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The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs.

Astrocytes and brain endothelial cells are components of the neurovascular unit that comprises the blood-brain barrier (BBB) and their dysfunction contributes to pathogenesis in Huntington's disease (HD). Defining the contribution of these cells to disease can inform cell-type-specific effects and uncover new disease-modifying therapeutic targets. These cells express integrin (ITG) adhesion receptors that anchor the cells to the extracellular matrix (ECM) to maintain the integrity of the BBB. We used HD patient-derived induced pluripotent stem cell (iPSC) modeling to study the ECM-ITG interface in astrocytes and brain microvascular endothelial cells and found ECM-ITG dysregulation in human iPSC-derived cells that may contribute to the dysfunction of the BBB in HD. This disruption has functional consequences since reducing ITG expression in glia in an HD Drosophila model suppressed disease-associated CNS dysfunction. Since ITGs can be targeted therapeutically and manipulating ITG signaling prevents neurodegeneration in other diseases, defining the role of ITGs in HD may provide a novel strategy of intervention to slow CNS pathophysiology to treat HD.

Neonatal lupus (NLE) is a rare acquired autoimmune disorder caused by transplacental passage of maternal autoantibodies to Sjogren's Syndrome A or B (SSA-SSB) autoantigens (Vanoni et al. in Clin Rev Allerg Immunol 53:469-476, 2017) which target fetal and neonatal tissues for immune destruction. The cardiac trademark of NLE is autoimmune heart block, which accounts for more than 80% of cases of complete atrioventricular heart block (AVB) in newborns with a structurally normal heart (Martin in Cardiol Young 24: 41-46, 2014). NLE presenting with cardiac alterations not involving rhythm disturbances are described in the literature, but they are rare. Here, we report a case of a neonate with high anti-SSA antibodies who developed severe ventricular dysfunction in the absence of rhythm abnormalities, endocardial fibroelastosis, and dilated cardiomyopathy (Trucco et al. in J Am Coll Cardiol 57:715-723, https://doi.org/10.1016/j.jacc.2010.09.044 , 2011), the most common cardiac presentations of NLE. The patient developed severe multiorgan dysfunction syndrome that required prolonged critical care support but fully recovered and was discharged home. We highlight the unusual clinical features of this NLE case and the importance of timely treatment of NLE allowing complete recovery of a critically ill neonate.

Objective: Life expectancy and obesity prevalence are increasing worldwide, leading to an increase in the prevalence of cardiovascular disease. High-density lipoprotein (HDL) functionality and immunosenescence play key roles in cardiovascular disease, longevity, and quality of aging. Both molecular hallmarks of aging are impacted by obesity and metabolic syndrome and can be modulated by lifestyle. We aimed to evaluate the effect of a lifestyle intervention focused on an energy-reduced Mediterranean diet (erMedDiet), physical activity (PA), and behavioral support on HDL cholesterol efflux capacity (CEC) and immunosenescence. Method: CEC and immunosenescent T cells were determined in 60 participants from the control group (CG) and 56 from the intervention group (IG) of the PREDIMED-Plus trial at baseline and after 1 and 3 years of follow-up. PREDIMED-Plus is a randomized, controlled, parallel-group trial with an IG of erMedDiet, PA promotion, and behavioral support for weight loss and a CG of usual primary care advice. The sample included 116 volunteers from the PREDIMED-Plus-IMDEA subsample of the PREDIMED-Plus trial. Men aged 55 to 75 years and women aged 60 to 75 years with a body mass index between 27 and 40 kg/m2 and metabolic syndrome were included. Results: Participants within the IG had significantly improved CEC (2.42% and 10.69% after 1 and 3 years of follow-up) and a decreased in senescent T cell profile (−3.32% ± 12.54% and −6.74% ± 11.2%, p < 0.001, after 1 and 3 years of follow-up). Baseline obesity status impacted the response to the intervention. Conclusions: A weight loss intervention program with erMedDiet and PA ameliorated senescence markers. [ABSTRACT FROM AUTHOR]

The NEXT experiment aims at searching for the hypothetical neutrinoless double-beta decay from the 136Xe isotope using a high-purity xenon TPC. Efficient discrimination of the events through pattern recognition of the topology of primary ionisation tracks is a major requirement for the experiment. However, it is limited by the diffusion of electrons. It is known that the addition of a small fraction of a molecular gas to xenon reduces electron diffusion. On the other hand, the electroluminescence (EL) yield drops and the achievable energy resolution may be compromised. We have studied the effect of adding several molecular gases to xenon (CO2, CH4 and CF4) on the EL yield and energy resolution obtained in a small prototype of driftless gas proportional scintillation counter. We have compared our results on the scintillation characteristics (EL yield and energy resolution) with a microscopic simulation, obtaining the diffusion coefficients in those conditions as well. Accordingly, electron diffusion may be reduced from about 10 mm/m for pure xenon down to 2.5 mm/m using additive concentrations of about 0.05%, 0.2% and 0.02% for CO2, CH4 and CF4, respectively. Our results show that CF4 admixtures present the highest EL yield in those conditions, but very poor energy resolution as a result of huge fluctuations observed in the EL formation. CH4 presents the best energy resolution despite the EL yield being the lowest. The results obtained with xenon admixtures are extrapolated to the operational conditions of the NEXT-100 TPC. CO2 and CH4 show potential as molecular additives in a large xenon TPC. While CO2 has some operational constraints, making it difficult to be used in a large TPC, CH4 shows the best performance and stability as molecular additive to be used in the NEXT-100 TPC, with an extrapolated energy resolution of 0.4% at 2.45 MeV for concentrations below 0.4%, which is only slightly worse than the one obtained for pure xenon. We demonstrate the possibility to have an electroluminescence TPC operating very close to the thermal diffusion limit without jeopardizing the TPC performance, if CO2 or CH4 are chosen as additives.[Figure not available: see fulltext.]

One of the major goals of the NEXT-White (NEW) detector is to demonstrate the energy resolution that an electroluminescent high pressure xenon TPC can achieve for high energy tracks. For this purpose, energy calibrations with 137Cs and 232Th sources have been carried out as a part of the long run taken with the detector during most of 2017. This paper describes the initial results obtained with those calibrations, showing excellent linearity and an energy resolution that extrapolates to approximately 1% FWHM at Qββ.

The NEXT-White (NEW) detector is currently the largest radio-pure high-pressure xenon gas time projection chamber with electroluminescent readout in the world. It has been operating at Laboratorio Subterr'aneo de Canfranc (LSC) since October 2016. This paper describes the calibrations performed using 83mKr decays during a long run taken from March to November 2017 (Run II). Krypton calibrations are used to correct for the finite drift-electron lifetime as well as for the dependence of the measured energy on the event transverse position which is caused by variations in solid angle coverage both for direct and reflected light and edge effects. After producing calibration maps to correct for both effects we measure an excellent energy resolution for 41.5 keV point-like deposits of (4.553 ± 0.010 (stat) ± 0.324 (sys))% FWHM in the full chamber and (3.804 ± 0.013 (stat) ± 0.112 (sys))% FWHM in a restricted fiducial volume. Using naive 1/E scaling, these values translate into resolutions of (0.5916 ± 0.0014 (stat) ± 0.0421 (sys))% FWHM and (0.4943 ± 0.0017 (stat) ± 0.0146 (sys))% FWHM at the Qββ energy of xenon double beta decay (2458 keV), well within range of our target value of 1%.

High pressure gas time projection chambers (HPGTPCs) are made with a variety of materials, many of which still await proper characterization in high pressure noble gas environments. As HPGTPCs increase in size toward ton-scale detectors, assemblies become larger and more complex, creating a need for detailed understanding of how structural supports and high voltage insulators behave. This includes identification of materials with predictable mechanical properties and without surface charge accumulation that may lead to field deformation or sparking. This paper explores the mechanical and electrical effects of high pressure gas environments on insulating polymers PTFE, HDPE, PEEK, POM and UHMW in argon and xenon, including studying gas absorption, swelling and high voltage insulation strength.

The measurement of the internal 222Rn activity in the NEXT-White detector during the so-called Run-II period with 136Xe-depleted xenon is discussed in detail, together with its implications for double beta decay searches in NEXT. The activity is measured through the alpha production rate induced in the fiducial volume by 222Rn and its alpha-emitting progeny. The specific activity is measured to be (38.1 ± 2.2 (stat.) ± 5.9 (syst.)) mBq/m3. Radon-induced electrons have also been characterized from the decay of the 214Bi daughter ions plating out on the cathode of the time projection chamber. From our studies, we conclude that radon-induced backgrounds are sufficiently low to enable a successful NEXT-100 physics program, as the projected rate contribution should not exceed 0.1 counts/yr in the neutrinoless double beta decay sample.[Figure not available: see fulltext.]

Xe–CO2 mixtures are important alternatives to pure xenon in Time Projection Chambers (TPC) based on secondary scintillation (electroluminescence) signal amplification with applications in the important field of rare event detection such as directional dark matter, double electron capture and double beta decay detection. The addition of CO2 to pure xenon at the level of 0.05–0.1% can reduce significantly the scale of electron diffusion from 10 mm/m to 2.5 mm/m, with high impact on the discrimination efficiency of the events through pattern recognition of the topology of primary ionization trails. We have measured the electroluminescence (EL) yield of Xe–CO2 mixtures, with sub-percent CO2 concentrations. We demonstrate that the EL production is still high in these mixtures, 70% and 35% relative to that produced in pure xenon, for CO2 concentrations around 0.05% and 0.1%, respectively. The contribution of the statistical fluctuations in EL production to the energy resolution increases with increasing CO2 concentration, being smaller than the contribution of the Fano factor for concentrations below 0.1% CO2.

Xe–CO2 mixtures are important alternatives to pure xenon in Time Projection Chambers (TPC) based on secondary scintillation (electroluminescence) signal amplification with applications in the important field of rare event detection such as directional dark matter, double electron capture and double beta decay detection. The addition of CO2 to pure xenon at the level of 0.05–0.1% can reduce significantly the scale of electron diffusion from 10 mm/m to 2.5 mm/m, with high impact on the discrimination efficiency of the events through pattern recognition of the topology of primary ionization trails. We have measured the electroluminescence (EL) yield of Xe–CO2 mixtures, with sub-percent CO2 concentrations. We demonstrate that the EL production is still high in these mixtures, 70% and 35% relative to that produced in pure xenon, for CO2 concentrations around 0.05% and 0.1%, respectively. The contribution of the statistical fluctuations in EL production to the energy resolution increases with increasing CO2 concentration, being smaller than the contribution of the Fano factor for concentrations below 0.1% CO2.

We investigate the potential of using deep learning techniques to reject background events in searches for neutrinoless double beta decay with high pressure xenon time projection chambers capable of detailed track reconstruction. The differences in the topological signatures of background and signal events can be learned by deep neural networks via training over many thousands of events. These networks can then be used to classify further events as signal or background, providing an additional background rejection factor at an acceptable loss of efficiency. The networks trained in this study performed better than previous methods developed based on the use of the same topological signatures by a factor of 1.2 to 1.6, and there is potential for further improvement.

To gain insight into how mutant huntingtin (mHtt) CAG repeat length modifies Huntington's disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat lengths. We found repeat length-dependent transcriptional signatures to be prominent in the striatum, less so in cortex, and minimal in the liver. Coexpression network analyses revealed 13 striatal and 5 cortical modules that correlated highly with CAG length and age, and that were preserved in HD models and sometimes in patients. Top striatal modules implicated mHtt CAG length and age in graded impairment in the expression of identity genes for striatal medium spiny neurons and in dysregulation of cyclic AMP signaling, cell death and protocadherin genes. We used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at the protein level, and validated 22 striatal module genes as modifiers of mHtt toxicities in vivo.

Background: Alzheimer's disease (AD) has a complex etiology where insults in multiple pathways conspire to disrupt neuronal function, yet molecular changes underlying AD remain poorly understood. Previously, we performed mass‐spectrometry on post‐mortem human brain tissue to identify >40 protein co‐expression modules correlated to AD pathological and clinical traits. Module 42 has the strongest correlation to AD pathology and consists of 32 proteins including SMOC1, a predicted driver of network behavior and potential biomarker for AD. SMOC1 is a matrisomal protein with conserved roles in modulating TGF‐Beta and wnt signaling during development, yet remains unstudied in the brain. Methods: We evaluate M42 using a high‐throughput robotic screening platform and video assisted software, enabling quantitative assessments of neurological function to identify proteins that modify Aβ‐ or tau‐induced neurodegeneration. We then focus on dSMOC1 using Drosophila genetics and cell biological approaches to determine its role in the brain. Finally, we use Mass Spectrometry to identify protein changes in the brains of dSMOC1‐/‐ flies. Results: Our screening assay identified 20 genes from M42 that modify tau toxicity and 5 for Aβ, including dSMOC1 and components of Wnt and TGF‐β signaling pathways. We find dSMOC1‐/‐ null flies suffer severely decreased survival and climbing defects upon aging. In the brain, dSMOC1 expression occurs primarily in glial cells while protein localizes around neuronal cell bodies, consistent with its role as a matrisomal protein. We show alteration of glypican levels in dSMOC1‐/‐ brains. Glypicans modulate Wnt and TGF‐β signaling further supporting a role connecting M42 in AD biology. Finally, we used mass spectrometry to determine protein changes in brains of dSMOC1‐/‐ flies and found perturbations in ECM/receptor interactions, proteostasis, KREBs/TCA cycle, and oxidative phosphorylation. Additional data suggests an age dependent shift from oxidative phosphorylation to glycolysis may compensate for reduced ATP levels in dSMOC1‐/‐ flies. Conclusion: The M42 protein module contains multiple proteins with links to AD. Multiple M42 proteins interact with specific AD triggers including SMOC1, wnt and TGF‐β signaling components. The genetics, proteomics, and cell biological data combine to support a mechanistic hypothesis where changes in SMOC1 levels disrupt critical signaling pathways leading to disruptions in metabolism affecting neuronal function. [ABSTRACT FROM AUTHOR]

Background: In Alzheimer's disease (AD), changes in the brain transcriptome are hypothesized to mediate the impact of neuropathology on cognition. Gene expression profiling from postmortem brain tissue is a promising approach to identify causal pathways; however, there are challenges to definitively resolve the upstream pathologic triggers along with the downstream consequences for AD clinical manifestations. Method: We have functionally dissected 30 AD‐associated gene coexpression modules using a cross‐species strategy in Drosophila melanogaster models. First, integrating longitudinal RNA‐sequencing and fly behavioral phenotyping, we interrogated unique and shared transcriptional responses to amyloid beta (Aβ) plaques, tau neurofibrillary tangles, and/or aging, along with potential links to progressive neuronal dysfunction. In order to confirm causal modules and pinpoint AD network drivers, we next performed systematic in vivo genetic manipulations of 357 conserved, prioritized targets to identify modifiers of Aβ‐ and/or tau‐induced neurodegeneration. We subsequently partitioned candidate causal subnetworks, which were further validated based on human or Drosophila genetic evidence. Result: Our results highlight hundreds of conserved, differentially expressed genes mapping to AD regulatory networks. Our systematic screening identified 144 tau/Aβ modifiers. We discovered an up‐regulated, causal network that is significantly enriched for both AD risk variants and markers of immunity / inflammation, and which promotes Aβ and tau‐mediated neurodegeneration based on fly genetic manipulations in neurons. By contrast, a promising synaptic regulatory network is strongly downregulated in human AD and is enriched for loss‐of‐function suppressors of Aβ/tau, consistent with a potential compensatory response to glutamatergic excitotoxic brain injury. Conclusion: our cross‐species, systems genetic approach establishes a putative causal chain linking AD pathology, large‐scale gene expression perturbations, and ultimately, neurodegeneration. [ABSTRACT FROM AUTHOR]