interphases and confinement to achieve dynamic and synergetic responses. We highlight cornerstone examples from natural materials with unique mechanical property combinations based on relatively simple building blocks produced in aqueous environments under ambient conditions. A particular focus is on structural hierarchies across multiple length scales to achieve multifunctionality and robustness. We further discuss recent advances, trends and emerging opportunities for combining biological and synthetic components, state-of-the-art characterization and modelling approaches to assess the physical principles underlying nature-inspired design and mechanical responses at multiple length scales. These multidisciplinary approaches promote the synergetic enhancement of individual materials properties and an improved predictive and prescriptive design of the next era of structural materials at multilength scales for a wide range of applications.

Interleukin-6 and interferon-alpha differentially regulate microglia function.

Previous reports have shown that IL-6 and IFN-⍺ induce distinct transcriptomic and morphological changes in microglia. Here, we demonstrate that IL-6 increases tissue surveillance, migration and phagocytosis in primary murine microglia, whereas IFN-⍺ inhibits these functions. Our results provide a crucial link between transcriptome and function. It holds the potential to serve as the foundation for future studies aimed at identifying therapeutic targets for cytokine-mediated neuroinflammatory diseases.

Neuroinflammatory disease signatures in SPG11-related hereditary spastic paraplegia patients.

Biallelic loss of SPG11 function constitutes the most frequent cause of complicated autosomal recessive hereditary spastic paraplegia (HSP) with thin corpus callosum, resulting in progressive multisystem neurodegeneration. While the impact of neuroinflammation is an emerging and potentially treatable aspect in neurodegenerative diseases and leukodystrophies, the role of immune cells in SPG11-HSP patients is unknown. Here, we performed a comprehensive immunological characterization of SPG11-HSP, including examination of three human postmortem brain donations, immunophenotyping of patients' peripheral blood cells and patient-specific induced pluripotent stem cell-derived microglia-like cells (iMGL). We delineate a previously unknown role of innate immunity in SPG11-HSP. Neuropathological analysis of SPG11-HSP patient brain tissue revealed profound microgliosis in areas of neurodegeneration, downregulation of homeostatic microglial markers and cell-intrinsic accumulation of lipids and lipofuscin in IBA1+ cells. In a larger cohort of SPG11-HSP patients, the ratio of peripheral classical and intermediate monocytes was increased, along with increased serum levels of IL-6 that correlated with disease severity. Stimulation of patient-specific iMGLs with IFNγ led to increased phagocytic activity compared to control iMGL as well as increased upregulation and release of proinflammatory cytokines and chemokines, such as CXCL10. On a molecular basis, we identified increased STAT1 phosphorylation as mechanism connecting IFNγ-mediated immune hyperactivation and SPG11 loss of function. STAT1 expression was increased both in human postmortem brain tissue and in an Spg11-/- mouse model. Application of an STAT1 inhibitor decreased CXCL10 production in SPG11 iMGL and rescued their toxic effect on SPG11 neurons. Our data establish neuroinflammation as a novel disease mechanism in SPG11-HSP patients and constitute the first description of myeloid cell/ microglia activation in human SPG11-HSP. IFNγ/ STAT1-mediated neurotoxic effects of hyperreactive microglia upon SPG11 loss of function indicate that immunomodulation strategies may slow down disease progression.

Secondary fracture prevention in primary care: a narrative review.

The global burden of osteoporosis continues to rise with an ageing population. Untreated osteoporotic fractures not only heighten the risk of subsequent fractures but are associated with excess mortality. Although primary care guidelines consistently stress the importance of secondary fracture prevention, fewer than 20% of patients are appropriately treated for osteoporosis following an initial osteoporotic fracture. This worldwide phenomenon is known as the osteoporosis care gap. This literature review examines the barriers to secondary fracture prevention in primary care and evaluates the effectiveness of targeted primary care interventions. Common themes emerged from the majority of qualitative studies, including a need for improved communication between the hospital team and primary care, better defined responsibilities and osteoporosis-directed education for the primary care physicians. Quantitative studies demonstrated that most targeted, intensive interventions aimed at educating patients and their primary care physician about osteoporosis treatment significantly increased rates of investigation and treatment. Greater uptake of models of secondary fracture prevention in primary care is urgently needed to address the osteoporosis care gap.

Small-bodied males invest in larger testes when highly ornamented.

Sperm competition and male mating rate are two non-mutually exclusive key evolutionary pressures selecting for larger testes within and across animal taxa. A few studies have tried to test the role of mating rate in the absence of sperm competition. Under the mating rate hypothesis, particular phenotypes of a given population that are expected to gain more mates (e.g., more ornamented males) are expected to make higher investments in testes size (a proxy for sperm production). We test this prediction in Polistes simillimus, a neotropical paper wasp in which females are single mated (no sperm competition) and males can mate with multiple partners. Testes size was predicted by body size (positive association), sexual ornamentation (negative association), and their interaction (among small males, testes size was positively related to ornamentation, but the opposite pattern was observed among large males). We propose that small-bodied well-ornamented males may face the highest risk of sperm depletion. Small-bodied males make relatively higher investment in testes size when highly ornamented. This strategy might be less profitable to large males, as they have overall larger testes. Our results provide strong evidence for the mating rate hypothesis.