Ultracompact and multifunctional integrated photonic platform.

Realizing a multifunctional integrated photonic platform is one of the goals for future optical information processing, which usually requires large size to realize due to multiple integration challenges. Here, we realize a multifunctional integrated photonic platform with ultracompact footprint based on inverse design. The photonic platform is compact with 86 inverse designed-fixed couplers and 91 phase shifters. The footprint of each coupler is 4 µm by 2 µm, while the whole photonic platform is 3 mm by 0.2 mm-one order of magnitude smaller than previous designs. One-dimensional Floquet Su-Schrieffer-Heeger model and Aubry-André-Harper model are performed with measured fidelities of 97.90 (±0.52) % and 99.34 (±0.44) %, respectively. We also demonstrate a handwritten digits classification task with the test accuracy of 87% using on-chip training. Moreover, the scalability of this platform has been proved by demonstrating more complex computing tasks. This work provides an effective method to realize an ultrasmall integrated photonic platform.

Neuroticism polygenic risk predicts conversion from mild cognitive impairment to Alzheimer's disease by impairing inferior parietal surface area.

The high prevalence of conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD) makes early prevention of AD extremely critical. Neuroticism, a heritable personality trait associated with mental health, has been considered a risk factor for conversion from aMCI to AD. However, whether the neuroticism genetic risk could predict the conversion of aMCI and its underlying neural mechanisms is unclear. Neuroticism polygenic risk score (N-PRS) was calculated in 278 aMCI patients with qualified genomic and neuroimaging data from ADNI. After 1-year follow-up, N-PRS in patients of aMCI-converted group was significantly greater than those in aMCI-stable group. Logistic and Cox survival regression revealed that N-PRS could significantly predict the early-stage conversion risk from aMCI to AD. These results were well replicated in an internal dataset and an independent external dataset of 933 aMCI patients from the UK Biobank. One sample Mendelian randomization analyses confirmed a potentially causal association from higher N-PRS to lower inferior parietal surface area to higher conversion risk of aMCI patients. These analyses indicated that neuroticism genetic risk may increase the conversion risk from aMCI to AD by impairing the inferior parietal structure.

Immunomodulatory Function of Pien Tze Huang in T Cell-Mediated Anti-tumor Activity against B16-F10, MC38 and Hep1-6 Tumor Models.

OBJECTIVE: To investigate the anti-tumor effects of Pien Tze Huang (PZH) in mouse models of B16-F10 melanoma, MC38 colorectal cancer, Hep1-6 hepatocellular carcinoma and chemically induced hepatocellular carcinoma model. METHODS: Various tumor models, including B16-F10, MC38 and Hep1-6 tumor hypodermic inoculation models, B16-F10 and Hep1-6 pulmonary metastasis models, Hep1-6 orthotopic implantation model, and chemically induced hepatocellular carcinoma model, were utilized to evaluate the anti-tumor function of PZH. Tumor growth was assessed by measuring tumor size and weight of solid tumors isolated from C57BL/6 mice. For cell proliferation and death of tumor cells in vitro, as well as T cell activation markers, cytokine production and immune checkpoints analysis, single-cell suspensions were prepared from mouse spleen, lymph nodes, and tumors after PZH treatment. RESULTS: PZH demonstrated significant therapeutic efficacy in inhibiting tumor growth (P<0.01). Treatment with PZH resulted in a reduction in tumor size in subcutaneous MC38 colon adenocarcinoma and B16-F10 melanoma models, and decreased pulmonary metastasis of B16-F10 melanoma and Hep1-6 hepatoma (P<0.01). However, in vitro experiments showed that PZH only had slight impact on the cell proliferation and survival of tumor cells (P>0.05). Nevertheless, PZH exhibited a remarkable ability to enhance T cell activation and the production of interferon gamma, tumor necrosis factor alpha, and interleukin 2 in CD4+ T cells in vitro (P<0.01 or P<0.05). Importantly, PZH substantially inhibited T cell exhaustion and boosted cytokine production by tumor-infiltrating CD8+ T cells (P<0.01 or P<0.05). CONCLUSION: This study has confirmed a novel immunomodulatory function of PZH in T cell-mediated anti-tumor immunity, indicating that PZH holds promise as a potential therapeutic agent for cancer treatment.

A simple fragility fracture risk score for type 2 diabetes patients: a derivation, validation, comparison, and risk stratification study.

OBJECTIVES: The aims of this study were to develop and validate 2 simple scores for stratification of the risks of (1) any fragility (AF) and (2) major osteoporotic fracture (MOF) in type 2 diabetes (T2D) patients; we also compared the performance of these scores with that of the Fracture Risk Assessment Tool (FRAX) and its adjustments. DESIGN AND METHODS: In this longitudinal cohort study, 1855 patients with T2D were enrolled from January 2015 to August 2019. Cox proportional hazard regression was used to model the 5-year risk of AF and MOF. These scores were internally validated using a bootstrap resampling method of 1000. RESULTS: During a median follow-up of 5 years, 119 (6.42%) cases of AF and 92 (4.96%) cases of MOFs were identified. Both the concordance index (C-index) and calibration plots indicated improved identification performance using the newly established scores. Furthermore, these scores also showed improved outcomes regarding the decision curve analysis (DCA) and area under the curve (AUC) compared to the widely used FRAX and its derivatives. More importantly, these scores successfully separated T2D patients into risk groups according to significant differences in fracture incidence. CONCLUSIONS: These novel scores enable simple and reliable fracture risk stratification in T2D patients. Future work is needed to validate these findings in external cohort(s).

Graphene/silicon heterojunction for reconfigurable phase-relevant activation function in coherent optical neural networks.

Optical neural networks (ONNs) herald a new era in information and communication technologies and have implemented various intelligent applications. In an ONN, the activation function (AF) is a crucial component determining the network performances and on-chip AF devices are still in development. Here, we first demonstrate on-chip reconfigurable AF devices with phase activation fulfilled by dual-functional graphene/silicon (Gra/Si) heterojunctions. With optical modulation and detection in one device, time delays are shorter, energy consumption is lower, reconfigurability is higher and the device footprint is smaller than other on-chip AF strategies. The experimental modulation voltage (power) of our Gra/Si heterojunction achieves as low as 1 V (0.5 mW), superior to many pure silicon counterparts. In the photodetection aspect, a high responsivity of over 200 mA/W is realized. Special nonlinear functions generated are fed into a complex-valued ONN to challenge handwritten letters and image recognition tasks, showing improved accuracy and potential of high-efficient, all-component-integration on-chip ONN. Our results offer new insights for on-chip ONN devices and pave the way to high-performance integrated optoelectronic computing circuits.

A multimodal prediction model for suicidal attempter in major depressive disorder.

Background: Suicidal attempts in patients with major depressive disorder (MDD) have become an important challenge in global mental health affairs. To correctly distinguish MDD patients with and without suicidal attempts, a multimodal prediction model was developed in this study using multimodality data, including demographic, depressive symptoms, and brain structural imaging data. This model will be very helpful in the early intervention of MDD patients with suicidal attempts. Methods: Two feature selection methods, support vector machine-recursive feature elimination (SVM-RFE) and random forest (RF) algorithms, were merged for feature selection in 208 MDD patients. SVM was then used as a classification model to distinguish MDD patients with suicidal attempts or not. Results: The multimodal predictive model was found to correctly distinguish MDD patients with and without suicidal attempts using integrated features derived from SVM-RFE and RF, with a balanced accuracy of 77.78%, sensitivity of 83.33%, specificity of 70.37%, positive predictive value of 78.95%, and negative predictive value of 76.00%. The strategy of merging the features from two selection methods outperformed traditional methods in the prediction of suicidal attempts in MDD patients, with hippocampal volume, cerebellar vermis volume, and supracalcarine volume being the top three features in the prediction model. Conclusions: This study not only developed a new multimodal prediction model but also found three important brain structural phenotypes for the prediction of suicidal attempters in MDD patients. This prediction model is a powerful tool for early intervention in MDD patients, which offers neuroimaging biomarker targets for treatment in MDD patients with suicidal attempts.

The liver microenvironment orchestrates FGL1-mediated immune escape and progression of metastatic colorectal cancer.

Colorectal cancer (CRC) patients with liver metastases usually obtain less benefit from immunotherapy, and the underlying mechanisms remain understudied. Here, we identify that fibrinogen-like protein 1 (FGL1), secreted from cancer cells and hepatocytes, facilitates the progression of CRC in an intraportal injection model by reducing the infiltration of T cells. Mechanistically, tumor-associated macrophages (TAMs) activate NF-ĸB by secreting TNFα/IL-1ß in the liver microenvironment and transcriptionally upregulate OTU deubiquitinase 1 (OTUD1) expression, which enhances FGL1 stability via deubiquitination. Disrupting the TAM-OTUD1-FGL1 axis inhibits metastatic tumor progression and synergizes with immune checkpoint blockade (ICB) therapy. Clinically, high plasma FGL1 levels predict poor outcomes and reduced ICB therapy benefits. Benzethonium chloride, an FDA-approved antiseptics, curbs FGL1 secretion, thereby inhibiting liver metastatic tumor growth. Overall, this study uncovers the critical roles and posttranslational regulatory mechanism of FGL1 in promoting metastatic tumor progression, highlighting the TAM-OTUD1-FGL1 axis as a potential target for cancer immunotherapy.

Targeting AMPK/eNOS pathway and mitochondria by sonlicromanol protects myocardial cells against ischemia-reperfusion injury.

This work evaluated the cardioprotective effects of sonlicromanol, a new mitochondrial-directed drug, on cardiac ischemia/reperfusion (I/R) injury and explored the involvement of inflammatory and oxidative responses via activation of AMPK-eNOS-mitochondrial pathway. Male Sprague-Dawley rats underwent regional I/R injury through in vivo left anterior descending (LAD) coronary artery ligation for 40 minutes followed by 24 hours of reperfusion. Pretreatment of rats with sonlicromanol considerably reduced cardiac I/R injury in a dose-dependent manner, as indicated by lower infarct size and serum creatine-kinase levels, and improved cardiac function after reperfusion. Sonlicromanol (50 mg/kg) significantly reduced TNF-α, interleukin-1ß, NF-κB-p65, and 8-isoprostane levels while increased manganese-superoxide dismutase and nitric-oxide levels and expression of eNOS and AMPK protein. It significantly reduced mitochondrial membrane depolarization and reactive oxygen species (ROS) levels. However, AMPK inhibition significantly reduced sonlicromanol protective actions. Cardioprotection by sonlicromanol was achieved by moderating inflammatory and oxidative responses, and AMPK/eNOS/mitochondrial signaling is a crucial regulator of these actions.

Comparing the prognostic value of the old and new sarcopenia criteria from the Asian Working Group on Sarcopenia in older adults with type 2 diabetes: Which set is more appropriate?

BACKGROUND: This study aimed to compare the prevalence of sarcopenia according to the old and new Asian Working Group on Sarcopenia (AWGS) operational criteria and explore the effects of sarcopenia on adverse outcomes in older adults with type 2 diabetes (T2D). METHODS: A total of 386 patients with T2D aged ≥ 60 years were recruited in retrospective cohort study. Sarcopenia was assessed with different versions of the AWGS consensus, including the AWGS2014, AWGS2019H (muscle mass adjusted for height), and AWGS2019B (muscle mass adjusted for body mass index). The median follow-up period was 47 months. The composite primary endpoint was the first occurrence of cardiovascular disease (CVD), fragility fracture, and all-cause mortality and the secondary outcomes included the three separate components of the primary outcome. RESULTS: In this study, the prevalence of sarcopenia under different criteria was significantly different, with AWGS2019H having the highest prevalence of 31.3%. The agreement among sarcopenia criteria was unsatisfactory. By Cox regression analysis, all three AWGS definitions of sarcopenia were associated with the composite outcome of all-cause mortality, fracture and CVD (hazard ratio [HR], 2.69 vs. HR, 2.63; vs. HR, 2.23; model 3). Further exploratory analysis, sarcopenia defined by the AWGS2019H criteria was an independent risk factor for death, incident CVD, and fractures. While AWGS2014 criteria was an increased risk factor of death and CVD. The AWGS2019B criteria were only associated with incident fractures. CONCLUSION: All three AWGS definitions of sarcopenia were associated the composite primary endpoint. Additionally, the AWGS2019H criteria may be a better independent risk factor for negative health outcomes.

IL-1ß-associated NNT acetylation orchestrates iron-sulfur cluster maintenance and cancer immunotherapy resistance.

Interleukin-1ß (IL-1ß) is a key protein in inflammation and contributes to tumor progression. However, the role of IL-1ß in cancer is ambiguous or even contradictory. Here, we found that upon IL-1ß stimulation, nicotinamide nucleotide transhydrogenase (NNT) in cancer cells is acetylated at lysine (K) 1042 (NNT K1042ac) and thereby induces the mitochondrial translocation of p300/CBP-associated factor (PCAF). This acetylation enhances NNT activity by increasing the binding affinity of NNT for NADP+ and therefore boosts NADPH production, which subsequently sustains sufficient iron-sulfur cluster maintenance and protects tumor cells from ferroptosis. Abrogating NNT K1042ac dramatically attenuates IL-1ß-promoted tumor immune evasion and synergizes with PD-1 blockade. In addition, NNT K1042ac is associated with IL-1ß expression and the prognosis of human gastric cancer. Our findings demonstrate a mechanism of IL-1ß-promoted tumor immune evasion, implicating the therapeutic potential of disrupting the link between IL-1ß and tumor cells by inhibiting NNT acetylation.

On-chip integrated exceptional surface microlaser.

The on-chip integrated visible microlaser is a core unit of high-speed visible-light communication with huge bandwidth resources, which needs robustness against fabrication errors, compressible linewidth, reducible threshold, and in-plane emission. However, until now, it has been a great challenge to meet these requirements simultaneously. Here, we report a scalable strategy to realize a robust on-chip integrated visible microlaser with further improved lasing performances enabled by the increased orders (n) of exceptional surfaces, and experimentally verify the strategy by demonstrating the performances of a second-order exceptional surface-tailored microlaser. We further prove the potential application of the strategy by discussing an exceptional surface-tailored topological microlaser with unique performances. This work lays a foundation for further development of on-chip integrated high-speed visible-light communication and processing systems, provides a platform for the fundamental study of non-Hermitian photonics, and proposes a feasible method of joint research for non-Hermitian photonics with nonlinear optics and topological photonics.

Screening of candidate genes related to differences in growth and development between Chinese indigenous and Western pig breeds.

Neijiang (NJ) and Yacha (YC) are two indigenous pig breeds in the Sichuan basin of China, displaying higher resistance to diseases, lower lean ratio, and slower growth rate than the commercial Western pig breed Yorkshire (YS). The molecular mechanisms underlying the differences in growth and development between these pig breeds are still unknown. In the present study, five pigs from NJ, YC, and YS breeds were subjected to the whole genome resequencing, and then the differential single-nucleotide polymorphisms (SNPs) were screened using a 10-kb window sliding in 1-kb step using the Fst method. Finally, 48,924, 48,543, and 46,228 nonsynonymous single-nucleotide polymorphism loci (nsSNPs) were identified between NJ and YS, NJ and YC, and YC and YS, which highly or moderately affected 2,490, 800, and 444 genes, respectively. Moreover, three nsSNPs were detected in the genes of acetyl-CoA acetyltransferase 1 (ACAT1) insulin-like growth factor 2 receptor (IGF2R), insulin-like growth factor 2 and mRNA-binding protein 3 (IGF2BP3), which potentially affected the transformation of acetyl-CoA to acetoacetyl-CoA and the normal functions of the insulin signaling pathways. Moreover, serous determinations revealed significantly lower acetyl-CoA content in YC than in YS, supporting that ACAT1 might be a reason explaining the differences in growth and development between YC and YS breeds. Contents of phosphatidylcholine (PC) and phosphatidic acid (PA) significantly differed between the pig breeds, suggesting that glycerophospholipid metabolism might be another reason for the differences between Chinese and Western pig breeds. Overall, these results might contribute basic information to understand the genetic differences determining the phenotypical traits in pigs.

Circular RNAs: Emerging regulators of glucose metabolism in cancer.

Aberrant glucose metabolism is one of the most striking characteristics of metabolic reprogramming in cancer. Thus, clarifying the regulatory mechanism of glucose metabolism is crucial to understanding tumor progression and developing novel therapeutic strategies for cancer patients. Recent developments in circular RNAs have explained the regulatory mechanism of glucose metabolism from a new dimension. In this review, we briefly summarize the recent advances in circRNA research on cancer glucose metabolism and emphasize the different regulatory mechanisms, including acting as miRNA sponges, interacting with proteins and being translated into proteins. Additionally, we discuss the future research directions of circular RNAs in the field of glucose metabolism.

Methionine deficiency facilitates antitumour immunity by altering m6A methylation of immune checkpoint transcripts.

OBJECTIVE: Methionine metabolism is involved in a myriad of cellular functions, including methylation reactions and redox maintenance. Nevertheless, it remains unclear whether methionine metabolism, RNA methylation and antitumour immunity are molecularly intertwined. DESIGN: The antitumour immunity effect of methionine-restricted diet (MRD) feeding was assessed in murine models. The mechanisms of methionine and YTH domain-containing family protein 1 (YTHDF1) in tumour immune escape were determined in vitro and in vivo. The synergistic effects of MRD or YTHDF1 depletion with PD-1 blockade were also investigated. RESULTS: We found that dietary methionine restriction reduced tumour growth and enhanced antitumour immunity by increasing the number and cytotoxicity of tumour-infiltrating CD8+ T cells in different mouse models. Mechanistically, the S-adenosylmethionine derived from methionine metabolism promoted the N6-methyladenosine (m6A) methylation and translation of immune checkpoints, including PD-L1 and V-domain Ig suppressor of T cell activation (VISTA), in tumour cells. Furthermore, MRD or m6A-specific binding protein YTHDF1 depletion inhibited tumour growth by restoring the infiltration of CD8+ T cells, and synergised with PD-1 blockade for better tumour control. Clinically, YTHDF1 expression correlated with poor prognosis and immunotherapy outcomes for cancer patients. CONCLUSIONS: Methionine and YTHDF1 play a critical role in anticancer immunity through regulating the functions of T cells. Targeting methionine metabolism or YTHDF1 could be a potential new strategy for cancer immunotherapy.

Sarcopenic obesity predicts negative health outcomes among older patients with type 2 diabetes: The Ageing and Body Composition of Diabetes (ABCD) cohort study.

BACKGROUND AND AIMS: The definition of and diagnostic criteria for sarcopenic obesity (SO) remain unclear, hindering the assessment of its prevalence as well as its clinical relevance to negative health outcomes, especially in diabetic patients, who are more prone to body composition changes. The aim of this study was to investigate the prevalence of SO and its impact on negative health outcomes among elderly patients with type 2 diabetes (T2DM) from the Ageing and Body Composition of Diabetes (ABCD) cohort. METHODS: This retrospective cohort study included 386 elderly patients with T2DM (177 males and 209 females, mean age of 67.91 ± 6.10 years). SO was defined as the coexistence of sarcopenia defined by the 2019 Asian Working Group for Sarcopenia up-to-date consensus and obesity identified by five alternative measurements as follows: body mass index (BMI)≥28 kg/m2 (BMI28), BMI≥25 kg/m2 (BMI25), body fat percentage (BF%)≥25% for men or 35% for women, visceral fat area (VFA)≥100 cm2, or android fat mass (AF) higher than the sex-specific median. The primary endpoint was all-cause death or fragility fracture, and the secondary endpoint was a composite of cardiovascular diseases (CVDs). Cox proportional hazards regression analysis was used to estimate the association between SO and negative health outcomes. RESULTS: The prevalence of SO was 0.2% (BMI28), 2.5% (BMI25), 9.8% (AF), and 18.7% (BF% or VFA) among elderly patients with T2DM, according to the different obesity surrogate markers. During a mean follow-up period of 3.46 ± 1.15 years, 50 patients reached the primary endpoint, and 33 patients had incident CVD. SO classified using BF% was significantly associated with the primary endpoint [hazard ratio (HR) = 2.94, 95% CI = 1.25-6.92] and incident CVD (HR = 6.02, 95% CI = 1.56-23.15), even after comprehensive adjustment for bone-, comorbidity-, and diabetes-specific confounding variables. When SO was classified using BMI25, VFA and AF, similar results were found for adverse outcomes. However, SO classified using BMI25 resulted in misclassification of SO for 61 participants, 19 of whom experienced adverse events during follow-up, and SO classified using VFA or AF was not significantly associated with incident CVD. CONCLUSIONS: SO is not uncommon in geriatric patients with T2DM, and its prevalence varies widely depending on the diverse surrogate indices of body fat excess. Furthermore, SO may be a better independent risk factor for negative health outcomes when classified using BF%.

Arginine methylation of MTHFD1 by PRMT5 enhances anoikis resistance and cancer metastasis.

Metastasis accounts for the major cause of cancer-related mortality. How disseminated tumor cells survive under suspension conditions and avoid anoikis is largely unknown. Here, using a metabolic enzyme-centered CRISPR-Cas9 genetic screen, we identified methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1 (MTHFD1) as a novel suppressor of anoikis. MTHFD1 depletion obviously restrained the capacity of cellular antioxidant defense and inhibited tumor distant metastasis. Mechanistically, MTHFD1 was found to bind the protein arginine methyltransferase 5 (PRMT5) and then undergo symmetric dimethylation on R173 by PRMT5. Under suspension conditions, the interaction between MTHFD1 and PRMT5 was strengthened, which increased the symmetric dimethylation of MTHFD1. The elevated methylation of MTHFD1 largely augmented its metabolic activity to generate NADPH, therefore leading to anoikis resistance and distant organ metastasis. Therapeutically, genetic depletion or pharmacological inhibition of PRMT5 declined tumor distant metastasis. And R173 symmetric dimethylation status was associated with metastasis and prognosis of ESCC patients. In conclusion, our study uncovered a novel regulatory role and therapeutic implications of PRMT5/MTHFD1 axis in facilitating anoikis resistance and cancer metastasis.

Associations of Polygenic Risk Score for Late-Onset Alzheimer's Disease With Biomarkers.

Late-onset Alzheimer's disease (LOAD) is a common irreversible neurodegenerative disease with heterogeneous genetic characteristics. Identifying the biological biomarkers with the potential to predict the conversion from normal controls to LOAD is clinically important for early interventions of LOAD and clinical treatment. The polygenic risk score for LOAD (AD-PRS) has been reported the potential possibility for reliably identifying individuals with risk of developing LOAD recently. To investigate the external phenotype changes resulting from LOAD and the underlying etiology, we summarize the comprehensive associations of AD-PRS with multiple biomarkers, including neuroimaging, cerebrospinal fluid and plasma biomarkers, cardiovascular risk factors, cognitive behavior, and mental health. This systematic review helps improve the understanding of the biomarkers with potential predictive value for LOAD and further optimizing the prediction and accurate treatment of LOAD.

Phosphorylated NFS1 weakens oxaliplatin-based chemosensitivity of colorectal cancer by preventing PANoptosis.

Metabolic enzymes have an indispensable role in metabolic reprogramming, and their aberrant expression or activity has been associated with chemosensitivity. Hence, targeting metabolic enzymes remains an attractive approach for treating tumors. However, the influence and regulation of cysteine desulfurase (NFS1), a rate-limiting enzyme in iron-sulfur (Fe-S) cluster biogenesis, in colorectal cancer (CRC) remain elusive. Here, using an in vivo metabolic enzyme gene-based clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 library screen, we revealed that loss of NFS1 significantly enhanced the sensitivity of CRC cells to oxaliplatin. In vitro and in vivo results showed that NFS1 deficiency synergizing with oxaliplatin triggered PANoptosis (apoptosis, necroptosis, pyroptosis, and ferroptosis) by increasing the intracellular levels of reactive oxygen species (ROS). Furthermore, oxaliplatin-based oxidative stress enhanced the phosphorylation level of serine residues of NFS1, which prevented PANoptosis in an S293 phosphorylation-dependent manner during oxaliplatin treatment. In addition, high expression of NFS1, transcriptionally regulated by MYC, was found in tumor tissues and was associated with poor survival and hyposensitivity to chemotherapy in patients with CRC. Overall, the findings of this study provided insights into the underlying mechanisms of NFS1 in oxaliplatin sensitivity and identified NFS1 inhibition as a promising strategy for improving the outcome of platinum-based chemotherapy in the treatment of CRC.