Small intestine and colon tissue-resident memory CD8+ T cells exhibit molecular heterogeneity and differential dependence on Eomes.

Tissue-resident memory CD8+ T (TRM) cells are a subset of memory T cells that play a critical role in limiting early pathogen spread and controlling infection. TRM cells exhibit differences across tissues, but their potential heterogeneity among distinct anatomic compartments within the small intestine and colon has not been well recognized. Here, by analyzing TRM cells from the lamina propria and epithelial compartments of the small intestine and colon, we showed that intestinal TRM cells exhibited distinctive patterns of cytokine and granzyme expression along with substantial transcriptional, epigenetic, and functional heterogeneity. The T-box transcription factor Eomes, which represses TRM cell formation in some tissues, exhibited unexpected context-specific regulatory roles in supporting the maintenance of established TRM cells in the small intestine, but not in the colon. Taken together, these data provide previously unappreciated insights into the heterogeneity and differential requirements for the formation vs. maintenance of intestinal TRM cells.

Mobile iodides capture for highly photolysis- and reverse-bias-stable perovskite solar cells.

For halide perovskites that are susceptible to photolysis and ion migration, iodide-related defects, such as iodine (I2) and iodine vacancies, are inevitable. Even a small number of these defects can trigger self-accelerating chemical reactions, posing serious challenges to the durability of perovskite solar cells. Fortunately, before I2 can damage the perovskites under illumination, they generally diffuse over a long distance. Therefore, detrimental I2 can be captured by interfacial materials with strong iodide/polyiodide (Ix-) affinities, such as fullerenes and perfluorodecyl iodide. However, fullerenes in direct contact with perovskites fail to confine Ix- ions within the perovskite layer but cause detrimental iodine vacancies. Perfluorodecyl iodide, with its directional Ix- affinity through halogen bonding, can both capture and confine Ix-. Therefore, inverted perovskite solar cells with over 10 times improved ultraviolet irradiation and thermal-light stabilities (under 85 °C and 1 sun illumination), and 1,000 times improved reverse-bias stability (under ISOS-V ageing tests) have been developed.

Estimation of the Time-Varying Effective Reproductive Number of COVID-19 Based on Multivariate Time Series of Severe Health Outcomes.

The time-varying effective reproduction number (Rt at time t) measures the transmissibility of SARS-CoV-2 and is conventionally based on daily case counts, which may suffer from time-varying ascertainment. We analyzed Rt estimates from case counts and severe COVID-19 (intensive care unit admissions, severe or critical cases, and mortality) across 2022 in Hong Kong's fifth and sixth waves of infection. Within the fifth wave, the severe disease-based Rt (3.5) was significantly higher than the case-based Rt (2.4) but not in the sixth wave. During periods with fluctuating underreporting, data based on severe diseases may provide more reliable Rt estimates.

Effectiveness of Vaccines and Antiviral Drugs in Preventing Severe and Fatal COVID-19, Hong Kong.

We compared the effectiveness and interactions of molnupiravir and nirmatrelvir/ritonavir and 2 vaccines, CoronaVac and Comirnaty, in a large population of inpatients with COVID-19 in Hong Kong. Both the oral antiviral drugs and vaccines were associated with lower risks for all-cause mortality and progression to serious/critical/fatal conditions (study outcomes). No significant interaction effects were observed between the antiviral drugs and vaccinations; their joint effects were additive. If antiviral drugs were prescribed within 5 days of confirmed COVID-19 diagnosis, usage was associated with lower risks for the target outcomes for patients >60, but not <60, years of age; no significant clinical benefit was found if prescribed beyond 5 days. Among patients >80 years of age, 3-4 doses of Comirnaty vaccine were associated with significantly lower risks for target outcomes. Policies should encourage COVID-19 vaccination, and oral antivirals should be made accessible to infected persons within 5 days of confirmed diagnosis.

Anaplastic Lymphoma Kinase (ALK) Inhibitors Show Activity in Colorectal Cancer With ALK Rearrangements: Case Series and Literature Review.

Anaplastic lymphoma kinase (ALK) rearrangement is a well-known driver oncogene detected in approximately 5% of non-small cell lung cancer. However, ALK rearrangement is much less frequent in other solid tumors outside the lungs, such as colorectal cancer (CRC); thus, the optimal management of CRC with ALK rearrangements has yet to be established. In this report, we describe 2 cases of ALK-positive CRC, both of which benefited from ALK tyrosine kinase inhibitor (ALK-TKI) therapy. Case 1 was a postoperative patient with poorly differentiated colon adenocarcinoma, who was diagnosed with metastatic relapse shortly after surgery. Both fluorouracil, leucovorin, and oxaliplatin (FOLFOX) and bevacizumab combined with 5-fluorouracil, l-leucovorin, and irinotecan (FOLFIRI) proved ineffective against the disease. The patient was then treated with ensartinib, as the CAD-ALK fusion gene was detected by genomic analysis. The patient was initially treated with ensartinib monotherapy for 9 months, then with ensartinib combined with local radiotherapy and fruquintinib for another 4 months for isolated hilar hepatic lymph node metastasis. The patient experienced disease progression with an acquired ALK G1202R resistance mutation that responded well to lorlatinib. Case 2 involved a 72-year-old man with advanced colon cancer (pT4bN2aM1b, stage IV) harboring an EML4-ALK fusion. The patient underwent resection of the right colon tumor due to intestinal obstruction, but the disease continued to progress after 12 courses of FOLFIRI and bevacizumab chemotherapy. However, the patient responded remarkably well to alectinib. Our report emphasizes the importance of gene detection in the treatment of malignant tumors, and the significance of ALK mutations in CRC.

PTEN Deficiency Facilitates Exosome Secretion and Metastasis in Cholangiocarcinoma by Impairing TFEB-mediated Lysosome Biogenesis.

BACKGROUND & AIMS: In eukaryotes, the ubiquitin-proteasome system and the autophagy-lysosome pathway are essential for maintaining cellular proteostasis and associated with cancer progression. Our previous studies have demonstrated that phosphatase and tensin homolog (PTEN), one of the most frequently mutated genes in human cancers, limits proteasome abundance and determines chemosensitivity to proteasome inhibitors in cholangiocarcinoma (CCA). However, whether PTEN regulates the lysosome pathway remains unclear. METHODS: We tested the effects of PTEN on lysosome biogenesis and exosome secretion using loss- and gain-of-function strategies in CCA cell lines. Using in vitro dephosphorylation assays, we explored the regulatory mechanism between PTEN and the key regulator of lysosome biogenesis, transcription factor EB (TFEB). Using the migration assays, invasion assays, and trans-splenic liver metastasis mouse models, we evaluated the function of PTEN deficiency, TFEB-mediated lysosome biogenesis, and exosome secretion on tumor metastasis. Moreover, we investigated the clinical significance of PTEN expression and exosome secretion by retrospective analysis. RESULTS: PTEN facilitated lysosome biogenesis and acidification through its protein phosphatase activity to dephosphorylate TFEB at Ser211. Notably, PTEN deficiency increased exosome secretion by reducing lysosome-mediated degradation of multi-vesicular bodies, which further facilitated the proliferation and invasion of CCA. TFEB agonist curcumin analog C1 restrained the metastatic phenotype caused by PTEN deficiency in mouse models, and we highlighted the correlation between PTEN deficiency and exosome secretion in clinical cohorts. CONCLUSIONS: In CCA, PTEN deficiency impairs lysosome biogenesis to facilitate exosome secretion and cancer metastasis in a TFEB phosphorylation-dependent manner.

Stable-Isotope N-Me Aziridination Enables Accurate Quantitative C═C Isomeric Lipidomics.

Accurate lipid quantification is essential to revealing their roles in physiological and pathological processes. However, difficulties in the structural resolution of lipid isomers hinder their further accurate quantification. To address this challenge, we developed a novel stable-isotope N-Me aziridination strategy that enables simultaneous qualification and quantification of unsaturated lipid isomers. The one-step introduction of the 1-methylaziridine structure not only serves as an activating group for the C═C bond to facilitate positional identification but also as an isotopic inserter to achieve accurate relative quantification. The high performance of this reaction for the identification of unsaturated lipids was verified by large-scale resolution of the C═C positions of 468 lipids in serum. More importantly, by using this bifunctional duplex labeling method, various unsaturated lipids such as fatty acids, phospholipids, glycerides, and cholesterol ester were accurately and individually quantified at the C═C bond isomeric level during the mouse brain ischemia. This study provides a new approach to quantitative structural lipidomics.

Evaluating the impact of extended dosing intervals on mRNA COVID-19 vaccine effectiveness in adolescents.

BACKGROUND: Extending the dosing interval of a primary series of mRNA COVID-19 vaccination has been employed to reduce myocarditis risk in adolescents, but previous evaluation of impact on vaccine effectiveness (VE) is limited to risk after second dose. METHODS: We quantified the impact of the dosing interval based on case notifications and vaccination uptake in Hong Kong from January to April 2022, based on calendar-time proportional hazards models and matching approaches. RESULTS: We estimated that the hazard ratio (HR) and odds ratio (OR) of infections after the second dose for extended (28 days or more) versus regular (21-27 days) dosing intervals ranged from 0.86 to 0.99 from calendar-time proportional hazards models, and from 0.85 to 0.87 from matching approaches, respectively. Adolescents in the extended dosing groups (including those who did not receive a second dose in the study period) had a higher hazard of infection than those with a regular dosing interval during the intra-dose period (HR 1.66; 95% CI 1.07, 2.59; p = 0.02) after the first dose. CONCLUSIONS: Implementing an extended dosing interval should consider multiple factors including the degree of myocarditis risk, the degree of protection afforded by each dose, and the extra protection achievable using an extended dosing interval.

T cell-mediated skin-brain axis: Bridging the gap between psoriasis and psychiatric comorbidities.

Psoriasis, a chronic inflammatory skin condition, is often accompanied by psychiatric comorbidities such as anxiety, depression, suicidal ideation, and other mental disorders. Psychological disorders may also play a role in the development and progression of psoriasis. The intricate interplay between the skin diseases and the psychiatric comorbidities is mediated by the 'skin-brain axis'. Understanding the mechanisms underlying psoriasis and psychiatric comorbidities can help improve the efficacy of treatment by breaking the vicious cycle of diseases. T cells and related cytokines play a key role in the pathogenesis of psoriasis and psychiatric diseases, and are crucial components of the 'skin-brain axis'. Apart from damaging the blood-brain barrier (BBB) directly, T cells and secreted cytokines could interact with the hypothalamic-pituitary-adrenal axis (HPA axis) and the sympathetic nervous system (SNS) to exacerbate skin diseases or mental disorders. However, few reviews have systematically summarized the roles and mechanisms of T cells in the interaction between psoriasis and psychiatric comorbidities. In this review, we discussed several key T cells and their roles in the 'skin-brain axis', with a focus on the mechanisms underlying the interplay between psoriasis and mental commodities, to provide data that might help develop effective strategies for the treatment of both psoriasis and psychiatric comorbidities.

Potential drug targets for gastroesophageal reflux disease and Barrett's esophagus identified through Mendelian randomization analysis.

Gastroesophageal reflux disease (GERD) is a prevalent chronic ailment, and present therapeutic approaches are not always effective. This study aimed to find new drug targets for GERD and Barrett's esophagus (BE). We obtained genetic instruments for GERD, BE, and 2004 plasma proteins from recently published genome-wide association studies (GWAS), and Mendelian randomization (MR) was employed to explore potential drug targets. We further winnowed down MR-prioritized proteins through replication, reverse causality testing, colocalization analysis, phenotype scanning, and Phenome-wide MR. Furthermore, we constructed a protein-protein interaction network, unveiling potential associations among candidate proteins. Simultaneously, we acquired mRNA expression quantitative trait loci (eQTL) data from another GWAS encompassing four different tissues to identify additional drug targets. Meanwhile, we searched drug databases to evaluate these targets. Under Bonferroni correction (P < 4.8 × 10-5), we identified 11 plasma proteins significantly associated with GERD. Among these, 7 are protective proteins (MSP, GPX1, ERBB3, BT3A3, ANTR2, CCM2, and DECR2), while 4 are detrimental proteins (TMEM106B, DUSP13, C1-INH, and LINGO1). Ultimately, C1-INH and DECR2 successfully passed the screening process and exhibited similar directional causal effects on BE. Further analysis of eQTLs highlighted 4 potential drug targets, including EDEM3, PBX3, MEIS1-AS3, and NME7. The search of drug databases further supported our conclusions. Our study indicated that the plasma proteins C1-INH and DECR2, along with 4 genes (EDEM3, PBX3, MEIS1-AS3, and NME7), may represent potential drug targets for GERD and BE, warranting further investigation.