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Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia

X-linked hypophosphataemia (XLH) is a rare metabolic bone disorder caused by pathogenic variants in the PHEX gene, which is predominantly expressed in osteoblasts, osteocytes and odontoblasts. XLH is characterized by increased synthesis of the bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23), which results in renal phosphate wasting with consecutive hypophosphataemia, rickets, osteomalacia, disproportionate short stature, oral manifestations, pseudofractures, craniosynostosis, enthesopathies and osteoarthritis. Patients with XLH should be provided with multidisciplinary care organized by a metabolic bone expert. Historically, these patients were treated with frequent doses of oral phosphate supplements and active vitamin D, which was of limited efficiency and associated with adverse effects. However, the management of XLH has evolved in the past few years owing to the availability of burosumab, a fully humanized monoclonal antibody that neutralizes circulating FGF23. Here, we provide updated clinical practice recommendations for the diagnosis and management of XLH to improve outcomes and quality of life in these patients.

Maternal effects in the model system Daphnia: the ecological past meets the epigenetic future

Maternal effects have been shown to play influential roles in many evolutionary and ecological processes. However, understanding how environmental stimuli induce within-generation responses that transverse across generations remains elusive, particularly when attempting to segregate confounding effects from offspring genotypes. This review synthesizes literature regarding resource- and predation-driven maternal effects in the model system Daphnia, detailing how the maternal generation responds to the environmental stimuli and the maternal effects seen in the offspring generation(s). Our goal is to demonstrate the value of Daphnia as a model system by showing how general principles of maternal effects emerge from studies on this system. By integrating the results across different types of biotic drivers of maternal effects, we identified broadly applicable shared characteristics: 1. Many, but not all, maternal effects involve offspring size, influencing resistance to starvation, infection, predation, and toxins. 2. Maternal effects manifest more strongly when the offspring’s environment is poor. 3. Strong within-generation responses are typically associated with strong across-generation responses. 4. The timing of the maternal stress matters and can raise or lower the magnitude of the effect on the offspring’s phenotype. 5. Embryonic exposure effects could be mistaken for maternal effects. We outline questions to prioritize for future research and discuss the possibilities for integration of ecologically relevant studies of maternal effects in natural populations with the molecular mechanisms that make them possible, specifically by addressing genetic variation and incorporating information on epigenetics. These small crustaceans can unravel how and why non-genetic information gets passed to future generations.

Neural codes track prior events in a narrative and predict subsequent memory for details

Throughout our lives, we learn schemas that specify what types of events to expect in particular contexts and the temporal order in which these events usually occur. Here, our first goal was to investigate how such context-dependent temporal structures are represented in the brain during processing of temporally extended events. To accomplish this, we ran a 2-day fMRI study (N = 40) in which we exposed participants to many unique animated videos of weddings composed of sequences of rituals; each sequence originated from one of two fictional cultures (North and South), where rituals were shared across cultures, but the transition structure between these rituals differed across cultures. The results, obtained using representational similarity analysis, revealed that context-dependent temporal structure is represented in multiple ways in parallel, including distinct neural representations for the culture, for particular sequences, and for past and current events within the sequence. Our second goal was to test the hypothesis that neural schema representations scaffold memory for specific details. In keeping with this hypothesis, we found that the strength of the neural representation of the North/South schema for a particular wedding predicted subsequent episodic memory for the details of that wedding.

Returning genetic risk information for hereditary cancers to participants in a population-based cohort study in Japan

Large-scale population cohort studies that collect genomic information are tasked with returning an assessment of genetic risk for hereditary cancers to participants. While several studies have applied to return identified genetic risks to participants, comprehensive surveys of participants’ understanding, feelings, and behaviors toward cancer risk remain to be conducted. Here, we report our experience and surveys of returning genetic risks to 100 carriers of pathogenic variants for hereditary cancers identified through whole genome sequencing of 50 000 individuals from the Tohoku Medical Megabank project, a population cohort study. The participants were carriers of pathogenic variants associated with either hereditary breast and ovarian cancer (n = 79, median age=41) or Lynch syndrome (n = 21, median age=62). Of these, 28% and 38% had a history of cancer, respectively. We provided information on cancer risk, heritability, and clinical actionability to the participants in person. The comprehension assessment revealed that the information was better understood by younger (under 60 years) females than by older males. Scores on the cancer worry scale were positively related to cancer experiences and general psychological distress. Seventy-one participants were followed up at Tohoku University Hospital; six females underwent risk-reducing surgery triggered by study participation and three were newly diagnosed with cancer during surveillance. Among first-degree relatives of hereditary breast and ovarian cancer carriers, participants most commonly shared the information with daughters. This study showed the benefits of returning genetic risks to the general population and will provide insights into returning genetic risks to asymptomatic pathogenic variant carriers in both clinical and research settings.

The role of rivers in the origin and future of Amazonian biodiversity

The rich biodiversity of Amazonia is shaped geographically and ecologically by its rivers and their cycles of seasonal flooding. Anthropogenic effects, such as deforestation, infrastructure development and extreme climatic events, threaten the ecological processes sustaining Amazonian ecosystems. In this Review, we explore the coupled evolution of Amazonian rivers and biodiversity associated with terrestrial and seasonally flooded environments, integrating geological, climatic, ecological and genetic evidence. Amazonia and its fluvial environments are highly heterogeneous, and the drainage system is historically dynamic and continually evolving; as a result, the discharge, sediment load and strength of rivers as barriers to biotic dispersal has changed through time. Ecological affinities of taxa, drainage rearrangements and variations in riverine landscape caused by past climate changes have mediated the evolution of the high diversity found in modern-day Amazonia. The connected history of the region’s biodiversity and landscape provides fundamental information for mitigating current and future impacts. However, incomplete knowledge about species taxonomy, distributions, habitat use, ecological interactions and occurrence patterns limits our understanding. Partnerships with Indigenous peoples and local communities, who have close ties to land and natural resources, are key to improving knowledge generation and dissemination, enabling better impact assessments, monitoring and management of the riverine systems at risk from evolving pressures.

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