Interlayer Delocalized Electrons Activate Basal Plane for Ultrahigh-Current-Density Hydrogen Evolution.

The basal plane of transition metal dichalcogenides (TMDCs) is inert for the hydrogen evolution reaction (HER) due to its low-efficiency charge transfer kinetics. We propose a strategy of filling the van der Waals (vdW) layer with delocalized electrons to enable vertical penetration of electrons from the collector to the adsorption intermediate vertically. Guided by density functional theory, we achieve this concept by incorporating Cu atoms into the interlayers of tantalum disulfide (TaS2). The delocalized electrons of d-orbitals of the interlayered Cu can constitute the charge transfer pathways in the vertical direction, thus overcoming the hopping migration through vdW gaps. The vertical conductivity of TaS2 increased by 2 orders of magnitude. The TaS2 basal plane HER activity was extracted with an on-chip microcell. Modified by the delocalized electrons, the current density increased by 20 times, reaching an ultrahigh value of 800 mA cm-2 at -0.4 V without iR compensation.

Room-Temperature Magnetic-Induced Circularly Polarized Photoluminescence in Two-Dimensional Er2O2S.

Two-dimensional (2D) materials with spin polarization have great potential for achieving next-generation spintronic applications. However, spin polarization of 2D materials is usually produced at a cryogenic temperature because of thermal fluctuations, which severely hinder their further applications. Here, we report room-temperature intrinsic magnetic-induced circularly polarized photoluminescence (PL) in 2D Er2O2S flakes. The geff factor of 2D Er2O2S stays at around -6.3 from the liquid He temperature limit to room temperature, which is independent of temperature. This anomalous phenomenon in Er2O2S is totally different from previous materials, which all have a decreasing Zeeman splitting with increasing temperature resulting from thermal fluctuations. The anomalous temperature-dependent magnetic-induced circularly polarized PL originates from the weak electron-phonon coupling in 2D Er2O2S, which has been proven by both the temperature-dependent Raman and theoretical calculations. This work sheds light on the understanding and manipulation of 2D materials for practical spintronic applications.

Fabrication of porous and defect-rich BiOI/MWCNTs photocatalyst by Ar plasma-etching for emerging pollutants degradation.

Carbon material modification and defect engineering are indispensable for bolstering the photocatalytic effectiveness of bismuth halide oxide (BiOX). In this study, a novel porous and defect-rich Ar-CB-2 photocatalyst was synthesized for emerging pollutants degradation. Leveraging the interfacial coupling effect of multi-walled carbon nanotubes (MWCNTs), we expanded the absorption spectrum of BiOI nanosheets and significantly suppressed the recombination of charge carriers. Introducing defects via Argon (Ar) plasma-etching further bolstered the adsorption efficacy and electron transfer properties of photocatalyst. In comparison to the pristine BiOI and CB-2, the Ar-CB-2 photocatalyst demonstrated superior photodegradation efficiency, with the first-order reaction rates for the photodegradation of tetracycline (TC) and bisphenol A (BPA) increasing by 2.83 and 4.53 times, respectively. Further probe experiments revealed that the steady-state concentrations of ·O2- and 1O2 in the Ar-CB-2/light system were enhanced by a factor of 1.67 and 1.28 compared to CB-2/light system. This result confirmed that the porous and defect-rich structure of Ar-CB-2 inhibited electron-hole recombination and boosted photocatalyst-oxygen interaction, swiftly transforming O2 into active oxygen species, thus accelerating their production. Furthermore, the possible degradation pathways for TC and BPA in the Ar-CB-2/light system were predicted. Overall, these findings offered a groundbreaking approach to the development of highly effective photocatalysts, capable of swiftly breaking down emerging pollutants.

Comprehensive reference intervals for white blood cell counts during pregnancy.

BACKGROUND: White blood cell (WBC) count increases during pregnancy, necessitating reliable reference intervals for assessing infections and pregnancy-related complications. This study aimed to establish comprehensive reference intervals for WBC counts during pregnancy. METHODS: The analysis included 17,737 pregnant women, with weekly WBC count measurements from pre-pregnancy to postpartum. A threshold linear regression model determined reference intervals, while Harris and Boyd's test partitioned the intervals. RESULTS: WBC count exhibited a significant increase during pregnancy, characterized by a rapid rise before 7 weeks of gestation, followed by a plateau. Neutrophils primarily drove this increase, showing a similar pattern. The threshold regression model and Harris and Boyd's test supported partitioned reference intervals for WBC counts: 4.0-10.0 × 10^9/L for < = 2 weeks, 4.7-11.9 × 10^9/L for 3-5 weeks, and 5.7-14.4 × 10^9/L for > = 6 weeks of gestation. These reference intervals identified pregnant women with high WBC counts, who had a higher incidence of pregnancy-related complications including placenta previa, oligohydramnios, secondary uterine inertia, and intrauterine growth restriction. CONCLUSION: This study establishes comprehensive reference intervals for WBC counts during pregnancy. Monitoring WBC counts is clinically relevant, as elevated levels are associated with an increased risk of infection and pregnancy-related complications.

Domain-limited thermal transformation preparation of novel graphitized carbon-supported layered double oxides for efficient tetracycline degradation.

The resource utilization of industrial lignin to construct high-performance catalysts for wastewater treatment field is pioneering research. Herein, the novel graphitized carbon-supported CuCoAl-layered double oxides (LDOs-GC) were successfully designed by the domain-limited thermal transformation technology using sodium lignosulfonate (LS) self-assembled CuCoAl-layered double hydroxides as the precursor. The optimized LDOs-GC catalyst owned the excellent tetracycline (TC) degradation of 98.0% within 15 min by activated peroxymonosulfate (PMS) under optimal conditions (20 mg/L catalyst, 1.5 mM PMS, 30 mg/L TC). The density of metal ions in the catalyst and the synergistic interaction between graphitized carbon (GC) and metal ions played a major role in TC degradation. Based on a comprehensive analysis, the TC degradation in LDOs-GC/PMS system was proved to be accomplished by a combination of free radicals (SO4·- and HO·) and non-radicals (1O2). Meanwhile, the possible degradation pathways of TC were proposed by the analysis of TC degradation intermediates and a comprehensive analysis of the rational reaction mechanism for TC degradation by LDOs-GC/PMS system was also performed. This work provides a new strategy for developing novel high-performance catalysts from industrial waste, while offering a green, cheap and sustainable approach to antibiotic degradation.

The association of uric acid with the development of thyroid nodules: a retrospective cohort study.

BACKGROUND: Uric acid was found to have a positive correlation with thyroid nodules in the cross-sectional studies recently. We aimed to conduct a retrospective cohort study to investigate whether uric acid is a risk factor for the development of thyroid nodules. METHODS: We reviewed the data of individuals who attended the medical check-ups in our hospital from 2010 to 2019. A total of 6587 adults without thyroid nodules at baseline were enrolled in this study. Logistic regression with or without restricted cubic spline function was used to investigate the non-linear or linear association between uric acid and thyroid nodules, respectively. RESULTS: Baseline characteristics showed that subjects mainly consisted of the healthy, young population. After fully adjusting for the potential confounders, such as age, sex, metabolic and inflammatory indicators, hepatic and renal function, a logistic restricted cubic spline regression model suggested that uric acid had a significant association (P = 0.028) with the development of thyroid nodules, but the association was not non-linear (P = 0.516). The results indicate that the association between them is linear, which was demonstrated by a logistic regression model, in which the odds ratio of uric acid per 100 mmol/L was 1.137 (P = 0.004). Age, sex, diastolic blood pressure, fasting blood sugar, and blood monocyte were found to be risk factors for thyroid nodules as well. CONCLUSION: Uric acid is an independent risk factor for the formation of thyroid nodules. This finding warrants attention to this risk factor in apparently healthy adults.

Effect of Strong Intermolecular Interaction in 2D Inorganic Molecular Crystals.

Strong intermolecular interactions in 2D organic molecular crystals arising from π-π stacking have been widely explored to achieve high thermal stability, high carrier mobility, and novel physical properties, which have already produced phenomenal progress. However, strong intermolecular interactions in 2D inorganic molecular crystals (2DIMCs) have rarely been investigated, severely limiting both the fundamental research in molecular physics and the potential applications of 2DIMCs for optoelectronics. Here, the effect of strong intermolecular interactions induced by unique short intermolecular Se-Se and P-Se contacts in 2D α-P4Se3 nanoflakes is reported. On the basis of theoretical calculations of the charge density distribution and an analysis of the thermal expansion and plastic-crystal transition, the physical picture of strong intermolecular interactions can be elucidated as a higher charge density between adjacent P4Se3 molecules, arising from an orderly and close packing of P4Se3 molecules. More importantly, encouraged by the strong intermolecular coupling, the in-plane mobility of α-P4Se3 nanoflakes is first calculated with a quantum nuclear tunneling model, and a competitive hole mobility of 0.4 cm2 V-1 s-1 is obtained. Our work sheds new light on the intermolecular interactions in 2D inorganic molecular crystals and is highly significant for promoting the development of molecular physics and optoelectronics.

Effects of chitinase-3-like protein 1 on brain death-induced hepatocyte apoptosis via PAR2-JNK-caspase-3.

Hepatocyte apoptosis is a crucial factor affecting liver quality in brain-dead donors. The identification of key molecular proteins involved in brain-death (BD)-induced hepatocyte apoptosis may help determine an effective method for improving the quality of livers from brain-dead donors. In this study, we used in vivo and in vitro models to investigate the role of chitinase-3-like protein 1 (CHI3L1) in promoting liver cell apoptosis after BD. Chitin was used to inhibit CHI3L1 in a rat model of BD. Macrophage polarization of THP-1 cells and hypoxia/reoxygenation (H/R) of LO-2 cells were used to mimic BD-induced cell stress in liver. We found that CHI3L1 played a vital role in promoting liver cell apoptosis. Six hours after BD, CHI3L1 expression was significantly upregulated in liver macrophages and was associated with BD-induced M1 polarization of these cells. In liver cells cultured under H/R conditions, recombinant CHI3L1 activated the protease-activated receptor 2 (PAR2)/c-June N-terminal kinase (JNK) apoptotic pathway and aggravated apoptosis. Compared with the control group, chitin particles inhibited the expression of CHI3L1 in the liver of brain dead rats, thereby reducing activation of the hepatocyte surface receptor, PAR2, and its downstream JNK/caspase-3 signaling pathway, ultimately reducing hepatocyte apoptosis. In conclusion, our results indicate that CHI3L1 relies on a PAR2/JNK-mediated mechanism to promote BD-induced hepatocyte apoptosis.

2D Rare Earth Material (EuOCl) with Ultra-Narrow Photoluminescence at Room Temperature.

High color purity and color rendition of 2D luminescent materials have long been pursued for applications in low-dimensional lighting, display, biolabeling, and laser. However, the reported photoluminescence (PL) linewidth of most 2D luminescent materials is about dozens of meV. Herein, a brand-new luminescent system of 2D rare earth (RE) material EuOCl (1.1 nm) with ultra-narrow linewidth (1.2 meV) at room temperature is successfully synthesized via chemical vapor deposition (CVD). The linewidth of EuOCl flakes at room temperature is even narrower than most 2D luminescent materials and heterostructures detected at below 10 K. Impressively, the as-synthesized EuOCl flakes show abnormal temperature-dependent photoluminescent properties, which is absolutely different from the relatively stable 4f-4f transitions in RE owing to shielding from outer shell electrons. J-mixing effect has been successfully applied for this phenomenon. Undoubtedly, luminescent 2D EuOCl flakes will open new territory for the applications of 2D RE materials in the 2D luminescent areas, especially for the applications at room temperature.

[Advances in biosynthesis of indigo in plants].

Natural indigo, as one of the oldest dyes, is also a pivotal dye utilized in cotton fabrics today. A diversity of plants rich in indigo compounds belong to traditional Chinese herbal medicines. Indigo compounds have a variety of biological and pharmacological activities, including anticonvulsant, antibacterial, antifungal, antiviral and anticancer activities. A substantial progress in indigo biosynthesis has been made lately. This paper summarizes the value of indigo from the aspects of cultural history, biosynthetic pathways and the medicinal activities of its related derivatives involved in the pathways. In addition, the latest research advancements in indigo biosynthetic pathways is demonstrated in this paper, which would lay the theoretical foundation for the exploration and utilization of natural indigo.

Novel insights into the apoptosis mechanism of DNA topoisomerase I inhibitor isoliquiritigenin on HCC tumor cell.

The inhibitory effect of DNA topoisomerase (Top I) by isoliquiritigenin(ISO) were investigated and their interaction mechanism was evaluated using methods including UV-vis absorption, fluorescence, coupled with molecular simulation, and using the MTT method of inhibition rate of HCC tumor cell SNU475 proliferation assay, finally, the interaction of ISO with calf thymus DNA was investigated by melting measurements and molecular docking studies. It was found that isoliquiritigenin reversibly inhibited DNA Top I in a competitive manner with the concentrations of ISO resulting in 50% activity lost (IC50) were estimated to be 0.178 ± 0.12 mM. Isoliquiritigenin exhibited a strong ability to quench the intrinsic fluorescence of Top I through a static quenching procedure. The positive values of enthalpy change and entropy change suggested that the binding of isoliquiritigenin to Top I was driven mainly by hydrophobic interactions. The molecular docking results revealed isoliquiritigenin actually interacted with the primary amino acid residues on the active site of Top I, and the detection results of fluorescence staining and the inhibitory effect on the growth of HCC SUN475 showed that isoliquiritigenin induced the apoptosis cells increased gradually. The interaction of ISO with DNA can cause the denaturation temperature to be increased, which indicated that the stabilization of the DNA helix was increased in the presence of ISO, which indicated that the results provide strong evidence for intercalative binding of ISO with DNA.

Preeclampsia/eclampsia impacts the structure and function of neonatal hearts probably by reducing myocardial compaction.

PURPOSE: Preeclampsia/Eclampsia (PE/E) poses significant risks to neonatal cardiac health. Traditional echocardiographic methods have limitations in detailing these impacts. This study hypothesized that echocardiographic radiomics could provide a more comprehensive assessment of the cardiac changes in neonates affected by PE/E. METHOD: In a comprehensive analysis, 2594 neonates underwent echocardiographic screening. From these, 556 were selected for detailed radiomics analysis, focusing on cardiac shape, movement, and texture features. A multiblock sparse partial least squares (sPLS) model integrated these features to assess their association with PE/E. RESULTS: Newborns from PE/E-affected pregnancies displayed lower left ventricular ejection fractions compared to the control group (61.1 % vs. 66.2 %). Our radiomics approach extracted 15,494 features per neonate, with the sPLS model identifying 17 features significantly correlated with PE/E. Among these, texture features representing myocardial non-compaction were most strongly correlated with PE/E (correlation coefficient r = 0.63). Detailed visualization of these texture features suggested that PE/E might lead to more pronounced myocardial non-compaction, characterized by a thicker non-compaction layer and increased cardiac trabeculation. CONCLUSIONS: Our findings demonstrate the potential of echocardiographic radiomics as a tool for assessing the impact of PE/E on neonatal cardiac function. The correlation between PE/E and myocardial non-compaction underlines the need for enhanced cardiac monitoring in neonates born to PE/E-affected mothers. This study contributes to a better understanding of PE/E's cardiac implications, potentially guiding future clinical practices.

Unraveling progression subtypes in people with Huntington's disease.

Background: Huntington's disease (HD) is a progressive neurodegenerative disease caused by a CAG trinucleotide expansion in the huntingtin gene. The length of the CAG repeat is inversely correlated with disease onset. HD is characterized by hyperkinetic movement disorder, psychiatric symptoms, and cognitive deficits, which greatly impact patient's quality of life. Despite this clear genetic course, high variability of HD patients' symptoms can be observed. Current clinical diagnosis of HD solely relies on the presence of motor signs, disregarding the other important aspects of the disease. By incorporating a broader approach that encompasses motor as well as non-motor aspects of HD, predictive, preventive, and personalized (3P) medicine can enhance diagnostic accuracy and improve patient care. Methods: Multisymptom disease trajectories of HD patients collected from the Enroll-HD study were first aligned on a common disease timescale to account for heterogeneity in disease symptom onset and diagnosis. Following this, the aligned disease trajectories were clustered using the previously published Variational Deep Embedding with Recurrence (VaDER) algorithm and resulting progression subtypes were clinically characterized. Lastly, an AI/ML model was learned to predict the progression subtype from only first visit data or with data from additional follow-up visits. Results: Results demonstrate two distinct subtypes, one large cluster (n = 7122) showing a relative stable disease progression and a second, smaller cluster (n = 411) showing a dramatically more progressive disease trajectory. Clinical characterization of the two subtypes correlates with CAG repeat length, as well as several neurobehavioral, psychiatric, and cognitive scores. In fact, cognitive impairment was found to be the major difference between the two subtypes. Additionally, a prognostic model shows the ability to predict HD subtypes from patients' first visit only. Conclusion: In summary, this study aims towards the paradigm shift from reactive to preventive and personalized medicine by showing that non-motor symptoms are of vital importance for predicting and categorizing each patients' disease progression pattern, as cognitive decline is oftentimes more reflective of HD progression than its motor aspects. Considering these aspects while counseling and therapy definition will personalize each individuals' treatment. The ability to provide patients with an objective assessment of their disease progression and thus a perspective for their life with HD is the key to improving their quality of life. By conducting additional analysis on biological data from both subtypes, it is possible to gain a deeper understanding of these subtypes and uncover the underlying biological factors of the disease. This greatly aligns with the goal of shifting towards 3P medicine. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00368-2.

Proteomic screens of SEL1L-HRD1 ER-associated degradation substrates reveal its role in glycosylphosphatidylinositol-anchored protein biogenesis.

Endoplasmic reticulum-associated degradation (ERAD) plays indispensable roles in many physiological processes; however, the nature of endogenous substrates remains largely elusive. Here we report a proteomics strategy based on the intrinsic property of the SEL1L-HRD1 ERAD complex to identify endogenous ERAD substrates both in vitro and in vivo. Following stringent filtering using a machine learning algorithm, over 100 high-confidence potential substrates are identified in human HEK293T and mouse brown adipose tissue, among which ~88% are cell type-specific. One of the top shared hits is the catalytic subunit of the glycosylphosphatidylinositol (GPI)-transamidase complex, PIGK. Indeed, SEL1L-HRD1 ERAD attenuates the biogenesis of GPI-anchored proteins by specifically targeting PIGK for proteasomal degradation. Lastly, several PIGK disease variants in inherited GPI deficiency disorders are also SEL1L-HRD1 ERAD substrates. This study provides a platform and resources for future effort to identify proteome-wide endogenous substrates in vivo, and implicates SEL1L-HRD1 ERAD in many cellular processes including the biogenesis of GPI-anchored proteins.

Linearly Polarized Broadband Emission and Multiwavelength Lasing in Solution-Processed Quantum Dots.

A miniature laser with linear polarization is a long sought-after component of photonic integrated circuits. In particular, for multiwavelength polarization lasers, it supports simultaneous access to multiple, widely varying laser wavelengths in a small spatial region, which is of great significance for advancing applications such as optical computing, optical storage, and optical sensing. However, there is a trade-off between the size of small-scale lasers and laser performance, and multiwavelength co-gain of laser media and multicavity micromachining in the process of laser miniaturization remain as significant challenges. Herein, room-temperature linearly polarized multiwavelength lasers in the visible and near-infrared wavelength ranges are demonstrated, by fabricating random cavities scattered with silica in an Er-doped Cs2Ag0.4Na0.6In0.98Bi0.02Cl6 double-perovskite quantum dots gain membrane. By regulating the local symmetry and enabling effective energy transfer in nanocrystals, multiwavelength lasers with ultralow thresholds are achieved at room temperature. The maximum degree of polarization reaches 0.89. With their advantages in terms of miniaturization, ultralow power consumption, and adaptability for integration, these lasers offer a prospective light source for future photonic integrated circuits aimed at high-capacity optical applications.

General synthesis of ionic-electronic coupled two-dimensional materials.

Two-dimensional (2D) AMX2 compounds are a family of mixed ionic and electronic conductors (where A is a monovalent metal ion, M is a trivalent metal, and X is a chalcogen) that offer a fascinating platform to explore intrinsic coupled ionic-electronic properties. However, the synthesis of 2D AMX2 compounds remains challenging due to their multielement characteristics and various by-products. Here, we report a separated-precursor-supply chemical vapor deposition strategy to manipulate the chemical reactions and evaporation of precursors, facilitating the successful fabrication of 20 types of 2D AMX2 flakes. Notably, a 10.4 nm-thick AgCrS2 flake shows superionic behavior at room temperature, with an ionic conductivity of 192.8 mS/cm. Room temperature ferroelectricity and reconfigurable positive/negative photovoltaic currents have been observed in CuScS2 flakes. This study not only provides an effective approach for the synthesis of multielement 2D materials with unique properties, but also lays the foundation for the exploration of 2D AMX2 compounds in electronic, optoelectronic, and neuromorphic devices.

Ubiquitination of cytoplasmic HMGB1 by RNF186 regulates hepatic lipophagy in non-alcoholic fatty liver disease.

BACKGROUND: Lipophagy is a vital biological process that maintains the balance of intracellular lipid metabolism in nonalcoholic fatty liver disease (NAFLD). However, the precise regulatory mechanism of RNF186 in hepatic lipophagy is still unclear. This study investigates the roles and mechanisms of RNF186 in the regulation of lipophagy during the development of NAFLD. METHODS: In this study, we employed RNF186 knockout mice as well as human liver cells and mouse primary hepatocytes (MPHs) to investigate the role and mechanisms of RNF186 in lipophagy during the progression of NAFLD. Additionally, liver specimens from individuals with NAFLD were examined to assess the expression of RNF186 and its associated factors. RESULTS: Here, we provide evidence that depletion of RNF186 enhances lipophagy in hepatocytes of a NAFLD model. Mechanistically, RNF186 acts as an E3 ubiquitin ligase that targets cytoplasmic HMGB1 for lysine 48 (K48)- and K63-linked ubiquitination, leading to its subsequent proteasomal degradation. Importantly, the translocation of HMGB1 from the nucleus to the cytoplasm is responsible for inducing lipophagy in NAFLD samples. Knockdown of HMGB1 significantly reduces the activation of lipophagy and mediates the decrease in lipid accumulation caused by RNF186 depletion in hepatocytes. Furthermore, we find that maintaining the nuclear HMGB1 level and inhibiting its nuclear-cytoplasmic shuttling are critical for the proper function of RNF186 in NAFLD. Additionally, the expression of RNF186 and HMGB1 in human NAFLD samples, along with factors related to lipophagy, suggest that RNF186 may play a similar role in the pathogenesis of human fatty liver. CONCLUSION: RNF186 deficiency accelerates hepatic lipophagy in NAFLD through the inhibition of ubiquitination and degradation of cytoplasmic HMGB1. Consequently, targeting the RNF186-HMGB1 axis may offer a promising strategy for the prevention and treatment of NAFLD.

SEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex.

The SEL1L-HRD1 protein complex represents the most conserved branch of endoplasmic reticulum (ER)-associated degradation (ERAD). Despite recent advances in both mouse models and humans, in vivo evidence for the importance of SEL1L in the ERAD complex formation and its (patho-)physiological relevance in mammals remains limited. Here we report that SEL1L variant p.Ser658Pro (SEL1LS658P) is a pathogenic hypomorphic mutation, causing partial embryonic lethality, developmental delay, and early-onset cerebellar ataxia in homozygous mice carrying the bi-allelic variant. Biochemical analyses reveal that SEL1LS658P variant not only reduces the protein stability of SEL1L, but attenuates the SEL1L-HRD1 interaction, likely via electrostatic repulsion between SEL1L F668 and HRD1 Y30 residues. Proteomic screens of SEL1L and HRD1 interactomes reveal that SEL1L-HRD1 interaction is a prerequisite for the formation of a functional HRD1 ERAD complex, as SEL1L is required for the recruitment of E2 enzyme UBE2J1 as well as DERLIN to HRD1. These data not only establish the disease relevance of SEL1L-HRD1 ERAD, but also provide additional insight into the formation of a functional HRD1 ERAD complex.

Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders.

Recent studies using cell type-specific knockout mouse models have improved our understanding of the pathophysiological relevance of suppressor of lin-12-like-HMG-CoA reductase degradation 1 (SEL1L-HRD1) endoplasmic reticulum-associated (ER-associated) degradation (ERAD); however, its importance in humans remains unclear, as no disease variant has been identified. Here, we report the identification of 3 biallelic missense variants of SEL1L and HRD1 (or SYVN1) in 6 children from 3 independent families presenting with developmental delay, intellectual disability, microcephaly, facial dysmorphisms, hypotonia, and/or ataxia. These SEL1L (p.Gly585Asp, p.Met528Arg) and HRD1 (p.Pro398Leu) variants were hypomorphic and impaired ERAD function at distinct steps of ERAD, including substrate recruitment (SEL1L p.Gly585Asp), SEL1L-HRD1 complex formation (SEL1L p.Met528Arg), and HRD1 activity (HRD1 p.Pro398Leu). Our study not only provides insights into the structure-function relationship of SEL1L-HRD1 ERAD, but also establishes the importance of SEL1L-HRD1 ERAD in humans.

Biallelic Cys141Tyr variant of SEL1L is associated with neurodevelopmental disorders, agammaglobulinemia, and premature death.

Suppressor of lin-12-like-HMG-CoA reductase degradation 1 (SEL1L-HRD1) ER-associated degradation (ERAD) plays a critical role in many physiological processes in mice, including immunity, water homeostasis, and energy metabolism; however, its relevance and importance in humans remain unclear, as no disease variant has been identified. Here, we report a biallelic SEL1L variant (p. Cys141Tyr) in 5 patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. This variant disrupted the formation of a disulfide bond in the luminal fibronectin II domain of SEL1L, largely abolishing the function of the SEL1L-HRD1 ERAD complex in part via proteasomal-mediated self destruction by HRD1. This study reports a disease entity termed ENDI-agammaglobulinemia (ENDI-A) syndrome and establishes an inverse correlation between SEL1L-HRD1 ERAD functionality and disease severity in humans.