Sex differences orchestrated by androgens at single-cell resolution.

Sex differences in mammalian complex traits are prevalent and are intimately associated with androgens1-7. However, a molecular and cellular profile of sex differences and their modulation by androgens is still lacking. Here we constructed a high-dimensional single-cell transcriptomic atlas comprising over 2.3 million cells from 17 tissues in Mus musculus and explored the effects of sex and androgens on the molecular programs and cellular populations. In particular, we found that sex-biased immune gene expression and immune cell populations, such as group 2 innate lymphoid cells, were modulated by androgens. Integration with the UK Biobank dataset revealed potential cellular targets and risk gene enrichment in antigen presentation for sex-biased diseases. This study lays the groundwork for understanding the sex differences orchestrated by androgens and provides important evidence for targeting the androgen pathway as a broad therapeutic strategy for sex-biased diseases.

Post-translational control of beige fat biogenesis by PRDM16 stabilization.

Compelling evidence shows that brown and beige adipose tissue are protective against metabolic diseases1,2. PR domain-containing 16 (PRDM16) is a dominant activator of the biogenesis of beige adipocytes by forming a complex with transcriptional and epigenetic factors and is therefore an attractive target for improving metabolic health3-8. However, a lack of knowledge surrounding the regulation of PRDM16 protein expression hampered us from selectively targeting this transcriptional pathway. Here we identify CUL2-APPBP2 as the ubiquitin E3 ligase that determines PRDM16 protein stability by catalysing its polyubiquitination. Inhibition of CUL2-APPBP2 sufficiently extended the half-life of PRDM16 protein and promoted beige adipocyte biogenesis. By contrast, elevated CUL2-APPBP2 expression was found in aged adipose tissues and repressed adipocyte thermogenesis by degrading PRDM16 protein. Importantly, extended PRDM16 protein stability by adipocyte-specific deletion of CUL2-APPBP2 counteracted diet-induced obesity, glucose intolerance, insulin resistance and dyslipidaemia in mice. These results offer a cell-autonomous route to selectively activate the PRDM16 pathway in adipose tissues.

Bulk-disclination correspondence in topological crystalline insulators.

Most natural and artificial materials have crystalline structures from which abundant topological phases emerge1-6. However, the bulk-edge correspondence-which has been widely used in experiments to determine the band topology from edge properties-is inadequate in discerning various topological crystalline phases7-16, leading to challenges in the experimental classification of the large family of topological crystalline materials4-6. It has been theoretically predicted that disclinations-ubiquitous crystallographic defects-can provide an effective probe of crystalline topology beyond edges17-19, but this has not yet been confirmed in experiments. Here we report an experimental demonstration of bulk-disclination correspondence, which manifests as fractional spectral charge and robust bound states at the disclinations. The fractional disclination charge originates from the symmetry-protected bulk charge patterns-a fundamental property of many topological crystalline insulators (TCIs). Furthermore, the robust bound states at disclinations emerge as a secondary, but directly observable, property of TCIs. Using reconfigurable photonic crystals as photonic TCIs with higher-order topology, we observe these hallmark features via pump-probe and near-field detection measurements. It is shown that both the fractional charge and the localized states emerge at the disclination in the TCI phase but vanish in the trivial phase. This experimental demonstration of bulk-disclination correspondence reveals a fundamental phenomenon and a paradigm for exploring topological materials.

A highly stable and flexible zeolite electrolyte solid-state Li-air battery.

Solid-state lithium (Li)-air batteries are recognized as a next-generation solution for energy storage to address the safety and electrochemical stability issues that are encountered in liquid battery systems1-4. However, conventional solid electrolytes are unsuitable for use in solid-state Li-air systems owing to their instability towards lithium metal and/or air, as well as the difficulty in constructing low-resistance interfaces5. Here we present an integrated solid-state Li-air battery that contains an ultrathin, high-ion-conductive lithium-ion-exchanged zeolite X (LiX) membrane as the sole solid electrolyte. This electrolyte is integrated with cast lithium as the anode and carbon nanotubes as the cathode using an in situ assembly strategy. Owing to the intrinsic chemical stability of the zeolite, degeneration of the electrolyte from the effects of lithium or air is effectively suppressed. The battery has a capacity of 12,020 milliamp hours per gram of carbon nanotubes, and has a cycle life of 149 cycles at a current density of 500 milliamps per gram and at a capacity of 1,000 milliamp hours per gram. This cycle life is greater than those of batteries based on lithium aluminium germanium phosphate (12 cycles) and organic electrolytes (102 cycles) under the same conditions. The electrochemical performance, flexibility and stability of zeolite-based Li-air batteries confer practical applicability that could extend to other energy-storage systems, such as Li-ion, Na-air and Na-ion batteries.

A predictive model for therapy failure in chronic myeloid leukemia patients receiving tyrosine kinase inhibitor therapy.

Although tyrosine kinase inhibitor (TKI) therapy has markedly improved the survival of people with chronic-phase chronic myeloid leukemia (CML), 20-30% of people still experienced therapy failure. Data from 1,955 consecutive subjects with chronic-phase CML diagnosed by the European LeukemiaNet (ELN) recommendations from 1 center receiving initial TKI imatinib or a second-generation (2G-) TKI therapy were interrogated to develop a clinical prediction model for TKI therapy failure. This model was subsequently validated in 3,454 subjects from 76 other centers. Using the predictive clinical co-variates associated with TKI therapy failure, we developed a model that stratified subjects into low-, intermediate- and high-risk subgroups with significantly different cumulative incidences of therapy failure (p < 0.001). There was good discrimination and calibration in the external validation dataset, and the performance was consistent with that of the training dataset. Our model had the better prediction discrimination than the Sokal and ELTS scores did, with the greater time-dependent area under the receiver-operator characteristic curve (AUROC) values and a better ability to re-defined the risk of therapy failure. Our model could help physicians estimate the likelihood of initial imatinib or 2G-TKI therapy failure in people with chronic-phase CML.

Nomo1 deficiency causes autism-like behavior in zebrafish.

Patients with neuropsychiatric disorders often exhibit a combination of clinical symptoms such as autism, epilepsy, or schizophrenia, complicating diagnosis and development of therapeutic strategies. Functional studies of novel genes associated with co-morbidities can provide clues to understand the pathogenic mechanisms and interventions. NOMO1 is one of the candidate genes located at 16p13.11, a hotspot of neuropsychiatric diseases. Here, we generate nomo1-/- zebrafish to get further insight into the function of NOMO1. Nomo1 mutants show abnormal brain and neuronal development and activation of apoptosis and inflammation-related pathways in the brain. Adult Nomo1-deficient zebrafish exhibit multiple neuropsychiatric behaviors such as hyperactive locomotor activity, social deficits, and repetitive stereotypic behaviors. The Habenular nucleus and the pineal gland in the telencephalon are affected, and the melatonin level of nomo1-/- is reduced. Melatonin treatment restores locomotor activity, reduces repetitive stereotypic behaviors, and rescues the noninfectious brain inflammatory responses caused by nomo1 deficiency. These results suggest melatonin supplementation as a potential therapeutic regimen for neuropsychiatric disorders caused by NOMO1 deficiency.

Transparent ferroelectric crystals with ultrahigh piezoelectricity.

Transparent piezoelectrics are highly desirable for numerous hybrid ultrasound-optical devices ranging from photoacoustic imaging transducers to transparent actuators for haptic applications1-7. However, it is challenging to achieve high piezoelectricity and perfect transparency simultaneously because most high-performance piezoelectrics are ferroelectrics that contain high-density light-scattering domain walls. Here, through a combination of phase-field simulations and experiments, we demonstrate a relatively simple method of using an alternating-current electric field to engineer the domain structures of originally opaque rhombohedral Pb(Mg1/3Nb2/3)O3-PbTiO3 (PMN-PT) crystals to simultaneously generate near-perfect transparency, an ultrahigh piezoelectric coefficient d33 (greater than 2,100 picocoulombs per newton), an excellent electromechanical coupling factor k33 (about 94 per cent) and a large electro-optical coefficient γ33 (approximately 220 picometres per volt), which is far beyond the performance of the commonly used transparent ferroelectric crystal LiNbO3. We find that increasing the domain size leads to a higher d33 value for the [001]-oriented rhombohedral PMN-PT crystals, challenging the conventional wisdom that decreasing the domain size always results in higher piezoelectricity8-10. This work presents a paradigm for achieving high transparency and piezoelectricity by ferroelectric domain engineering, and we expect the transparent ferroelectric crystals reported here to provide a route to a wide range of hybrid device applications, such as medical imaging, self-energy-harvesting touch screens and invisible robotic devices.

Heterochromatin repeat organization at an individual level: Rex1BD and the 14-3-3 protein coordinate to shape the epigenetic landscape within heterochromatin repeats.

In eukaryotic cells, heterochromatin is typically composed of tandem DNA repeats and plays crucial roles in gene expression and genome stability. It has been reported that silencing at individual units within tandem heterochromatin repeats exhibits a position-dependent variation. However, how the heterochromatin is organized at an individual repeat level remains poorly understood. Using a novel genetic approach, our recent study identified a conserved protein Rex1BD required for position-dependent silencing within heterochromatin repeats. We further revealed that Rex1BD interacts with the 14-3-3 protein to regulate heterochromatin silencing by linking RNAi and HDAC pathways. In this review, we discuss how Rex1BD and the 14-3-3 protein coordinate to modulate heterochromatin organization at the individual repeat level, and comment on the biological significance of the position-dependent effect in heterochromatin repeats. We also identify the knowledge gaps that still need to be unveiled in the field.

Rex1BD and the 14-3-3 protein control heterochromatin organization at tandem repeats by linking RNAi and HDAC.

Tandem DNA repeats are often organized into heterochromatin that is crucial for genome organization and stability. Recent studies revealed that individual repeats within tandem DNA repeats can behave very differently. How DNA repeats are assembled into distinct heterochromatin structures remains poorly understood. Here, we developed a genome-wide genetic screen using a reporter gene at different units in a repeat array. This screen led to identification of a conserved protein Rex1BD required for heterochromatin silencing. Our structural analysis revealed that Rex1BD forms a four-helix bundle structure with a distinct charged electrostatic surface. Mechanistically, Rex1BD facilitates the recruitment of Clr6 histone deacetylase (HDAC) by interacting with histones. Interestingly, Rex1BD also interacts with the 14-3-3 protein Rad25, which is responsible for recruiting the RITS (RNA-induced transcriptional silencing) complex to DNA repeats. Our results suggest that coordinated action of Rex1BD and Rad25 mediates formation of distinct heterochromatin structure at DNA repeats via linking RNAi and HDAC pathways.

Near-room-temperature water-mediated densification of bulk van der Waals materials from their nanosheets.

The conventional fabrication of bulk van der Waals (vdW) materials requires a temperature above 1,000 °C to sinter from the corresponding particulates. Here we report the near-room-temperature densification (for example, ∼45 °C for 10 min) of two-dimensional nanosheets to form strong bulk materials with a porosity of <0.1%, which are mechanically stronger than the conventionally made ones. The mechanistic study shows that the water-mediated activation of van der Waals interactions accounts for the strong and dense bulk materials. Initially, water adsorbed on two-dimensional nanosheets lubricates and promotes alignment. The subsequent extrusion closes the gaps between the aligned nanosheets and densifies them into strong bulk materials. Water extrusion also generates stresses that increase with moulding temperature, and too high a temperature causes intersheet misalignment; therefore, a near-room-temperature moulding process is favoured. This technique provides an energy-efficient alternative to design a wide range of dense bulk van der Waals materials with tailored compositions and properties.

Transcription factor CmHSFA4-CmMYBS3 complex enhances salt tolerance in chrysanthemum by repressing CmMYB121 expression.

Excessive soil salinity not only hampers plant growth and development but can also lead to plant death. Previously, we found that heat shock factor A4 (CmHSFA4) enhances the tolerance of chrysanthemum (Chrysanthemum morifolium) to salt. However, the underlying molecular mechanism remains unclear. In this study, we identified a candidate MYB transcription factor, CmMYB121, which responded to salt stress. We observed that the CmMYB121 transcription is suppressed by CmHSFA4. Moreover, overexpression of CmMYB121 exacerbated chrysanthemum sensitivity to salt stress. CmHSFA4 directly bound to the promoter of CmMYB121 at the heat shock element (HSE). Protein-protein interaction assays identified an interaction between CmHSFA4 and CmMYBS3, a transcriptional repressor, and recruited the corepressor TOPLESS (CmTPL) to inhibit CmMYB121 transcription by impairing the H3 and H4 histone acetylation levels of CmMYB121. Our study demonstrated that a CmHSFA4-CmMYBS3-CmTPL complex modulates CmMYB121 expression, consequently regulating the tolerance of chrysanthemum to salt. The findings shed light on the responses of plants to salt stress.

IL-21 promoting angiogenesis contributes to the development of psoriasis.

BACKGROUND: Elevated IL-21 expression which can effectively induce Th17 cell differentiation has been implicated in the pathogenesis of psoriasis, but its role in angiogenesis remains poorly understood. METHODS: PASI and PSI score assessment was applied to evaluate the severity of psoriatic lesions. The expression of IL-21, IL-21 receptor (IL-21R), CD31, VEGFA, MMP-9, and ICAM-1 in skin was determined by immunohistochemistry or quantitative real-time polymerase chain reaction. The serum level of IL-21 was measured by enzyme-linked immunosorbent assay (ELISA). Then, their correlation was analyzed statistically. Human umbilical vein endothelial cells (HUVECs) cocultured with conditional medium from normal human epidermal keratinocytes (NHEKs) were treated with IL-21 and/or M5 cocktail (mixture of IL-1α, IL-17A, IL-22, TNF-α, and oncostatin M). The migration and tube formation of HUVECs were detected, and the levels of VEGFA, MMP-9, and ICAM-1 in NHEKs were measured by Western blotting or ELISA. RESULTS: Increased IL-21 and IL-21R expression was observed in psoriatic sera or skin specimens, with IL-21R mainly locating in keratinocytes and IL-21 in immune cells. Pearson analysis showed significantly positive correlation between IL-21/IL-21R and erythema scores/microvessel density in psoriatic lesions. Moreover, the expression of proangiogenic genes, VEGFA, ICAM-1, and MMP-9 was upregulated in skins of psoriasis. Additionally, in M5 microenvironment, migration and tube formation could be magnified in HUVECs using IL-21 pre-treated NHEK medium. Mechanically, the co-stimulation of IL-21 and M5 to NEHKs increased the expression of ICAM-1. CONCLUSION: IL-21 could regulate keratinocytes to secrete ICAM-1, thereby promoting angiogenesis in psoriasis.

Downregulation of miR-503-5p Promotes the Development of Pancreatic Cancer by Targeting Cyclin E2.

This study aimed to elucidate the role of microRNA-503 (miR-503) in pancreatic cancer (PC) progression and the underlying regulatory mechanisms. We acquired miR-503-3p and miR-503-5p expression data along with survival times of PC and normal samples from the UCSC Xena database. Using the t-test, we compared the expression of miR-503-3p and miR-503-5p between PC and normal samples, and evaluated their prognostic significance via Kaplan-Meier survival analysis. The expression of miR-503-5p in PC cells was detected by quantitative PCR. We subsequently overexpressed miR-503-5p in PC cells and examined cell viability, apoptosis, and migration through CCK8 assay, flow cytometry, and Transwell assay, respectively. Potential functional targets were identified using miRTarBase and validated by dual-luciferase reporter assay. Both miR-503-3p and miR-503-5p expression were found to be downregulated in PC; however, only miR-503-5p was linked to cancer prognosis based on public data. In vitro experiments demonstrated that overexpression of miR-503-5p substantially decreased cell viability, induced apoptosis, caused G0/G1 arrest, and inhibited cell migration. miR-503-5p was found to target cyclin E2 (CCNE2), and overexpression of CCNE2 could counteract the effects of miR-503-5p on PC cells. Conclusion: The downregulation of miR-503-5p enhances the progression of PC by targeting CCNE2. The detection of miR-503-5p expression may provide valuable insights for the prevention and prognostic evaluation of PC.

Ciliary neurotrophic factor promotes the development of homocysteine-induced vascular endothelial injury through inflammation mediated by the JAK2/STAT3 signaling pathway.

Elevated homocysteine (Hcy) levels have been recognized as significant risk factor for cardiovascular and cerebrovascular diseases, closely related to endothelial injury. While expression of Ciliary Neurotrophic Factor (CNTF) significantly increases during Hcy-induced vascular endothelial cell injury, the precise molecular pathways through which CNTF operates remain to be clarified. To induce vascular endothelial cell injury, human umbilical vein endothelial cells (HUVECs) were treated with Hcy. Cell viability and apoptosis in HUVECs were assessed using the CCK-8 assay and flow cytometry. Western blot analysis determined the expression levels of the JAK2-STAT3 pathway, inflammation-related factors (IL-1ß, NLRP3, ICAM-1, VCAM-1), and apoptosis-related factors (cleaved Caspase-3 and Bax). Immunofluorescence staining and western blotting were employed to examine CD31 and α-SMA expression. Knockdown of CNTF was achieved using lentiviral interference, and its effects on inflammation and cell injury were evaluated. Chromatin immunoprecipitation (ChIP) and dual luciferase reporter analysis were conducted to investigate the interaction between the MAFK and CNTF promoters. Our results indicated that Hcy induced high expression of CNTF and activated the JAK2-STAT3 signaling pathway, thereby upregulating factors associated with inflammation and cell apoptosis. Inhibiting CNTF alleviated Hcy-induced inflammation and cell injury. MAFK was identified as a transcription factor promoting CNTF transcription, and its overexpression exacerbated inflammation and cell injury in Hcy-treated HUVECs through the CNTF-JAK2-STAT3 axis, which could be reversed by knocking down CNTF. Activation of MAFK leads to CNTF upregulation, which activates the JAK2-STAT3 signaling pathway, regulating inflammation and inducing injury in Hcy-exposed vascular endothelial cells. Targeting CNTF or its upstream regulator MAFK may represent potential therapeutic strategies for mitigating endothelial dysfunction associated with hyperhomocysteinemia and cardiovascular diseases.

Differential cortical gray matter changes in early- and late-onset patients with amyotrophic lateral sclerosis.

Age at onset may be an important feature associated with distinct subtypes of amyotrophic lateral sclerosis (ALS). Little is known about the neuropathological mechanism of early-onset ALS (EO-ALS) and late-onset ALS (LO-ALS). Ninety ALS patients were divided into EO-ALS and LO-ALS group, and 128 healthy controls were matched into young controls(YCs) and old controls (OCs). A voxel-based morphometry approach was employed to investigate differences in gray matter volume (GMV). Significant age at onset-by-diagnosis interactions were found in the left parietal operculum, left precentral gyrus, bilateral postcentral gyrus, right occipital gyrus, and right orbitofrontal cortex. Post hoc analysis revealed a significant decrease in GMV in all affected regions of EO-ALS patients compared with YCs, with increased GMV in 5 of the 6 brain regions, except for the right orbitofrontal cortex, in LO-ALS patients compared with OCs. LO-ALS patients had a significantly increased GMV than EO-ALS patients after removing the aging effect. Correspondingly, GMV of the left postcentral gyrus correlated with disease severity in the 2 ALS groups. Our findings suggested that the pathological mechanisms in ALS patients with different ages at onset might differ. These findings provide unique insight into the clinical and biological heterogeneity of the 2 ALS subtypes.

Shared and differing functional connectivity abnormalities of the default mode network in mild cognitive impairment and Alzheimer's disease.

Alzheimer's disease (AD) and mild cognitive impairment (MCI) both show abnormal resting-state functional connectivity (rsFC) of default mode network (DMN), but it is unclear to what extent these abnormalities are shared. Therefore, we performed a comprehensive meta-analysis, including 31 MCI studies and 20 AD studies. MCI patients, compared to controls, showed decreased within-DMN rsFC in bilateral medial prefrontal cortex/anterior cingulate cortex (mPFC/ACC), precuneus/posterior cingulate cortex (PCC), right temporal lobes, and left angular gyrus and increased rsFC between DMN and left inferior temporal gyrus. AD patients, compared to controls, showed decreased rsFC within DMN in bilateral mPFC/ACC and precuneus/PCC and between DMN and left inferior occipital gyrus and increased rsFC between DMN and right dorsolateral prefrontal cortex. Conjunction analysis showed shared decreased rsFC in mPFC/ACC and precuneus/PCC. Compared to MCI, AD had decreased rsFC in left precuneus/PCC and between DMN and left inferior occipital gyrus and increased rsFC in right temporal lobes. MCI and AD share a decreased within-DMN rsFC likely underpinning episodic memory deficits and neuropsychiatric symptoms, but differ in DMN rsFC alterations likely related to impairments in other cognitive domains such as language, vision, and execution. This may throw light on neuropathological mechanisms in these two stages of dementia.

Serum Proteomics Identifies Biomarkers Associated With the Pathogenesis of Idiopathic Pulmonary Fibrosis.

The heterogeneity of idiopathic pulmonary fibrosis (IPF) limits its diagnosis and treatment. The association between the pathophysiological features and the serum protein signatures of IPF currently remains unclear. The present study analyzed the specific proteins and patterns associated with the clinical parameters of IPF based on a serum proteomic dataset by data-independent acquisition using MS. Differentiated proteins in sera distinguished patients with IPF into three subgroups in signal pathways and overall survival. Aging-associated signatures by weighted gene correlation network analysis coincidently provided clear and direct evidence that aging is a critical risk factor for IPF rather than a single biomarker. Expression of LDHA and CCT6A, which was associated with glucose metabolic reprogramming, was correlated with high serum lactic acid content in patients with IPF. Cross-model analysis and machine learning showed that a combinatorial biomarker accurately distinguished patients with IPF from healthy individuals with an area under the curve of 0.848 (95% CI = 0.684-0.941) and validated from another cohort and ELISA assay. This serum proteomic profile provides rigorous evidence that enables an understanding of the heterogeneity of IPF and protein alterations that could help in its diagnosis and treatment decisions.

Single-cell transcriptome analysis reveals the association between histone lactylation and cisplatin resistance in bladder cancer.

Patients with bladder cancer (BCa) frequently acquires resistance to platinum-based chemotherapy, particularly cisplatin. This study centered on the mechanism of cisplatin resistance in BCa and highlighted the pivotal role of lactylation in driving this phenomenon. Utilizing single-cell RNA sequencing, we delineated the single-cell landscape of Bca, pinpointing a distinctive subset of BCa cells that exhibit marked resistance to cisplatin with association with glycolysis metabolism. Notably, we observed that H3 lysine 18 lactylation (H3K18la) plays a crucial role in activating the transcription of target genes by enriching in their promoter regions. Targeted inhibition of H3K18la effectively restored cisplatin sensitivity in these cisplatin-resistant epithelial cells. Furthermore, H3K18la-driven key transcription factors YBX1 and YY1 promote cisplatin resistance in BCa. These findings enhance our understanding of the mechanisms underlying cisplatin resistance, offering valuable insights for identifying novel intervention targets to overcome drug resistance in Bca.

Increased oxygen stimulation promotes chemoresistance and phenotype shifting through PLCB1 in gliomas.

Gliomas, the most common CNS (central nerve system) tumors, face poor survival due to severe chemoresistance exacerbated by hypoxia. However, studies on whether altered hypoxic conditions benefit for chemo-sensitivity and how gliomas react to increased oxygen stimulation are limited. In this study, we demonstrated that increased oxygen stimulation promotes glioma growth and chemoresistance. Mechanically, increased oxygen stimulation upregulates miR-1290 levels. miR-1290, in turn, downregulates PLCB1, while PLCB1 facilitates the proteasomal degradation of ß-catenin and active-ß-catenin by increasing the proportion of ubiquitinated ß-catenin in a destruction complex-independent mechanism. This process inhibits PLCB1 expression, leads to the accumulation of active-ß-catenin, boosting Wnt signaling through an independent mechanism and ultimately promoting chemoresistance in glioma cells. Pharmacological inhibition of Wnt by WNT974 could partially inhibit glioma volume growth and prolong the shortened survival caused by increased oxygen stimulation in a glioma-bearing mouse model. Moreover, PLCB1, a key molecule regulated by increased oxygen stimulation, shows promising predictive power in survival analysis and has great potential to be a biomarker for grading and prognosis in glioma patients. These results provide preliminary insights into clinical scenarios associated with altered hypoxic conditions in gliomas, and introduce a novel perspective on the role of the hypoxic microenvironment in glioma progression. Furthermore, the outcomes reveal the potential risks of utilizing hyperbaric oxygen treatment (HBOT) in glioma patients, particularly when considering HBOT as a standalone option to ameliorate neuro-dysfunctions or when combining HBOT with a single chemotherapy agent without radiotherapy.