The circadian E3 ligase FBXL21 regulates myoblast differentiation and sarcomere architecture via MYOZ1 ubiquitination and NFAT signaling.

Numerous molecular and physiological processes in the skeletal muscle undergo circadian time-dependent oscillations in accordance with daily activity/rest cycles. The circadian regulatory mechanisms underlying these cyclic processes, especially at the post-transcriptional level, are not well defined. Previously, we reported that the circadian E3 ligase FBXL21 mediates rhythmic degradation of the sarcomere protein TCAP in conjunction with GSK-3ß, and Psttm mice harboring an Fbxl21 hypomorph allele show reduced muscle fiber diameter and impaired muscle function. To further elucidate the regulatory function of FBXL21 in skeletal muscle, we investigated another sarcomere protein, Myozenin1 (MYOZ1), that we identified as an FBXL21-binding protein from yeast 2-hybrid screening. We show that FBXL21 binding to MYOZ1 led to ubiquitination-mediated proteasomal degradation. GSK-3ß co-expression and inhibition were found to accelerate and decelerate FBXL21-mediated MYOZ1 degradation, respectively. Previously, MYOZ1 has been shown to inhibit calcineurin/NFAT signaling important for muscle differentiation. In accordance, Fbxl21 KO and MyoZ1 KO in C2C12 cells impaired and enhanced myogenic differentiation respectively compared with control C2C12 cells, concomitant with distinct effects on NFAT nuclear localization and NFAT target gene expression. Importantly, in Psttm mice, both the levels and diurnal rhythm of NFAT2 nuclear localization were significantly diminished relative to wild-type mice, and circadian expression of NFAT target genes associated with muscle differentiation was also markedly dampened. Furthermore, Psttm mice exhibited significant disruption of sarcomere structure with a considerable excess of MYOZ1 accumulation in the Z-line. Taken together, our study illustrates a pivotal role of FBXL21 in sarcomere structure and muscle differentiation by regulating MYOZ1 degradation and NFAT2 signaling.

Association between high levels of nitrogen dioxide and increased cumulative incidence of lung cancer in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Lung cancer is a fatal complication of idiopathic pulmonary fibrosis (IPF) with a poor prognosis. However, the association between individual exposure to air pollutants and lung cancer development in patients with IPF is unknown. This study aimed to assess the effect of individual exposure to nitrogen dioxide (NO2) on lung cancer development in patients with IPF. METHODS: We enrolled 1085 patients from an IPF cohort in the Republic of Korea (mean age 65.6 years, males 80.6%). We estimated individual-level long-term exposures to NO2 at the patients' residential addresses using a national-scale exposure prediction model based on data from air quality regulatory monitoring stations. To evaluate the association between NO2 levels and lung cancer development in IPF, we used an individual- and area-level covariates adjusted model as our primary model. RESULTS: The estimated average annual NO2 concentration was 23.1 ppb. During a median follow-up of 4.3 years, 86 patients (7.9%) developed lung cancer. NO2 concentration was associated with lung cancer development in an unadjusted model (HR 1.219; p=0.042), while a marginal association was found in the primary model (HR 1.280; p=0.084). When NO2 concentration was stratified by the median value (21.0 ppb), exposure to high NO2 levels (≥21.0 ppb) was associated with a 2.0-fold increase in the risk of lung cancer development (HR 2.023; p=0.047) in the primary model. CONCLUSION: Individual exposure to high NO2 levels may increase the risk of lung cancer development in patients with IPF.

Consumption of Sugar-Sweetened Soft Drinks and Risk of Gastrointestinal Cancer: A Systematic Review and Meta-Analysis of Observational Studies.

INTRODUCTION: Previous observational studies have reported inconsistent findings on the association between consumption of sugar-sweetened soft drinks (SSSDs) and the risk of gastrointestinal (GI) cancer. This study investigated the associations between SSSD consumption and the risk of GI cancer using a systematic review and meta-analysis. METHODS: Observational epidemiological studies were searched from the PubMed and EMBASE databases until June 2021. We conducted a meta-analysis of all included studies and subgroup meta-analyses based on various factors. RESULTS: In a meta-analysis of 27 studies with nine case-control studies and 18 cohort studies, the consumption of SSSDs was modestly associated with an increased risk of GI cancer (odds ratio [OR]/relative risk [RR]: 1.08; 95% confidence interval [CI]: 1.01-1.16), with a significant positive dose-response relationship. In the subgroup meta-analysis by study design, there was a significant positive association between the consumption of SSSDs and GI cancer in cohort studies (RR: 1.11; 95% CI: 1.03-1.20; n = 18), but not in case-control studies. In the subgroup meta-analysis by type of cancer, consumption of SSSDs was significantly associated with an increased risk of colorectal cancer (OR/RR: 1.13; 95% CI: 1.07-1.19). CONCLUSIONS: This meta-analysis suggests that SSSD consumption significantly increases the risk of GI cancer, specifically colorectal cancer.

Pragmatic nationwide master observational trial based on genomic alterations in advanced solid tumors: KOrean Precision Medicine Networking Group Study of MOlecular profiling guided therapy based on genomic alterations in advanced Solid tumors (KOSMOS)-II study protocol KCSG AL-22-09.

BACKGROUND: Next-generation sequencing (NGS) has been introduced to many Korean institutions to support molecular diagnostics in cancer since 2017, when it became eligible for reimbursement by the National Health Insurance Service. However, the uptake of molecularly guided treatment (MGT) based on NGS results has been limited because of stringent regulations regarding prescriptions outside of approved indications, a lack of clinical trial opportunities, and limited access to molecular tumor boards (MTB) at most institutions. The KOSMOS-II study was designed to demonstrate the feasibility and effectiveness of MGT, informed by MTBs, using a nationwide precision medicine platform. METHODS: The KOSMOS-II trial is a large-scale nationwide master observational study. It involves a framework for screening patients with metastatic solid tumors for actionable genetic alterations based on local NGS testing. It recommends MGT through a remote and centralized MTB meeting held biweekly. MGT can include one of the following options: Tier 1, the therapeutic use of investigational drugs targeting genetic alterations such as ALK, EGFR, ERBB2, BRAF, FH, ROS1, and RET, or those with high tumor mutational burden; Tier 2, comprising drugs with approved indications or those permitted for treatment outside of the indications approved by the Health Insurance Review and Assessment Service of Korea; Tier 3, involving clinical trials matching the genetic alterations recommended by the MTB. Given the anticipated proportion of patients receiving MGT in the range of 50% ± 3.25%, this study aims to enroll 1,000 patients. Patients must have progressed to one or more lines of therapy and undergone NGS before enrollment. DISCUSSION: This pragmatic master protocol provides a mass-screening platform for rare genetic alterations and high-quality real-world data. Collateral clinical trials, translational studies, and clinico-genomic databases will contribute to generating evidence for drug repositioning and the development of new biomarkers. TRIAL REGISTRATION: NCT05525858.

Germline PTCH1: c.361_362insAlu alteration identified by comprehensive exome and RNA sequencing in a patient with Gorlin syndrome.

Gorlin syndrome can be caused by pathogenic/likely pathogenic (P/LP) variants in the tumor suppressor gene PTCH1 (9q22.1-q31), which encodes the receptor for the sonic hedgehog (SHH) ligand. We present a 12-month-old boy clinically diagnosed with Gorlin syndrome who was found to have significantly delayed development, palmar pitting, palmar and plantar keratosis, short hands, frontal bossing, coarse face, hypertelorism, a bifid rib, misaligned and missing teeth, and SHH-activated medulloblastoma. Genetic testing, including a pediatric cancer panel and genome sequencing with peripheral blood, failed to identify any P/LP variants in PTCH1. Paired tumor/normal exome sequencing was performed, which identified a germline NM_000264.5 (PTCH1): c.361_362ins? alteration through manual review of sequencing reads. Clinical RNA sequencing further demonstrated an Alu insertion at this region (PTCH1: c.361_362insAlu), providing molecular confirmation of Gorlin syndrome. This finding exemplifies a unique mechanism for PTCH1 disruption in the germline and highlights the importance of comprehensive analysis, including manual review of DNA sequencing reads and the utility of RNA analysis to detect variant types which may not be identified by routine genetic screening techniques.

14q22.3 duplication including OTX2 in a girl with medulloblastoma: A case report with literature review.

Orthodenticle homeobox 2 (OTX2) is a known oncogenic driver of medulloblastoma. Germline duplication of 14q22.3 including OTX2 is a rare condition reported in patients with combined pituitary hormone deficiency, oculo-auriculo-vertebral spectrum, and hemifacial microsomia. There has been one previously published case of a patient carrying a 14q22.3 duplication that included OTX2 with hemifacial microsomia who also developed medulloblastoma. Here, we present a case of a 6-year-old girl with a history of delayed development who was diagnosed with medulloblastoma. Genetic evaluations revealed that she inherited a germline duplication of 14q22.3, which included OTX2. This genetic alteration was passed down from her mother, who also had a history of delayed development. Results from other genetic testing, including exome sequencing, fragile X syndrome, and mtDNA testing, were negative/normal. This is the second report of a 14q22.3 duplication that included OTX2 in a patient with medulloblastoma. Further studies are necessary to establish a clear association.

Effects of Ambient Air Pollution on Brain Cortical Thickness and Subcortical Volume: A Longitudinal Neuroimaging Study.

INTRODUCTION: Several cross-sectional studies have shown that long-term exposures to air pollutants are associated with smaller brain cortical volume or thickness. Here, we investigated longitudinal associations of long-term air pollution exposures with cortical thickness and subcortical volume. METHODS: In this longitudinal study, we included a prospective cohort of 361 adults residing in four cities in the Republic of Korea. Long-term concentrations of particulate matter with aerodynamic diameters of ≤10 µm (PM10) and ≤2.5 µm (PM2.5) and nitrogen dioxide (NO2) at residential addresses were estimated. Neuroimaging markers (cortical thickness and subcortical volume) were obtained from brain magnetic resonance images at baseline (August 2014 to March 2017) and at the 3-year follow-up (until September 2020). Linear mixed-effects models were used, adjusting for covariates. RESULTS: A 10-µg/m3 increase in PM10 was associated with reduced whole-brain mean (ß = -0.45, standard error [SE] = 0.10; p < 0.001), frontal (ß = -0.53, SE = 0.11; p < 0.001) and temporal thicknesses (ß = -0.37, SE = 0.12; p = 0.002). A 10-ppb increase in NO2 was associated with a decline in the whole-brain mean cortical thickness (ß = -0.23, SE = 0.05; p < 0.001), frontal (ß = -0.25, SE = 0.05; p < 0.001), parietal (ß = -0.12, SE = 0.05; p = 0.025), and temporal thicknesses (ß = -0.19, SE = 0.06; p = 0.001). Subcortical structures associated with air pollutants included the thalamus. CONCLUSIONS: Long-term exposures to PM10 and NO2 may lead to cortical thinning in adults.

Regulation of headache response and transcriptomic network by the trigeminal ganglion clock.

OBJECTIVE: To characterize the circadian features of the trigeminal ganglion in a mouse model of headache. BACKGROUND: Several headache disorders, such as migraine and cluster headache, are known to exhibit distinct circadian rhythms of attacks. The circadian basis for these rhythmic pain responses, however, remains poorly understood. METHODS: We examined trigeminal ganglion ex vivo and single-cell cultures from Per2::LucSV reporter mice and performed immunohistochemistry. Circadian behavior and transcriptomics were investigated using a novel combination of trigeminovascular and circadian models: a nitroglycerin mouse headache model with mechanical thresholds measured every 6 h, and trigeminal ganglion RNA sequencing measured every 4 h for 24 h. Finally, we performed pharmacogenomic analysis of gene targets for migraine, cluster headache, and trigeminal neuralgia treatments as well as trigeminal ganglion neuropeptides; this information was cross-referenced with our cycling genes from RNA sequencing data to identify potential targets for chronotherapy. RESULTS: The trigeminal ganglion demonstrates strong circadian rhythms in both ex vivo and single-cell cultures, with core circadian proteins found in both neuronal and non-neuronal cells. Using our novel behavioral model, we showed that nitroglycerin-treated mice display circadian rhythms of pain sensitivity which were abolished in arrhythmic Per1/2 double knockout mice. Furthermore, RNA-sequencing analysis of the trigeminal ganglion revealed 466 genes that displayed circadian oscillations in the control group, including core clock genes and clock-regulated pain neurotransmitters. In the nitroglycerin group, we observed a profound circadian reprogramming of gene expression, as 331 of circadian genes in the control group lost rhythm and another 584 genes gained rhythm. Finally, pharmacogenetics analysis identified 10 genes in our trigeminal ganglion circadian transcriptome that encode target proteins of current medications used to treat migraine, cluster headache, or trigeminal neuralgia. CONCLUSION: Our study unveiled robust circadian rhythms in the trigeminal ganglion at the behavioral, transcriptomic, and pharmacogenetic levels. These results support a fundamental role of the clock in pain pathophysiology. PLAIN LANGUAGE SUMMARY: Several headache diseases, such as migraine and cluster headache, have headaches that occur at the same time each day. We learned that the trigeminal ganglion, an important pain structure in several headache diseases, has a 24-hour cycle that might be related to this daily cycle of headaches. Our genetic analysis suggests that some medications may be more effective in treating migraine and cluster headache when taken at specific times of the day.

Clinical and laboratory findings in scrub typhus associated Guillain-Barré syndrome in South Korea.

BACKGROUND AND AIMS: Scrub typhus is an endemic disease in the fall season that occurs in a limited number of places known as the Tsutsugamushi Triangle. Peripheral neuropathy is a common complication of scrub typhus. Herein, we encountered several patients with ascending paralysis after scrub typhus infection, who were diagnosed with Guillain-Barré syndrome (GBS). We aimed to investigate the clinical and laboratory characteristics of patients who developed GBS after scrub typhus. METHODS: Patients were retrospectively recruited from six nationwide tertiary centers in South Korea from January 2017 to December 2021. Patients who had been clinically diagnosed with GBS and confirmed to have scrub typhus via laboratory examination and/or the presence of an eschar before the onset of acute limb paralysis were included. The GBS-associated clinical and electrophysiological characteristics, outcomes, and scrub typhus-associated features were collected. RESULTS: Of the seven enrolled patients, six were female and one was male. The median time from scrub typhus infection to the onset of limb weakness was 6 (range: 2-14) days. All patients had eschar on their bodies. Four patients (57.1%) were admitted to the intensive care unit and received artificial ventilation for respiratory distress. At 6 months, the median GBS disability score was 2 (range, 1-4) points. INTERPRETATION: Patients with scrub typhus-associated GBS have a severe clinical presentation and require intensive treatment with additional immunotherapies. Therefore, GBS should be included in the differential diagnosis when peripheral neuropathies develop during scrub typhus treatment. Notably, scrub typhus is associated to GBS.

Exposure to ambient air pollution mixture and senescence-associated secretory phenotype proteins among middle-aged and older women.

Our study aimed to investigate the impact of environmental exposures, such as ambient air pollutants, on systemic inflammation and cellular senescence in middle-aged and older women. We utilized epidemiological data linked with exposure data of six air pollutants (particulate matters [PM10, PM2.5], sulphur dioxide [SO2], nitrogen dioxide [NO2], carbon monoxide [CO], and ozone [O3]) and blood samples of 380 peri- and postmenopausal women participants of the Korean Genome and Epidemiology Study. We measured blood high-sensitivity C-reactive protein (hsCRP) and age-related 27 circulatory senescence-associated secretory phenotypes (SASP) produced by senescent cells. We employed single exposure models to explore the general pattern of association between air pollution exposure and proteomic markers. Using quantile g-computation models, we assessed the association of six air pollutant mixtures with hsCRP and SASP proteins. In single-exposure, single-period models, nine out of the 27 SASP proteins including IFN-γ (ß = 0.04, 95% CI: 0.01, 0.07 per interquartile range-increase), IL-8 (0.15, 95% CI: 0.09, 0.20), and MIP1α (0.11, 95% CI: 0.04, 0.18) were positively associated with the average level of O3 over one week. Among the age-related SASP proteins, IFN-γ (0.11, 95% CI: 0.03, 0.20) and IL-8 (0.22, 95% CI: 0.05, 0.39) were positively associated with exposure to air pollutant mixture over one week. The MIP1ß was higher with an increasing one-month average concentration of the air pollutant mixture (0.11, 95% CI: 0.00, 0.21). The IL-8 showed consistently positive association with the ambient air pollutant mixture for the exposure periods ranging from one week to one year. O3 predominantly showed positive weights in the associations between air pollutant mixtures and IL-8. These findings underscore the potential of proteomic indicators as markers for biological aging attributed to short-term air pollution exposure.

Thyroid hormone receptor phosphorylation regulates acute fasting-induced suppression of the hypothalamic-pituitary-thyroid axis.

Fasting induces profound changes in the hypothalamic-pituitary-thyroid (HPT) axis. After binding thyroid hormone (TH), the TH receptor beta 2 isoform (THRB2) represses Trh and Tsh subunit genes and is the principle negative regulator of the HPT axis. Using mass spectrometry, we identified a major phosphorylation site in the AF-1 domain of THRB2 (serine 101, S101), which is conserved among many members of the nuclear hormone receptor superfamily. More than 50% of THRB2 is phosphorylated at S101 in cultured thyrotrophs (TαT1.1) and in the mouse pituitary. All other THR isoforms lack this site and exhibit limited overall levels of phosphorylation. To determine the importance of THRB2 S101 phosphorylation, we used the TαT1.1 cell line and S101A mutant knock-in mice (Thrb2S101A ). We found that TH promoted S101 THRB2 phosphorylation and was essential for repression of the axis at physiologic TH concentrations. In mice, THRB2 phosphorylation was also increased by fasting and mimicked Trh and Tshb repression by TH. In vitro studies demonstrated that a master metabolic sensor, AMP-activated kinase (AMPK) induced phosphorylation at the same site and caused Tshb repression independent of TH. Furthermore, we identified cyclin-dependent kinase 2 (CDK2) as a direct kinase phosphorylating THRB2 S101 and propose that AMPK or TH increase S101 phosphorylation through the activity of CDK2. This study provides a physiologically relevant function for THR phosphorylation, which permits nutritional deprivation and TH to use a common mechanism for acute suppression of the HPT axis.

Cervical enamel projections from a periodontal perspective: A scoping review.

Cervical enamel projections (CEPs) represent a unique developmental and anatomical anomaly wherein the enamel structure extends apically beyond the cemento-enamel junction of the tooth. In this scoping review, the existing literature on CEPs was evaluated to delineate their characteristics, prevalence, predilection for specific teeth and surfaces, clinical significance, and management approaches. Searches were conducted on MEDLINE (PubMed), Cochrane Library, and Embase databases using the keywords "enamel projection(s)" or "ectopic enamel." In total, 24 studies meeting inclusion criteria were included in the review. The prevalence of CEPs varied widely (8.3%-85.1%), predominantly manifesting as grade I or grade III. Mandibular first and second molars exhibited a higher incidence of CEPs, with a notable predilection for buccal surfaces. The consensus in most studies was that CEPs are associated with localized periodontal diseases. Recommendations inclined toward the removal of ectopic enamel during periodontal surgery to enhance periodontal attachment formation. However, decision-making should involve careful consideration of the benefits and drawbacks based on individual circumstances.

Outcomes of 11 dogs with short radius syndrome treated with acute arthroscopically assisted ulnar shortening.

OBJECTIVE: To describe the short-term outcome of acute arthroscopically assisted ulnar shortening (AUS), to treat short radius syndrome in dogs. STUDY DESIGN: Case series. ANIMALS: Eleven client owned dogs. METHODS: Records of dogs that had undergone AUS for treatment of short radius syndrome were reviewed for inclusion. Reporting data included among others pre- and postoperative radioulnar, humeroradial and humeroulnar distances, lameness scores, surgical times, complications and clinical outcome. RESULTS: Following AUS, radiohumeral articulation was improved in all dogs. Median presurgery radioulnar, humeroradial and humeroulnar values were 4.5, 3.2, and 2.2 mm and were improved with surgery by a median of 3.2, 1.8, and 1.2 mm, respectively. Median surgery time was 140 min. Median time to bone healing was 8 weeks (range: 4-14). Median time to last follow-up was 9 weeks (4-468). Median lameness score (scale 0-4) improved from 2 to 1. No major complications were reported. Short-term clinical outcome was graded by the surgeons as full function in four cases and acceptable function in seven. CONCLUSION AND CLINICAL RELEVANCE: Radiographic and arthroscopic radiohumeral articulation were improved and short-term clinical improvement was documented following AUS in all 11 dogs.

Lipid raft protein flotillin-1 is important for the interaction between SOS1 and H-Ras/K-Ras, leading to Ras activation.

Ras mutations have been frequently observed in human cancer. Although there is a high degree of similarity between Ras isomers, they display preferential coupling in specific cancer types. The binding of Ras to the plasma membrane is essential for its activation and biological functions. The present study elucidated Ras isoform-specific interactions with the membrane and their role in Ras-mediated biological activities. We investigated the role of a lipid raft protein flotillin-1 (Flot-1) in the activations of Ras. We found that Flot-1 was co-localized with H-Ras, but not with N-Ras, in lipid rafts of MDA-MB-231 human breast cells. The amino-terminal hydrophobic domain (1-38) of Flot-1 interacted with the hypervariable region of H-Ras. The epidermal growth factor-stimulated activation of H-Ras required Flot-1 which was not necessary for that of N-Ras in breast cancer cells. Flot-1 interacted with son of sevenless (SOS)-1, which promotes the conversion of Ras-bound GDP to GTP. Notably, Flot-1 was crucial for the interaction between SOS1 and H-Ras/K-Ras in breast and pancreatic cancer cells. Stable knockdown of Flot-1 reduced the in vivo metastasis in a mouse xenograft model with human breast carcinoma cells. A tissue microarray composed of 61 human pancreatic cancer samples showed higher levels of Flot-1 expression in pancreatic tumor tissues compared to normal tissues, and a correlation between K-Ras and Flot-1. Taken together, our findings suggest that Flot-1 may serve as a membrane platform for the interaction of SOS1 with H-Ras/K-Ras in human cancer cells, presenting Flot-1 as a potential target for Ras-driven cancers.

Aminal-Linked Covalent Organic Frameworks with hxl-a and Quasi-hcb Topologies for Efficient C2 H6 /C2 H4 Separation.

In reticular chemistry, topology is a powerful concept for defining the structures of covalent organic frameworks (COFs). However, due to the lack of diversity in the symmetry and reaction stoichiometry of the monomers, only 5% of the two-dimensional topologies have been reported to be COFs. To overcome the limitations of COF connectivity and pursue novel topologies in COF structures, two aminal-linked COFs, KUF-2 and KUF-3, are prepared, with dumbbell-shaped secondary building units. Linear dialdehydes and piperazine are condensed at a ratio of 1:2 to construct an aminal linkage, leading to unreported hxl-a (KUF-2) and quasi-hcb (KUF-3) structures. Notably, KUF-3 displays top-tier C2 H6 /C2 H4 selectivity and C2 H6 uptake at 298 K, outperforming most porous organic materials. The intrinsic aromatic ring-rich and Lewis basic pore environments, and appropriate pore widths enable the selective adsorption of C2 H6 , as confirmed by Grand Canonical Monte Carlo simulations. Dynamic breakthrough curves revealed that C2 H6 can be selectively separated from a gas mixture of C2 H6 and C2 H4 . This study suggests that topology-based design of aminal-COFs is an effective strategy for expanding the field of reticular chemistry and provides the facile integration of strong Lewis basic sites for selective C2 H6 /C2 H4 separation.

Export of Diverse and Bioactive Small Proteins through a Type I Secretion System.

Small proteins perform a diverse array of functions, from microbial competition, to endocrine signaling, to building biomaterials. Microbial systems that can produce recombinant small proteins enable discovery of new effectors, exploration of sequence activity relationships, and have the potential for in vivo delivery. However, we lack simple systems for controlling small-protein secretion from Gram-negative bacteria. Microcins are small-protein antibiotics secreted by Gram-negative bacteria that inhibit the growth of neighboring microbes. They are exported from the cytosol to the environment in a one-step process through a specific class of type I secretion systems (T1SSs). However, relatively little is known about substrate requirements for small proteins exported through microcin T1SSs. Here, we investigate the prototypic microcin V T1SS from Escherichia coli and show that it can export a remarkably wide range of natural and synthetic small proteins. We demonstrate that secretion is largely independent of the cargo protein's chemical properties and appears to be constrained only by protein length. We show that a varied range of bioactive sequences, including an antibacterial protein, a microbial signaling factor, a protease inhibitor, and a human hormone, can all be secreted and elicit their intended biological effect. Secretion through this system is not limited to E. coli, and we demonstrate its function in additional Gram-negative species that can inhabit the gastrointestinal tract. Our findings uncover the highly promiscuous nature of small-protein export through the microcin V T1SS, which has implications for native-cargo capacity and the use of this system in Gram-negative bacteria for small-protein research and delivery. IMPORTANCE Type I secretion systems for microcin export in Gram-negative bacteria transport small antibacterial proteins from the cytoplasm to the extracellular environment in a single step. In nature, each secretion system is generally paired with a specific small protein. We know little about the export capacity of these transporters and how cargo sequence influences secretion. Here, we investigate the microcin V type I system. Remarkably, our studies show that this system can export small proteins of diverse sequence composition and is only limited by protein length. Furthermore, we demonstrate that a wide range of bioactive small proteins can be secreted and that this system can be used in Gram-negative species that colonize the gastrointestinal tract. These findings expand our understanding of secretion through type I systems and their potential uses in a variety of small-protein applications.

Ibrutinib combination therapy for advanced gastrointestinal and genitourinary tumours: results from a phase 1b/2 study.

BACKGROUND: Ibrutinib, a first-in-class inhibitor of Bruton's tyrosine kinase, is approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. Based on encouraging preclinical data, safety and efficacy of ibrutinib combined with companion drugs for advanced renal cell carcinoma (RCC), gastric/gastroesophageal junctional adenocarcinoma (GC), and colorectal adenocarcinoma (CRC) were evaluated. METHODS: Ibrutinib 560 mg or 840 mg once daily was administered with standard doses of everolimus for RCC, docetaxel for GC, and cetuximab for CRC. Endpoints included determination of the recommended phase 2 dose (RP2D) of ibrutinib in phase 1b and efficacy (overall response rate [ORR] for GC and CRC; progression-free survival [PFS] for CRC) in phase 2. RESULTS: A total of 39 (RCC), 46 (GC), and 50 (RCC) patients were enrolled and received the RP2D. Safety profiles were consistent with the individual agents used in the study. Confirmed ORRs were 3% (RCC), 21% (GC), and 19% (CRC). Median (90% CI) PFS was 5.6 (3.9-7.5) months in RCC, 4.0 (2.7-4.2) months in GC, and 5.4 (4.1-5.8) months in CRC. CONCLUSIONS: Clinically meaningful increases in efficacy were not observed compared to historical controls; however, the data may warrant further evaluation of ibrutinib combinations in other solid tumours. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02599324.

Barriers against and strategies for malaria control during the COVID-19 pandemic in low- and middle-income countries: a systematic review.

BACKGROUND: The COVID-19 pandemic has disrupted malaria control activities globally. Notably, high levels of excess malaria morbidity and mortality in low- and middle-income countries (LMICs) were reported. Although it is crucial to systematically understand the main causes of the disruption to malaria control and synthesize strategies to prepare for future pandemics, such studies are scarce. Therefore, this study aims to better identify barriers against and strategies for malaria control. METHODS: Following the PRISMA guidelines and through searches of electronic databases and Google Scholar, a systematic literature review was conducted to identify studies pertaining to malaria control published between January 2020 and December 2021. Only studies that discussed reported barriers and/or strategies related to malaria were included for the review. The Mixed Methods Quality Appraisal Tool (MMAT) and the Authority, Accuracy, Coverage, Objectivity, Date and Significance (AACODS) checklist were used for quality appraisal. Key information such as literature type, study design, setting and population, interventions, outcomes, barriers, and strategies were extracted. With an existing framework of four dimensions (accessibility, affordability, availability, and acceptability) further subdivided by the supply and demand sides, this study synthesized information on barriers and strategies related to malaria control and further categorized the strategies based on the time frame. RESULTS: From the 30 selected studies, 27 barriers and 39 strategies were identified. The lockdown measures, which mainly threatened geographic accessibility and availability of malaria control services, were identified to be the main barrier hindering effective mobilization of community health workers and resources. Among the identified strategies, clear risk communication strategies would alleviate psychosocial barriers, which challenged acceptability. Some strategies that cross-cut points across all four dimensions would, require systems-level integration to enhance availability and affordability of malaria control. The strategies were distinguished between short-term, for instant response, and mid to long-term for future readiness. CONCLUSIONS: The pandemic resulted in complex barriers to malaria control, particularly imposing a double burden on LMICs. Identifying strategies to overcome said barriers provides useful insights in the decision-making processes for the current and future pandemic. Cross-cutting strategies that integrate all dimensions need to be considered. Health system strengthening and resilience strategy appropriate for country-specific context is fundamental.

Exposure assessment for air pollution epidemiology: A scoping review of emerging monitoring platforms and designs.

BACKGROUND: Both exposure monitoring and exposure prediction have played key roles in assessing individual-level long-term exposure to air pollutants and their associations with human health. While there have been notable advances in exposure prediction methods, improvements in monitoring designs are also necessary, particularly given new monitoring paradigms leveraging low-cost sensors and mobile platforms. OBJECTIVES: We aim to provide a conceptual summary of novel monitoring designs for air pollution cohort studies that leverage new paradigms and technologies, to investigate their characteristics in real-world examples, and to offer practical guidance to future studies. METHODS: We propose a conceptual summary that focuses on two overarching types of monitoring designs, mobile and non-mobile, as well as their subtypes. We define mobile designs as monitoring from a moving platform, and non-mobile designs as stationary monitoring from permanent or temporary locations. We only consider non-mobile studies with cost-effective sampling devices. Then we discuss similarities and differences across previous studies with respect to spatial and temporal representation, data comparability between design classes, and the data leveraged for model development. Finally, we provide specific suggestions for future monitoring designs. RESULTS: Most mobile and non-mobile monitoring studies selected monitoring sites based on land use instead of residential locations, and deployed monitors over limited time periods. Some studies applied multiple design and/or sub-design classes to the same area, time period, or instrumentation, to allow comparison. Even fewer studies leveraged monitoring data from different designs to improve exposure assessment by capitalizing on different strengths. In order to maximize the benefit of new monitoring technologies, future studies should adopt monitoring designs that prioritize residence-based site selection with comprehensive temporal coverage and leverage data from different designs for model development in the presence of good data compatibility. DISCUSSION: Our conceptual overview provides practical guidance on novel exposure assessment monitoring for epidemiological applications.

Role of geographic characteristics in the spatial cluster detection of cancer: Evidence in South Korea, 1999-2013.

BACKGROUND: Identification of high-risk areas of cancer, referred to as spatial clusters, can inform targeted policies for cancer control. Although cancer cluster detection could be affected by various geographic characteristics including sociodemographic and environmental factors which impacts could also vary over time, studies accounting for such influence remain limited. This study aims to assess the role of geographic characteristics in the spatial cluster detection for lung and stomach cancer over an extended period. METHODS: We obtained sex-specific age-standardized incidence and mortality rates of lung and stomach cancer as well as geographic characteristics across 233 districts in South Korea for three five-year periods between 1999 and 2013. We classified geographic characteristics of each district into four categories: demography, socioeconomic status, behaviors, and physical environments. Specifically, we quantified physical environments using measures of greenness, concentrations of particulate matter and nitrogen dioxide, and air pollution emissions. Finally, we conducted cluster detection analyses using weighted normal spatial scan statistics with the residuals from multiple regression analyses performed with the four progressive sets of geographic attributes. RESULTS: We found that the size of clusters reduced as we progressively adjusted for geographic covariates. Among the four categories, physical environments had the greatest impact on the reduction or disappearance of clusters particularly for lung cancer consistently over time. Whereas older population affected a decrease of lung cancer clusters in the early period, the contribution of education was large in the recent period. The impact was less clear in stomach cancer than lung cancer. CONCLUSION: Our findings highlight the importance of geographic characteristics in explaining the existing cancer clusters and identifying new clusters, which jointly provides practical guidance to cancer control.