The X-linked epigenetic regulator UTX controls NK cell-intrinsic sex differences.

Viral infection outcomes are sex biased, with males generally more susceptible than females. Paradoxically, the numbers of antiviral natural killer (NK) cells are increased in males. We demonstrate that while numbers of NK cells are increased in male mice, they display decreased effector function compared to females in mice and humans. These differences were not solely dependent on gonadal hormones, because they persisted in gonadectomized mice. Kdm6a (which encodes the protein UTX), an epigenetic regulator that escapes X inactivation, was lower in male NK cells, while NK cell-intrinsic UTX deficiency in female mice increased NK cell numbers and reduced effector responses. Furthermore, mice with NK cell-intrinsic UTX deficiency showed increased lethality to mouse cytomegalovirus. Integrative multi-omics analysis revealed a critical role for UTX in regulating chromatin accessibility and gene expression critical for NK cell homeostasis and effector function. Collectively, these data implicate UTX as a critical molecular determinant of sex differences in NK cells.

Cutting Edge: Hypoxia Sensing by the Histone Demethylase UTX (KDM6A) Limits Colitogenic CD4+ T Cells in Mucosal Inflammation.

Hypoxia is a hallmark of inflammatory conditions (e.g., inflammatory bowel disease [IBD]), and adaptive responses have consequently evolved to protect against hypoxia-associated tissue injury. Because augmenting hypoxia-induced protective responses is a promising therapeutic approach for IBD, a more complete understanding of these pathways is needed. Recent work has demonstrated that the histone demethylase UTX is oxygen-sensitive, but its role in IBD is unclear. In this study, we show that hypoxia-induced deactivation of UTX downregulates T cell responses in mucosal inflammation. Hypoxia results in decreased T cell proinflammatory cytokine production and increased immunosuppressive regulatory T cells, and these findings are recapitulated by UTX deficiency. Hypoxia leads to T cell accumulation of H3K27me3 histone modifications, suggesting that hypoxia impairs UTX's histone demethylase activity to dampen T cell colitogenic activity. Finally, T cell-specific UTX deletion ameliorates colonic inflammation in an IBD mouse model, implicating UTX's oxygen-sensitive demethylase activity in counteracting hypoxic inflammation.

The role of adjuvant transcatheter arterial chemoembolization following repeated curative resection/ablation for hepatocellular carcinoma with early recurrence: a propensity score matching analysis.

BACKGROUND: The role of adjuvant transcatheter arterial chemoembolization (TACE) following repeated resection/ablation for recurrent hepatocellular carcinoma (HCC) remains uncertain. The aim of this study was to assess the effectiveness of adjuvant TACE following repeated resection or ablation in patients with early recurrent HCC. METHODS: Information for patients who underwent repeated surgery or radiofrequency ablation (RFA) for early recurrent HCCs (< 2 years) at our institution from January 2017 to December 2020 were collected. Patients were divided into adjuvant TACE and observation groups according to whether they received adjuvant TACE or not. The recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups before and after propensity score matching (PSM). RESULTS: Of the 225 patients enrolled, the median time of HCC recurrence was 11 months (IQR, 6-16 months). After repeated surgery or radiofrequency ablation (RFA) for recurrent tumors, 45 patients (20%) received adjuvant TACE while the remaining 180 (80%) didn't. There were no significant differences in RFS (P = 0.325) and OS (P = 0.072) between adjuvant TACE and observation groups before PSM. There were also no significant differences in RFS (P = 0.897) and OS (P = 0.090) between the two groups after PSM. Multivariable analysis suggested that multiple tumors, liver cirrhosis, and RFA were independent risk factors for the re-recurrence of HCC. CONCLUSION: Adjuvant TACE after repeated resection or ablation for early recurrent HCCs was not associated with a long-term survival benefit in this single-center cohort.

Risk of colorectal cancer in patients with primary sclerosing cholangitis and concomitant inflammatory bowel disease compared with primary sclerosing cholangitis only.

AIM: Primary sclerosing cholangitis (PSC) increases the risk of colorectal cancer (CRC) in inflammatory bowel disease (IBD) patients; however, there is a paucity of literature to suggest PSC alone as an independent risk factor for CRC. We aimed to determine if PSC is an independent risk factor for CRC in a large tertiary care medical center. Optimizing screening intervals is of great importance, given the burden and risks associated with a lifetime of colonoscopy screening. METHODS: This retrospective cohort study consists of patients diagnosed with PSC preceding IBD (PSC-IBD) and PSC-only before January 6, 2023 from a large, tertiary, academic medical center. Patients diagnosed with IBD concurrently or before PSC were excluded to reduce IBD's impact on CRC risk. Demographic data and colonoscopy findings were collected and assessed. RESULTS: Overall, 140 patients from all NYU Langone Health clinical settings were included. Patients with PSC-IBD were more likely to be diagnosed with CRC (23.3% vs. 1.8%, p < 0.01) and either low-grade or uncharacterized dysplasia (16.7% vs. 0.0%, p < 0.01) compared with those with PSC-only. Among PSC-only patients, the estimated CRC risk was significantly elevated compared with that expected of the standard NYU Langone population (SIR 9.2, 95% CI 1.1, 33.2). CONCLUSIONS: Our study revealed a significantly heightened CRC risk in PSC-IBD patients compared with those with PSC-only. Importantly, individuals with PSC-only also face a greater CRC risk compared with the general population. Individuals with PSC-alone may require extended screening and surveillance colonoscopy intervals compared with those with PSC-IBD, yet still require more frequent monitoring than screening guidelines recommend for the general population.

Hidden symmetries generate rigid folding mechanisms in periodic origami.

We consider the zero-energy deformations of periodic origami sheets with generic crease patterns. Using a mapping from the linear folding motions of such sheets to force-bearing modes in conjunction with the Maxwell-Calladine index theorem we derive a relation between the number of linear folding motions and the number of rigid body modes that depends only on the average coordination number of the origami's vertices. This supports the recent result by Tachi [T. Tachi, Origami 6, 97-108 (2015)] which shows periodic origami sheets with triangular faces exhibit two-dimensional spaces of rigidly foldable cylindrical configurations. We also find, through analytical calculation and numerical simulation, branching of this configuration space from the flat state due to geometric compatibility constraints that prohibit finite Gaussian curvature. The same counting argument leads to pairing of spatially varying modes at opposite wavenumber in triangulated origami, preventing topological polarization but permitting a family of zero-energy deformations in the bulk that may be used to reconfigure the origami sheet.

The role of gut microbiota in hepatitis B disease progression and treatment.

Current therapeutic interventions can only suppress hepatitis B virus (HBV) replication or reduce complications without a cure. Therefore, further development of new treatment methods is critical for the global eradication of HBV. Accumulating evidence suggests that the liver and gut share an interconnected relationship referred to as the 'Gut-Liver Axis', where exchanges happen bi-directionally. The gut itself is the host to a unique microbiota profile which has metabolic, immunological, neurological and nutritional functions. Gut microbiota is not only constantly intersecting with the liver but also associated with hepatic injury when dysbiosis occurs. In recent years, there has been increased interest in gut microbiota and its implications on liver disease treatment. Progress has been made in understanding the complex relationship between chronic hepatitis B (CHB) and gut microbiota. New investigative techniques such as colony-free sequencing enabled new perspectives into this field. Mouse models and human studies revealed that HBV infection is associated with significant alteration of gut microbiota, which differ depending on the stage of CHB disease progression. Different mechanisms of the hepatic injury from gut microbiota dysbiosis have also been proposed based on findings of increased intestinal permeability to toxins, disruption of normal bacterial metabolism, and colonization of the gut by oral microbiota. New treatment methods targeting gut microbiota in CHB, such as probiotics and faecal microbiota transplant, have also gained promising results in recent years. The current review recapitulated the most recent investigations into the relationship between gut microbiota and CHB to provide research directions towards the new therapeutic target of CHB.

A systematic review and meta-analysis of the mental health symptoms during the Covid-19 pandemic in Southeast Asia.

AIMS: The Covid-19 pandemic has had a substantial impact on the mental health of the general public and high-risk groups worldwide. Due to its proximity and close links to China, Southeast Asia was one of the first regions to be affected by the outbreak. The aim of this systematic review was to evaluate the prevalence of anxiety, depression and insomnia in the general adult population and healthcare workers (HCWs) in Southeast Asia during the course of the first year of the pandemic. METHODS: Several literature databases were systemically searched for articles published up to February 2021 and two reviewers independently evaluated all relevant studies using pre-determined criteria. The prevalence rates of mental health symptoms were calculated using a random-effect meta-analysis model. RESULTS: In total, 32 samples from 25 studies with 20 352 participants were included. Anxiety was assessed in all 25 studies and depression in 15 studies with pooled prevalence rates of 22% and 16%, respectively. Only two studies assessed insomnia, which was estimated at 19%. The prevalence of anxiety and depression was similar among frontline HCWs (18%), general HCWs (17%), and students (20%) while being noticeably higher in the general population (27%). CONCLUSIONS: This is the first systematic review to investigate the mental health impact of the Covid-19 pandemic in Southeast Asia. A considerable proportion of the general population and HCWs reported mild to moderate symptoms of anxiety and depression; the pooled prevalence rater, however, remain significantly lower than those reported in other areas such as China and Europe.

lncRNA-POIR promotes epithelial-mesenchymal transition and suppresses sorafenib sensitivity simultaneously in hepatocellular carcinoma by sponging miR-182-5p.

Sorafenib (SOR) resistance remains a major obstacle in the effective treatment of hepatocellular carcinoma (HCC). A number of long noncoding RNAs (lncRNAs) are responsible for this chemoresistance. This study aimed to reveal the essential function of a recently defined lncRNA, lncRNA-POIR, in the epithelial-mesenchymal transition (EMT) and SOR sensitivity of HCC cells. SOR-induced cytotoxicity was analyzed via cell counting kit-8 and ethynyl-2'-deoxyuridine incorporation assays, whereas immunoblotting and confocal immunofluorescence were used to determine the expression levels of EMT markers. Furthermore, loss- or gain-of-function approaches were used to demonstrate the role of lncRNA-POIR/miR-182-5p on EMT and SOR sensitivity in HCC. The direct interaction between lncRNA-POIR and miR-182-5p was verified using a luciferase reporter assay. We found that knockdown of lncRNA-POIR sensitized HCC cells to SOR and simultaneously reversed EMT. As expected, miR-182-5p was confirmed as the downstream target of lncRNA-POIR. Moreover, miR-182-5p overexpression clearly reversed EMT and promoted SOR-induced cytotoxicity in representative HCC cells, whereas miR-182-5p downregulation played a contrasting role; miR-182-5p knockdown abolished the modulatory effects of lncRNA-POIR siRNA on EMT and SOR sensitivity. Together, these pieces of data suggest that lncRNA-POIR promotes EMT progression and suppresses SOR sensitivity simultaneously by sponging miR-182-5p. Thus, we proposed a compelling rationale for the use of lncRNA-POIR as a promising predictor of SOR response and as a potential therapeutic target for HCC treatment in the future.

Topology in Nonlinear Mechanical Systems.

Many advancements have been made in the field of topological mechanics. The majority of the work, however, concerns the topological invariant in a linear theory. In this Letter, we present a generic prescription to define topological indices that accommodates nonlinear effects in mechanical systems without taking any approximation. Invoking the tools of differential geometry, a Z-valued quantity in terms of a topological index in differential geometry known as the Poincaré-Hopf index, which features the topological invariant of nonlinear zero modes (ZMs), is predicted. We further identify one type of topologically protected solitons that are robust to disorders. Our prescription constitutes a new direction of searching for novel topologically protected nonlinear ZMs in the future.

Typhoon eye effect versus ripple effect: the role of family size on mental health during the COVID-19 pandemic in Pakistan.

BACKGROUND: The recent outbreak of COVID-19 has impacted adversely upon the mental health of millions of people worldwide. Impacts on the mental health conditions and the associated predictors relating to adults in Pakistan, the fifth most populous country in the world, during the COVID-19 remain understudied. Our aim was to investigate distress, anxiety, and overall mental health and their associated predictors among Pakistani adults in this pandemic. We specifically examine mental health issues based on the distance from the epicenter, (a predictor that has revealed opposing evidence in other countries) based on the theories of typhoon eye effect and ripple effect. The sample consisted of 601 adults who were surveyed online about 2.5 months into the outbreak across Pakistan with varying distances from the epicenter of COVID-19 of Karachi. RESULTS: The results showed that 9.2 and 19.0% of the participants surpassed the cut-off criteria for distress and anxiety disorders, respectively. Overall, the distance from the epicenter positively predicted the mental health of adults in Pakistan, and family size negatively moderated this effect. The distance from the epicenter negatively predicted distress and anxiety disorders for adults in large families, which are quite common in Pakistan. CONCLUSION: The evidence of the study interestingly finds that the prediction of the mental health of people by their distance from the epicenter depends on family size. The evidence of this study can help to provide initial indicators for mental health care providers to screen vulnerable groups in Pakistan, a populous country that continues struggling to cope with the COVID-19 pandemic.

Carcinosarcoma of the pancreas: comprehensive clinicopathological and molecular characterization.

BACKGROUND: Carcinosarcoma of pancreas is a rare subtype of pancreatic cancer. The aim of this study was to comprehensively elaborate the clinicopathological and molecular features of this rare malignancy. METHODS: Patients who were diagnosed with carcinosarcoma of the pancreas were retrospectively identified from pathology database of a single institution between 2012 and 2018. RESULTS: A total of nine patients were identified. Pathological examination of tumor tissues from included patients showed coexisting carcinomatous and sarcomatous components. These two components were distinguished by mutually exclusive expression of cytokeratin and vimentin. The sarcomatous tissue exhibited more extensive proliferation, as revealed by Ki67 staining, and necrosis compared with the carcinomatous counterpart. Genomic analysis of tumor tissues for two patients demonstrated hotspot mutation at KRAS and TP53. Carcinomatous and sarcomatous components were separately obtained via laser captured microdissection in one patient, and mutations of driving genes were highly concordant between them. Besides, immunostaining of frequently-altered tumor suppressor genes for these two components suggested consistent expression patterns. The median overall survival for six patients with adequate follow-up was 14 months. CONCLUSION: Carcinosarcoma of the pancreas represent a rare malignancy with distinct histological characteristics. Genomic and molecular analysis suggested monoclonal origin of carcinomatous and sarcomatous components.

Distortion-controlled isotropic swelling: numerical study of free boundary swelling patterns.

Modern fabrication tools have now provided a number of platforms for designing flat sheets that, by virtue of their nonuniform growth, can buckle and fold into target three-dimensional structures. Theoretically, there is an infinitude of growth patterns that can produce the same shape, yet almost nothing is understood about which of these many growth patterns is optimal from the point of view of experiment, and few can even be realized at all. Here, we ask the question: what is the optimal way to design isotropic growth patterns for a given target shape? We propose a computational algorithm to produce optimal growth patterns by introducing cuts into the target surfaces. Within this framework, we propose that the patterns requiring the fewest or shortest cuts produce the best approximations to the target shape at finite thickness. The results are tested by simulation on spherical surfaces, and new challenges are highlighted for surfaces with both positive and negative Gaussian curvatures.

The role of rigidity in controlling material failure.

We investigate how material rigidity acts as a key control parameter for the failure of solids under stress. In both experiments and simulations, we demonstrate that material failure can be continuously tuned by varying the underlying rigidity of the material while holding the amount of disorder constant. As the rigidity transition is approached, failure due to the application of uniaxial stress evolves from brittle cracking to system-spanning diffuse breaking. This evolution in failure behavior can be parameterized by the width of the crack. As a system becomes more and more floppy, this crack width increases until it saturates at the system size. Thus, the spatial extent of the failure zone can be used as a direct probe for material rigidity.

Nonlinear conduction via solitons in a topological mechanical insulator.

Networks of rigid bars connected by joints, termed linkages, provide a minimal framework to design robotic arms and mechanical metamaterials built of folding components. Here, we investigate a chain-like linkage that, according to linear elasticity, behaves like a topological mechanical insulator whose zero-energy modes are localized at the edge. Simple experiments we performed using prototypes of the chain vividly illustrate how the soft motion, initially localized at the edge, can in fact propagate unobstructed all of the way to the opposite end. Using real prototypes, simulations, and analytical models, we demonstrate that the chain is a mechanical conductor, whose carriers are nonlinear solitary waves, not captured within linear elasticity. Indeed, the linkage prototype can be regarded as the simplest example of a topological metamaterial whose protected mechanical excitations are solitons, moving domain walls between distinct topological mechanical phases. More practically, we have built a topologically protected mechanism that can perform basic tasks such as transporting a mechanical state from one location to another. Our work paves the way toward adopting the principle of topological robustness in the design of robots assembled from activated linkages as well as in the fabrication of complex molecular nanostructures.

Mechanical Weyl Modes in Topological Maxwell Lattices.

We show that two-dimensional mechanical lattices can generically display topologically protected bulk zero-energy phonon modes at isolated points in the Brillouin zone, analogs of massless fermion modes of Weyl semimetals. We focus on deformed square lattices as the simplest Maxwell lattices, characterized by equal numbers of constraints and degrees of freedom, with this property. The Weyl points appear at the origin of the Brillouin zone along directions with vanishing sound speed and move away to the zone edge (or return to the origin) where they annihilate. Our results suggest a design strategy for topological metamaterials with bulk low-frequency acoustic modes and elastic instabilities at a particular, tunable finite wave vector.

Topological Mechanics of Origami and Kirigami.

Origami and kirigami have emerged as potential tools for the design of mechanical metamaterials whose properties such as curvature, Poisson ratio, and existence of metastable states can be tuned using purely geometric criteria. A major obstacle to exploiting this property is the scarcity of tools to identify and program the flexibility of fold patterns. We exploit a recent connection between spring networks and quantum topological states to design origami with localized folding motions at boundaries and study them both experimentally and theoretically. These folding motions exist due to an underlying topological invariant rather than a local imbalance between constraints and degrees of freedom. We give a simple example of a quasi-1D folding pattern that realizes such topological states. We also demonstrate how to generalize these topological design principles to two dimensions. A striking consequence is that a domain wall between two topologically distinct, mechanically rigid structures is deformable even when constraints locally match the degrees of freedom.

Origami multistability: from single vertices to metasheets.

We show that the simplest building blocks of origami-based materials-rigid, degree-four vertices-are generically multistable. The existence of two distinct branches of folding motion emerging from the flat state suggests at least bistability, but we show how nonlinearities in the folding motions allow generic vertex geometries to have as many as five stable states. In special geometries with collinear folds and symmetry, more branches emerge leading to as many as six stable states. Tuning the fold energy parameters, we show how monostability is also possible. Finally, we show how to program the stability features of a single vertex into a periodic fold tessellation. The resulting metasheets provide a previously unanticipated functionality-tunable and switchable shape and size via multistability.

Decreased expression of H19/miR-675 ameliorates hypoxia-induced oxaliplatin resistance in colorectal cancer.

Hypoxic microenvironment, a hallmark of solid tumors, contributes to chemoresistance, and long noncoding (lnc) RNAs are involved in hypoxia-induced drug resistance. However, the role of lncRNAs in hypoxic tumor chemotherapy resistance remains unclear. Here, we aimed to elucidate the effects of lncRNAs in hypoxia-mediated resistance in colorectal cancer (CRC), as well as the underlying mechanisms. The results indicated that the expression of lncRNA H19 was enhanced in hypoxia- or oxaliplatin-treated CRC cells; moreover, H19 contributed to drug resistance in CRC cells both in vitro and in vivo. Mechanistically, H19 was noted to act as a competitive endogenous RNA of miR-675-3p to regulate epithelial-mesenchymal transition (EMT). Notably, an miR-675-3p mimic could attenuate the effects of H19 deficiency in CRC cells with hypoxia-induced chemoresistance. In conclusion, H19 downregulation may counteract hypoxia-induced chemoresistance by sponging miR-675-3p to regulate EMT; as such, the H19/miR-675-3p axis might be a promising therapeutic target for drug resistance in CRC.

ABO-adjusted cPRA metric for kidney allocation in an Asian-predominant population.

Recent studies showed that ABO-adjusted calculated panel reactive antibody (ABO-cPRA) may better reflect the histocompatibility level in a multi-ethnic population, but such data in Asians is not available. We developed an ABO-adjusted cPRA metric on a cohort of waitlist kidney transplant patients (n = 647, 99% Chinese) in Hong Kong, based on HLA alleles and ABO frequencies of local donors. The concordance between the web-based ABO-cPRA calculator and the impact on kidney allocation were evaluated. The blood group distribution for A, B, O and AB among waitlist kidney candidates were 26.2%, 27.5%, 40.1%, and 6.1%, and their chances of encountering incompatible blood group donors were 32.6%, 32.4%, 57.6%, and 0%, respectively. There is poor agreement between web-based ABO-cPRA calculator and our locally developed metrics. Over 90% of patients showed an increase in cPRA after ABO adjustment, most notably in those with cPRA between 70% and 79%. Blood group O patients had a much greater increase in cPRA scores after adjustment while patients of blood group A and B had similar increment. 10.6% of non-AB blood group waitlist patients had ABO-cPRA elevated to ≥80%. A local ABO-adjusted cPRA metric is required for Asian populations and may improve equity in kidney distribution for patients with disadvantageous blood groups. The result from the current study potentially helps other countries/localities in establishing their own unified ABO-cPRA metrics and predict the impact on kidney allocation.

Application of enzyme-linked immunosorbent assay to detect antimicrobial peptides in human intestinal lumen.

Intestinal transplantation is the definitive treatment for intestinal failure. However, tissue rejection and graft-versus-host disease are relatively common complications, necessitating aggressive immunosuppression that can itself pose further complications. Tracking intraluminal markers in ileal effluent from standard ileostomies may present a noninvasive and sensitive way to detect developing pathology within the intestinal graft. This would be an improvement compared to current assessments, which are limited by poor sensitivity and specificity, contributing to under or over-immunosuppression, respectively, and by the need for invasive biopsies. Herein, we report an approach to reproducibly analyze ileal fluid obtained through stoma sampling for antimicrobial peptide/protein concentrations, reasoning that these molecules may provide an assessment of intestinal homeostasis and levels of intestinal inflammation over time. Concentrations of lysozyme (LYZ), myeloperoxidase (MPO), calprotectin (S100A8/A9) and ß-defensin 2 (DEFB2) were assessed using adaptations of commercially available enzyme-linked immunosorbent assays (ELISAs). The concentration of α-defensin 5 (DEFA5) was assessed using a newly developed sandwich ELISA. Our data support that with proper preparation of ileal effluent specimens, precise and replicable determination of antimicrobial peptide/protein concentrations can be achieved for each of these target molecules via ELISA. This approach may prove to be reliable as a clinically useful assessment of intestinal homeostasis over time for patients with ileostomies.