The hidden acceleration pump uncovers the role of shellfish in oceanic carbon sequestration.

Whether shellfish mariculture should be included in the blue carbon profile as a strategy to combat climate change has been controversial. It is highly demanding not only to provide calibration quantitation, but also to provide an ecosystem-based mechanism. In this study, we chose mussel farms as a case study to evaluate their contributions to carbon sinks and their responses to sedimentary carbon fixation and sequestration. First, we quantified the air-sea CO2 flux in the mussel aquacultural zone and observed a weak carbon sink (-0.15 ± 0.07 mmol·m-2·d-1) during spring. Next, by analyzing the carbon composition in the sediment, we recorded a noticeable and unexpected increase in the sedimentary recalcitrant carbon (RC) content in the mussel farming case. To address this surprising sedimentary phenomenon, a long-term indoor experimental test was conducted to distinguish the consequences of mussel engagement with sedimentary RC. Our observational data support the idea that mussel engagement promotes accumulation of RC in sediments by 2.5-fold. Furthermore, the relative intensity of carboxylic-rich alicyclic molecule (CRAM)-like compounds (recalcitrant dissolved organic matter (RDOM)) increased by 451.4 % in the mussel-engaged sedimentary dissolved organic matter (DOM) in comparison to the initial state. Mussel engagement had a significantly positive effect on the abundance of sedimentary carbon-fixing genes. Therefore, we definitively conclude that mussel farming is blue carbon positive and propose a new alternative theory that mussel farming areas may have high carbon sequestration potential via an ecologically integrated "3 M" (microalgae-mussel-microbiota) consortium. The "mussel pump" accelerates carbon sequestration and enhances climate-related ecosystem services.

Malaysian Medical Students' Career Intention (MMSCI): a cross-sectional study.

BACKGROUND: In recent years, there have been many instances of negative sentiments expressed by and resignations observed from doctors working in the Ministry of Health (MOH), Malaysia. However, little is known about the perspectives of medical students and their career intentions. This study aims to determine the current Malaysian medical students' career intentions immediately after graduation and upon completing the 2 years of housemanship and to establish the factors influencing these intentions. METHODS: This was a cross-sectional study of 859 Malaysian medical students from 21 medical schools who voluntarily completed a self-administered online questionnaire that was disseminated by representatives from medical schools nationwide and social media platforms of a national medical student society. RESULTS: 37.8% of the respondents were optimistic about a career with the Ministry of Health (MOH), Malaysia in the future. Most of the respondents (91.2%) plan to join and complete the MOH Housemanship programme as soon as possible after graduation, with the majority of them (66.2%) planning to complete it in their state of origin. After 2 years of Housemanship programme, only more than half of the respondents (63.1%) plan to continue their careers in MOH. Slightly more than a quarter (27.1%) of the total respondents plan to emigrate to practise medicine, with 80.7% of them planning to return to Malaysia to practise medicine after some years or after completing specialisation training. Combining the career intentions of Malaysian medical students immediately after graduation and upon completion of the 2 years housemanship programme, only a slight majority (57.5%) of the respondents plan to continue their career in MOH eventually. Most of the respondents (85.0%) intend to specialise. CONCLUSION: A concerning number of Malaysian medical students plan to leave the Ministry of Health workforce, the main healthcare provider in Malaysia, in the future. Urgent government interventions are needed to address the underlying factors contributing to the potential exodus of future doctors to prevent further straining of the already overburdened healthcare system, posing a significant threat to public well-being. An annual national study to track medical students' career intentions is recommended to gather crucial data for the human resources for health planning in Malaysia.

Clinicopathological features of hepatoid adenocarcinoma and non-hepatoid adenocarcinoma of the stomach: A systematic review and meta-analysis.

BACKGROUND: Hepatoid adenocarcinoma of the stomach (HAS) is an extremely rare and unique malignant gastric tumor with a significantly worse prognosis than non-hepatoid adenocarcinoma of the stomach (non-HAS). The present study explored the clinicopathological features of HAS and non-HAS patients to provide insights into HAS treatment strategies. METHODS: From December 26, 2023, we performed a comprehensive search of the PubMed, Web of Science, Cochrane Library, and Embase.com databases for relevant studies. Two authors independently screened the studies, evaluated their quality, extracted data, and performed the analyses. This study was registered with PROSPERO on January 2, 2024. RESULTS: Nine retrospective studies were included for analysis after screening 833 articles. A total of 350 and 924 patients were enrolled in the HAS and non-HAS groups, respectively. While no significant differences were observed in age, sex, tumor size, T3 or T4 stage, and N2 or N3 stage between the two groups, the HAS group exhibited higher rates of lymph node metastasis (OR = 1.93, 95% CI: 1.19-3.13, p = 0.007), liver metastasis (OR = 3.45, 95% CI: 2.26-5.28, p < 0.001), and vascular invasion (OR = 2.76, 95% CI: 2.05-3.71, p < 0.001). Additionally, the HAS group had lower 3-year survival rates (HR = 2.35, 95% CI: 1.70-3.25, p < 0.001) and 5-year survival rates (HR = 3.63, 95% CI: 1.49-8.88, p = 0.005), but lower rates of lymphatic permeation (OR = 0.68, 95% CI: 0.47-0.99, p = 0.040). CONCLUSION: Based on the current clinical evidence, patients with HAS present distinct clinicopathological features, greater invasiveness, and poorer prognosis than non-HAS patients. Further research is warranted to develop optimal treatment strategies for HAS.

Image-Based Hidden Damage Detection Method: Combining Stereo Digital Image Correlation and Finite Element Model Updating.

Maintenance and damage detection of structures are crucial for ensuring their safe usage and longevity. However, damage hidden beneath the surface can easily go unnoticed during inspection and assessment processes. This study proposes a detection method based on image techniques to detect and assess internal structural damage, breaking the limitation of traditional image methods that only analyze the structure's surface. The proposed method combines full-field response on the structure's surface with finite element model updating to reconstruct the structural model, using the reconstructed model to detect and assess hidden structural damage. Initially, numerical experiments are conducted to generate known damaged areas and parameter distributions. Data from these experiments are used to update the finite element model, establish and validate the proposed model updating method, and assess its accuracy in evaluating hidden damage, achieving an accuracy rate of 90%. Furthermore, discussions on more complex damage scenarios are carried out through numerical experiments to demonstrate the feasibility and applicability of the proposed method in reconstructing different forms of damage. Ultimately, this study utilizes stereoscopic digital imaging techniques to acquire full-field information on surfaces, and applies the proposed method to reconstruct the structure, enabling the detection and assessment of hidden damage with an accuracy rate of 86%.

Center of Pressure Measurement Accuracy via Insoles with a Reduced Pressure Sensor Number during Gaits.

The objective was to compare simplified pressure insoles integrating different sensor numbers and to identify a promising range of sensor numbers for accurate center of pressure (CoP) measurement. Twelve participants wore a 99-sensor Pedar-X insole (100 Hz) during walking, jogging, and running. Eight simplified layouts were simulated, integrating 3-17 sensors. Concordance correlation coefficients (CCC) and root mean square errors (RMSE) between the original and simplified layouts were calculated for time-series mediolateral (ML) and anteroposterior (AP) CoP. Differences between layouts and between gait types were assessed via ANOVA and Friedman test. Concordance between the original and simplified layouts varied across layouts and gaits (CCC: 0.43-0.98; χ(7)2 ≥ 34.94, p < 0.001). RMSEML and RMSEAP [mm], respectively, were smaller in jogging (5 ± 2, 15 ± 9) than in walking (8 ± 2, 22 ± 4) and running (7 ± 4, 20 ± 7) (ηp2: 0.70-0.83, p < 0.05). Only layouts with 11+ sensors achieved CCC ≥ 0.80 in all tests across gaits. The 13-sensor layout achieved CCC ≥ 0.95 with 95% confidence, representing the most promising compromise between sensor number and CoP accuracy. Future research may refine sensor placement, suggesting the use of 11-13 sensors. For coaches, therapists, and applied sports scientists, caution is recommended when using insoles with nine or fewer sensors. Consulting task-specific validation results for the intended products is advisable.

Enhancement noise margin and delay time performance of novel punch-through nMOS for single-carrier CMOS.

In this paper, we propose the use of punch-through nMOS (PTnMOS) as an alternative to pMOS in complementary metal oxide semiconductor (CMOS) circuits. According to the TCAD simulation results, PTnMOS exhibit sub-threshold characteristics similar to those of pMOS and can be formed by simply changing the doping concentration of the source and drain. Without the need for sizing, which solves the area occupation problem caused by the need to increase the width of pMOS due to insufficient hole mobility. In addition, we compose a PTnMOS and nMOS without sizing to form a single-carrier CMOS in which only electrons are transmitted, and We extract its performance for comparison with conventional CMOS (Wp/Wn = 1). The results indicate that single-carrier CMOS has symmetric noise margin and 29% faster delay time compared to conventional CMOS (Wp/Wn = 1). If III-V or II-VI group materials could be applied to single-carrier CMOS, not only could costs be reduced and wafer area occupancy minimized, but also significant improvements in the performance and bandwidth application of microwave circuits could be achieved.

The HD-ZIP II gene PaHAT14 increases cuticle deposition by down-regulating ERF gene PaERF105 in Phalaenopsis.

To analyze the gene involved in orchid floral development, a HD-Zip II gene PaHAT14, which specifically and highly expressed in perianth during early flower development was identified from Phalaenopsis. Transgenic Arabidopsis plants expressing 35S::PaHAT14 and 35S::PaHAT14+SRDX (fused with the repressor motif SRDX) exhibited similar altered phenotypes, including small leaves, early flowering, and bending petals with increased cuticle production. This suggests that PaHAT14 acts as a repressor. In contrast, transgenic Arabidopsis plants expressing 35S::PaHAT14+VP16 (fused with the activation domain VP16) exhibited curled leaves, late flowering, and folded petals with decreased cuticle production within hardly opened flowers. Additionally, the expression of the ERF gene DEWAX2, which negatively regulates cuticular wax biosynthesis, was down-regulated in 35S::PaHAT14 and 35S::PaHAT14+SRDX transgenic Arabidopsis, while it was up-regulated in 35S::PaHAT14+VP16 transgenic Arabidopsis. Furthermore, transient overexpression of PaHAT14 in Phalaenopsis petal/sepal increased cuticle deposition due to the down-regulation of PaERF105, a Phalaenopsis DEWAX2 orthologue. On the other hand, transient overexpression of PaERF105 decreased cuticle deposition, whereas cuticle deposition increased and the rate of epidermal water loss was reduced in PaERF105 VIGS Phalaenopsis flowers. Moreover, ectopic expression of PaERF105 not only produced phenotypes similar to those in 35S::PaHAT14+VP16 Arabidopsis but also compensated for the altered phenotypes observed in 35S::PaHAT14 and 35S::PaHAT14+SRDX Arabidopsis. These results suggest that PaHAT14 promotes cuticle deposition by negatively regulating downstream gene PaERF105 in orchid flowers.

Transitioning weathered oil fields towards new energy: A review on utilizing hydrogenotrophic methanogens for petroleum hydrocarbons remediation.

The weathering process can cause the volatilization of light components in crude oil, leading to the accumulation of total petroleum hydrocarbons (TPH) in weathered oil field soils. These TPH compounds are relatively resistant to biodegradation, posing a significant environmental hazard by contributing to soil degradation. TPH represents a complex mixture of petroleum-based hydrocarbons classified as persistent organic pollutants in soil and groundwater. The release of TPH pollutants into the environment poses serious threats to ecosystems and human health. Currently, various methods are available for TPH-contaminated soil remediation, with bioremediation technology recognized as an environmentally friendly and cost-effective approach. While converting TPH to CO2 is a common remediation method, the complex structures and diverse types of petroleum hydrocarbons (PHs) involved can result in excessive CO2 generation, potentially exacerbating the greenhouse effect. Alternatively, transforming TPH into energy forms like methane through bioremediation, followed by collection and reuse, can reduce greenhouse gas emissions and energy consumption. This process relies on the synergistic interaction between Methanogens archaea and syntrophic bacteria, forming a consortium known as the oil-degrading bacterial consortium. Methanogens produce methane through anaerobic digestion (AD), with hydrogenotrophic methanogens (HTMs) utilizing H2 as an electron donor, playing a crucial role in biomethane production. Candidatus Methanoliparia (Ca. Methanoliparia) was found in the petroleum archaeal community of weathered Oil field in northeast China. Ca. Methanoliparia has demonstrated its independent ability to decompose and produce new energy (biomethane) without symbiosis, contribute to transitioning weathered oil fields towards new energy. Therefore, this review focuses on the principles, mechanisms, and developmental pathways of HTMs during new energy production in the degradation of PHs. It also discusses strategies to enhance TPH degradation and recovery methods.

The effect of new e-commerce platform's OSC promotion on consumer cognition: from cognitive legitimacy and cognitive psychology perspective.

Introduction: In the realm of emerging e-commerce platforms, the influence of online shopping events, specifically online carnival promotions (OSC), on consumer behavior is a significant area of interest.This paper delves into the effects of such promotions on consumer perceptions, a topic that has not been extensively explored in academic research. Methods: To investigate this phenomenon, two distinct studies were conducted. The first study employed a questionnaire-based experiment involving 220 participants, divided into two groups. The first study examined the mediating role of cognitive legitimacy in the relationship between OSC events organized by new e-commerce platforms and the perceptions of consumers. The second study utilized an event-related potentials (ERPs) experiment with 33 participants to explore the differences in consumer perceptions between OSC promotions and general promotions by new e-commerce platforms. This study measured the brain's response to promotional stimuli to gain insights into the cognitive processes involved. Results: The first study yielded results that suggest OSC activities can facilitate the establishment of cognitive legitimacy for new e-commerce platforms. This, in turn, was found to be associated with an increase in positive purchase intentions among consumers. In the second study, the ERPs data indicated that exposure to OSC promotional materials elicited larger P2 and N2 ERP components when participants were presented with the logo of a new e-commerce platform. This was in contrast to the response to general promotional materials, suggesting a heightened cognitive and perceptual engagement with OSC promotions. Discussion: The findings from both studies collectively imply that OSC promotions have a distinct impact on consumer perceptions and cognitive processes. The implicit memory triggered by these promotions appears to influence the identification of new platforms and the mechanisms of cognitive control during online shopping. This, in turn, may have implications for explicit consumer behavior, suggesting that OSC promotions could be a powerful tool for shaping consumer attitudes and behaviors in the e-commerce space. The results underscore the importance of understanding the nuances of consumer engagement with new e-commerce platforms and the role of promotional strategies in fostering a positive brand image and consumer loyalty.

Melatonin activates Nrf2/HO-1 signalling pathway to antagonizes oxidative stress-induced injury via melatonin receptor 1 (MT1) in cryopreserved mice ovarian tissue.

Our previous research has shown that melatonin (MLT) can reduce cryopreserved ovarian damage in mice. Yet, the molecular mechanism of MLT protection is still unclear. Some studies have shown that melatonin receptor 1 (MT1) is very important for animal reproductive system. To evaluate whether MLT exerts its protective effect on cryopreserved mice ovarian tissue via MT1, we added antagonist of MT1/MT2 (Luzindor) or antagonist of MT2 (4P-PDOT) to the freezing solution, followed by cryopreservation and thawing of ovarian tissue. The levels of total superoxide dismutase (T-SOD), catalase (CAT), nitric oxide (NO) and malondialdehyde (MDA) were detected. Besides, by using RT-PCR and Western blotting, the expression of Bcl-2, Bax and Nrf2/HO-1 signalling pathway-related proteins was detected. These findings demonstrated that compared with the melatonin group, the addition of Luzindor increased apoptosis, NO and MDA activities, decreased CAT and T-SOD activities and inhibited Nrf2/HO-1 signalling pathway. In conclusion, melatonin can play a protective role in cryopreserved ovarian tissue of mice through MT1 receptor.

Study on intestinal parasitic infections and gut microbiota in cancer patients at a tertiary teaching hospital in Malaysia.

Intestinal parasitic infections (IPIs) can lead to significant morbidity and mortality in cancer patients. While they are unlikely to cause severe disease and are self-limiting in healthy individuals, cancer patients are especially susceptible to opportunistic parasitic infections. The gut microbiota plays a crucial role in various aspects of health, including immune regulation and metabolic processes. Parasites occupy the same environment as bacteria in the gut. Recent research suggests intestinal parasites can disrupt the normal balance of the gut microbiota. However, there is limited understanding of this co-infection dynamic among cancer patients in Malaysia. A study was conducted to determine the prevalence and relationship between intestinal parasites and gut microbiota composition in cancer patients. Stool samples from 134 cancer patients undergoing active treatment or newly diagnosed were collected and examined for the presence of intestinal parasites and gut microbiota composition. The study also involved 17 healthy individuals for comparison and control. Sequencing with 16S RNA at the V3-V4 region was used to determine the gut microbial composition between infected and non-infected cancer patients and healthy control subjects. The overall prevalence of IPIs among cancer patients was found to be 32.8%. Microsporidia spp. Accounted for the highest percentage at 20.1%, followed by Entamoeba spp. (3.7%), Cryptosporidium spp. (3.0%), Cyclospora spp. (2.2%), and Ascaris lumbricoides (0.8%). None of the health control subjects tested positive for intestinal parasites. The sequencing data analysis revealed that the gut microbiota diversity and composition were significantly different in cancer patients than in healthy controls (p < 0.001). A significant dissimilarity was observed in the bacterial composition between parasite-infected and non-infected patients based on Bray-Curtis (p = 0.041) and Jaccard (p = 0.021) measurements. Bacteria from the genus Enterococcus were enriched in the parasite-infected groups, while Faecalibacterium prausnitzii reduced compared to non-infected and control groups. Further analysis between different IPIs and non-infected individuals demonstrated a noteworthy variation in Entamoeba-infected (unweighted UniFrac: p = 0.008), Cryptosporidium-infected (Bray-Curtis: p = 0.034) and microsporidia-infected (unweighted: p = 0.026; weighted: p = 0.019; Jaccard: p = 0.031) samples. No significant dissimilarity was observed between Cyclospora-infected groups and non-infected groups. Specifically, patients infected with Cryptosporidium and Entamoeba showed increased obligate anaerobic bacteria. Clostridiales were enriched with Entamoeba infections, whereas those from Coriobacteriales decreased. Bacteroidales and Clostridium were found in higher abundance in the gut microbiota with Cryptosporidium infection, while Bacillales decreased. Additionally, bacteria from the genus Enterococcus were enriched in microsporidia-infected patients. In contrast, bacteria from the Clostridiales order, Faecalibacterium, Parabacteroides, Collinsella, Ruminococcus, and Sporosarcina decreased compared to the non-infected groups. These findings underscore the importance of understanding and managing the interactions between intestinal parasites and gut microbiota for improved outcomes in cancer patients.

Distinct oral-associated gastric microbiota and Helicobacter pylori communities for spatial microbial heterogeneity in gastric cancer.

The gastric microbial community plays a fundamental role in gastric cancer (GC), and the two main anatomical subtypes of GC, non-cardia and cardia GC, are associated with different risk factors (Helicobacter pylori for non-cardia GC). To decipher the different microbial spatial communities of GC, we performed a multicenter retrospective analysis to characterize the gastric microbiota in 223 GC patients, including H. pylori-positive or -negative patients, with tumors and paired adjacent normal tissues, using third-generation sequencing. In the independent validation cohort, both dental plaque and GC tumoral tissue samples were collected and sequenced. The prevalence of H. pylori and oral-associated bacteria was verified using fluorescence in situ hybridization (FISH) assays in GC tumoral tissues and matched nontumoral tissues. We found that the vertical distribution of the gastric microbiota, at the upper, middle, and lower third sites of GC, was likely an important factor causing microbial diversity in GC tumor tissues. The oral-associated microbiota cluster, which included Veillonella parvula, Streptococcus oralis, and Prevotella intermedia, was more abundant in the upper third of the GC. However, H. pylori was more abundant in the lower third of the GC and exhibited a significantly high degree of microbial correlation. The oral-associated microbiota module was co-exclusive with H. pylori in the lower third site of the GC tumoral tissue. Importantly, H. pylori-negative GC patients with oral-associated gastric microbiota showed worse overall survival, while the increase in microbial abundance in H. pylori-positive GC patients showed no difference in overall survival. The prevalence of V. parvula in both the dental plaque and GC tissue samples was concordant in the independent validation phase. We showed that the oral-associated species V. parvula and S. oralis were correlated with overall survival. Our study highlights the roles of the oral-associated microbiota in the upper third of the GC. In addition, oral-associated species may serve as noninvasive screening tools for the management of GC and an independent prognostic factor for H. pylori-negative GCs. IMPORTANCE: Our study highlights the roles of the oral-associated microbiota in the upper third of gastric cancer (GC).We showed that the oral-associated species Veillonella parvula and Streptococcus oralis were correlated with overall survival. In addition, oral-associated species may serve as noninvasive screening tools for the management of GC and an independent prognostic factor for Helicobacter pylori-negative GCs.

The effectiveness of gliding arc discharge plasma in sterilizing artificial seawater contaminated with Vibrio parahaemolyticus.

The rapid proliferation of the halophilic pathogen Vibrio parahaemolyticus poses a severe health hazard to halobios and significantly impedes intensive mariculture. This study aimed to evaluate the potential application of gliding arc discharge plasma (GADP) to control the infection of Vibrio parahaemolyticus in mariculture. This study investigated the inactivation ability of GADP against Vibrio parahaemolyticus in artificial seawater (ASW), changes in the water quality of GADP-treated ASW, and possible inactivation mechanisms of GADP against Vibrio parahaemolyticus in ASW. The results indicate that GADP effectively inactivated Vibrio parahaemolyticus in ASW. As the volume of ASW increased, the time required for GADP sterilization also increased. However, the complete sterilization of 5000 mL of ASW containing Vibrio parahaemolyticus of approximately 1.0 × 104 CFU/mL was achieved within 20 min. Water quality tests of the GADP-treated ASW demonstrated that there were no significant changes in salinity or temperature when Vibrio parahaemolyticus (1.0 ×104 CFU/mL) was completely inactivated. In contrast to the acidification observed in plasma-activated water (PAW) in most studies, the pH of ASW did not decrease after treatment with GADP. The H2O2 concentration in the GADP-treated ASW decreased after post-treatment. The NO2-concentration in the GADP-treated ASW remained unchanged after post-treatment. Further analysis revealed that GADP induced oxidative stress in Vibrio parahaemolyticus, which increased cell membrane permeability and intracellular ROS levels of Vibrio parahaemolyticus. This study provides a viable solution for infection with the halophilic pathogen Vibrio parahaemolyticus and demonstrates the potential of GADP in mariculture.

Mitigating adverse social determinants of health in the vulnerable population: Insights from a home visitation programme.

Introduction: Low-income families are exposed to adverse childhood experiences and psychosocial risks that impact child development. At the KK Women's and Children's Hospital in Singapore, Kids Integrated Development Service (KIDS0-3) is a home visitation programme that aims to optimise the development of children from low-income families. Method: Data comprising family demographics, maternal psychosocial risks and outcomes of child development were collated through a chart review of 469 mother-child dyads enrolled from June 2014 to October 2022. Results: Based on the Family and Adult Support Tool, 312 families (67%) were identified as moderate or high-risk. Children from moderate and high-risk families had poorer Bayley cognitive (mean 95.88 [SD 8.25] versus [vs] 98.44 [SD 8.72], P=0.014) and language scores (mean 87.38 [SD 10.35] vs 90.43 [SD 9.61], P=0.016] at 24 months of age, compared to the low-risk group. Children of teenage mothers had lower Bayley cognitive scores (mean 95.16 [SD 8.42] vs 97.76 [SD 8.55], P=0.037), and children of mothers who experienced sexual abuse had lower Bayley cognitive scores (mean 93.1 [SD 5.68] vs 99.7 [SD 8.17], P=0.013) and language scores (mean 82.3 [SD 12.87] vs 91.3 [SD 10.86], P=0.021]. Antenatal enrolment yielded better child language (mean 90.1 [SD 9.37] vs 87.13 [SD 10.79], P=0.04) and motor outcomes (mean 99.62 [SD 9.45] vs 94.72 [SD 9.51], P=0 .001) than postnatal enrolment. Conclusion: Psychosocial risks impact the development of children from low-income families in Singapore. Findings underscore the importance of early, integrated intervention for vulnerable families.

Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Identification of a Homozygous Mutation of CCDC40 in a Chinese Infertile Man with MMAF and PCD-like Phenotypes.

Aims: Asthenozoospermia is the most common factor of male infertility, mainly caused by multiple morphological abnormalities of the sperm flagella (MMAF) and primary ciliary dyskinesia (PCD). Previous studies have shown that genetic factors may contribute to MMAF and PCD. The study aimed to identify novel potentially pathogenic gene mutations in a Chinese infertile man with MMAF and PCD-like phenotypes. Methods: A Chinese infertile man with MMAF and PCD was enrolled in this study. Whole exome sequencing and Sanger sequencing were performed to identify potential causative genes and mutations. Results: A novel homozygous missense mutation (c.1450G>A; p.E484K) of CCDC40 was finally identified and Sanger sequencing confirmed that the patient carried the homozygous mutation, which was inherited from his parents. We reported the first homozygous missense CCDC40 mutation in infertile men with MMAF but had other milder PCD symptoms. Conclusion: Our findings not only broaden the disease-causing mutation spectrum of CCDC40 but also provide new insight into the correlation between CCDC40 mutations and MMAF.

Impact on Quality during In-Use Preparation of an Antibody Drug Conjugate with Eight Different Closed System Transfer Device Brands.

The aim of this study was to investigate the in-use compatibility of eight commercially available closed system transfer device brands (CSTDs) with a formulated model antibody drug conjugate (ADC). Overall, in-use simulated dosing preparation applying the CSTD systems investigated raised concerns for several product quality attributes. The incompatibilities observed were mainly associated with increased visible and subvisible particles formation as well as significant changes in holdup volumes. Visible and subvisible particles contained heterogeneous mixtures of particle classes, with the majority of subvisible particles associated with silicone oil leaching from CSTD systems during simulated dose preparation upon contact with the ADC formulation. These observations demonstrate that CSTD use may adversely impact product quality and delivered dose which could potentially lead to safety and efficacy concerns during administration. Other product quality attributes measured including turbidity, color, ADC recovery, and purity by size exclusion HPLC, did not show relevant changes. It is therefore strongly recommended to test and screen the compatibility of CSTDs with the respective ADC, in a representative in-use simulated administration setting, during early CMC development, i.e., well before the start of clinical studies, to include information about compatibility and to ensure that the CSTD listed in the manuals of preparation for clinical handling has been thoroughly assessed before human use.

Lanthanide Inorganic Nanoparticles Enhance Semiconducting Polymer Nanoparticles Afterglow Luminescence for In Vivo Afterglow/Magnetic Resonance Imaging.

Dual/multimodal imaging strategies are increasingly recognized for their potential to provide comprehensive diagnostic insights in cancer imaging by harnessing complementary data. This study presents an innovative probe that capitalizes on the synergistic benefits of afterglow luminescence and magnetic resonance imaging (MRI), effectively eliminating autofluorescence interference and delivering a superior signal-to-noise ratio. Additionally, it facilitates deep tissue penetration and enables noninvasive imaging. Despite the advantages, only a limited number of probes have demonstrated the capability to simultaneously enhance afterglow luminescence and achieve high-resolution MRI and afterglow imaging. Herein, we introduce a cutting-edge imaging platform based on semiconducting polymer nanoparticles (PFODBT) integrated with NaYF4@NaGdF4 (Y@Gd@PFO-SPNs), which can directly amplify afterglow luminescence and generate MRI and afterglow signals in tumor tissues. The proposed mechanism involves lanthanide nanoparticles producing singlet oxygen (1O2) upon white light irradiation, which subsequently oxidizes PFODBT, thereby intensifying afterglow luminescence. This innovative platform paves the way for the development of high signal-to-background ratio imaging modalities, promising noninvasive diagnostics for cancer.

Transcription factors as molecular switches regulating plant responses to drought stress.

Plants often experience abiotic stress, which severely affects their growth. With the advent of global warming, drought stress has become a pivotal factor affecting crop yield and quality. Increasing numbers of studies have focused on elucidating the molecular mechanisms underlying plant responses to drought stress. As molecular switches, transcription factors (TFs) are key participants in drought-resistance regulatory networks in crops. TFs regulate the transcription of downstream genes and are regulated by various upstream regulatory factors. Therefore, understanding the mechanisms of action of TFs in regulating drought stress can help enhance the adaptive capacity of crops under drought conditions. In this review, we summarize the structural characteristics of several common TFs, their multiple drought-response pathways, and recently employed research strategies. We describe the application of new technologies such as analysis of stress granule dynamics and function, multi-omics data, gene editing, and molecular crosstalk between TFs in drought resistance. This review aims to familiarize readers with the regulatory network of TFs in drought resistance and to provide a reference for examining the molecular mechanisms of drought resistance in plants and improving agronomic traits.

Histone deacetylase Hos2 regulates protein expression noise by potentially modulating the protein translation machinery.

Non-genetic variations derived from expression noise at transcript or protein levels can result in cell-to-cell heterogeneity within an isogenic population. Although cells have developed strategies to reduce noise in some cellular functions, this heterogeneity can also facilitate varying levels of regulation and provide evolutionary benefits in specific environments. Despite several general characteristics of cellular noise having been revealed, the detailed molecular pathways underlying noise regulation remain elusive. Here, we established a dual-fluorescent reporter system in Saccharomyces cerevisiae and performed experimental evolution to search for mutations that increase expression noise. By analyzing evolved cells using bulk segregant analysis coupled with whole-genome sequencing, we identified the histone deacetylase Hos2 as a negative noise regulator. A hos2 mutant down-regulated multiple ribosomal protein genes and exhibited partially compromised protein translation, indicating that Hos2 may regulate protein expression noise by modulating the translation machinery. Treating cells with translation inhibitors or introducing mutations into several Hos2-regulated ribosomal protein genes-RPS9A, RPS28B and RPL42A-enhanced protein expression noise. Our study provides an effective strategy for identifying noise regulators and also sheds light on how cells regulate non-genetic variation through protein translation.