Site-Selective Distal C(sp3)-H Bromination of Aliphatic Amines as a Gateway for Forging Nitrogen-Containing sp3 Architectures.

Herein, we disclose a new strategy that rapidly and reliably incorporates bromine atoms at distal, secondary C(sp3)-H sites in aliphatic amines with excellent and predictable site-selectivity pattern. The resulting halogenated building blocks serve as versatile linchpins to enable a series of carbon-carbon and carbon-heteroatom bond-formations at remote C(sp3) sites, thus offering a new modular and unified platform that expedites the access to advanced sp3 architectures possessing valuable nitrogen-containing saturated heterocycles of interest in medicinal chemistry settings.

Large malignant tracheo-oesophageal fistula with lung abscesses.

Tracheo-oesophageal fistula (TOF) can arise as a rare complication of malignancy (especially oesophageal or lung cancers) and pose difficult diagnostic and management dilemmas. We explore a challenging case of large malignant TOF below.

Modified Danzhi Xiaoyao Powder (MDXP) improves the corneal damage in dry eye disease (DED) mice through phagocytosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Modified Danzhi Xiaoyao Powder (MDXP) is a traditional Chinese medicine formula remedy for treating Dry Eye Disease (DED). It showed the function of dispersing stagnated liver Qi for relieving Qi stagnation and clearing heat, which can be effective in treating conditions such as Dry Eye Disease (DED) and irregular menstruation due to liver depression and fire transformation. AIM OF THE STUDY: This study investigated the mechanism of the effect of MDXP in mice with DED. MATERIALS AND METHODS: A DED model was induced in mice using chronic painful stimulation (tail clamping) in combination with Benzalkonium Chloride Solution drops administered in a dry box for 28 days. After modeling, the MDXP groups were given Chinese medicine with different dosages by gavage for 14 days. The following parameters were recorded in each group: body mass, anal temperature, tear secretion, tear film rupture time, and corneal fluorescein staining. Behavioral changes were evaluated by elevating cross-maze and open-field experiments. The levels of inflammatory factors serum tumor necrosis factor-α (TNF-α), interleukin 1ß (IL-1ß), fcγR-mediated phagocytosis pathway cell division control protein 42 homolog (CDC42), actin-related protein 2/3 complex subunit 2 (ARPC2), and actin-related protein 3 (ACTR3) were measured by using Enzyme-linked immunoassay (ELISA), immunohistochemical staining, and real-time fluorescent qualitative polymerase chain reaction (RT-qPCR). RESULTS: MDXP increased body mass and lowered body temperature, prolonged tear film break-up time, promoted tear secretion, repaired corneal damage, decreased horizontal and vertical scores, elevated percentage of open arm times and boom opening time percentage, and reduced the expression levels of inflammatory factors of TNF-α, IL-1ß and pathway-related proteins CDC42, ARPC2, and ACTR3 in mice. MDXP also reduced the expression levels of inflammatory factors of TNF-α and IL-1ß in human corneal endothelial cells (HCECs), mouse mononuclear macrophage cells (RAW264.7), and human myeloid leukemia mononuclear cells (THP-1). CONCLUSIONS: MDXP can relieve tension and anxiety, inhibit apoptosis, reduce phagocytosis, reduce the expression of pro-inflammatory factors, repair corneal damage, and improve the symptoms in DED mice. The mechanism of action may be through the fcγR-mediated phagocytosis pathway.

CRH neurons in the lateral hypothalamic area regulate feeding behavior of mice.

Food cues serve as pivotal triggers for eliciting physiological responses that subsequently influence food consumption. The magnitude of response induced by these cues stands as a critical determinant in the context of obesity risk. Nonetheless, the underlying neural mechanism that underpins how cues associated with edible food potentiate feeding behaviors remains uncertain. In this study, we revealed that corticotropin-releasing hormone (CRH)-expressing neurons in the lateral hypothalamic area played a crucial role in promoting consummatory behaviors in mice, shedding light on this intricate process. By employing an array of diverse assays, we initially established the activation of these neurons during feeding. Manipulations using optogenetic and chemogenetic assays revealed that their activation amplified appetite and promoted feeding behaviors, whereas inhibition decreased them. Additionally, our investigation identified downstream targets, including the ventral tegmental area, and underscored the pivotal involvement of the CRH neuropeptide itself in orchestrating this regulatory network. This research casts a clarifying light on the neural mechanism underlying the augmentation of appetite and the facilitation of feeding behaviors in response to food cues. VIDEO ABSTRACT.

Physical activity and sedentary time distribution among adult residents during COVID-19 circuit breaker movement restrictions in Singapore: a public health perspective.

Introduction: Social lockdowns and quarantines have been enforced in various populations to mitigate the spread of coronavirus disease 2019 (COVID-19) in the community. This study investigated the impact of COVID-19 lockdown, known as circuit breaker movement restrictions (CBMR), on physical activity (PA) and sedentary time (ST) distribution patterns among Singapore residents aged 21-65 years. Methods: This was a cross-sectional retrospective study that utilised a 44-item questionnaire that included sections to determine PA and ST distribution patterns before and during CBMR. It also included information on sleep duration, PA preference and routine, awareness of local initiatives and perceptions on barriers towards PA during the CBMR period. Results: There was an overall decrease in PA and a significant increase in physical inactivity and ST during the CBMR period. A greater proportion of participants reported sleeping for longer hours, suggesting positive adaptations in sleep habits during CBMR. Majority were unaware of online exercise initiatives and programmes offered during the CBMR period, and >50% of the respondents never used an online resource for exercise. Singapore residents seemed to prefer outdoor and facility-based venues for exercise and PA, and closure of facilities was the primary barrier for PA during the CBMR period. Conclusion: Reduced PA and increased ST during CBMR reflect negative lifestyle adaptations and may have adverse public health implications. Increased sleep duration suggests successful coping, which may consequently lead to physical and mental health benefits. While Singapore adult residents may be flexible with certain aspects of being physically active, they seemed less adaptive to changes in type of exercise, facility and environment.

Dephosphorylation of the pre-initiation complex is critical for origin firing.

In eukaryotes, cyclin-dependent kinase (CDK) ensures that the genome is duplicated exactly once by inhibiting helicase loading factors before activating origin firing. CDK activates origin firing by phosphorylating two substrates, Sld2 and Sld3, forming a transient and limiting intermediate-the pre-initiation complex (pre-IC). Here, we show in the budding yeast Saccharomyces cerevisiae that the CDK phosphorylations of Sld3 and Sld2 are rapidly turned over during S phase by the PP2A and PP4 phosphatases. PP2ARts1 targets Sld3 specifically through an Rts1-interaction motif, and this targeted dephosphorylation is important for origin firing genome-wide, for formation of the pre-IC at origins and for ensuring that Sld3 is dephosphorylated in G1 phase. PP2ARts1 promotes replication in vitro, and we show that targeted Sld3 dephosphorylation is critical for viability. Together, these studies demonstrate that phosphatases enforce the correct ordering of replication factor phosphorylation and in addition to kinases are also key drivers of replication initiation.

Characterisation of corrosion-induced crack in concrete using ultrasonic diffuse coda wave.

Corrosion damage in reinforcing steel bars has been a major cause of cracking and spalling of reinforced concrete. To extend the service life of concrete structures, non-destructive testing methods are necessary to assess the corrosion status in order to conduct a timely repair. At the early stage of corrosion, rust grows from the reinforcing bar, subsequently generates cracks towards the surface of the concrete. Ultrasonic methods have been widely used to detect cracks in concrete. However, it is challenging to characterise them due to the heterogeneous material properties of the concrete. In this paper, ultrasonic imaging technique based on diffuse coda wave has been explored to inspect and characterise corrosion-induced cracks. In this method, scattering cross-section of the crack is reconstructed with the Locadiff imaging technique. Based on the assumption that both crack tips have the same scattering cross-section, the size of the crack can be estimated when the location of the reinforcing bar is known. Numerical simulations were carried out to image straight and curved cracks, showing excellent accuracy. Experiments were designed subsequently on concrete samples with accelerated corrosion. The induced cracks were characterised by the proposed ultrasonic method, and compared with X-ray CT results, showing very good agreement.

Graph neural network-based cell switching for energy optimization in ultra-dense heterogeneous networks.

The development of ultra-dense heterogeneous networks (HetNets) will cause a significant rise in energy consumption with large-scale base station (BS) deployments, requiring cellular networks to be more energy efficient to reduce operational expense and promote sustainability. Cell switching is an effective method to achieve the energy efficiency goals, but traditional heuristic cell switching algorithms are computationally demanding with limited generalization abilities for ultra-dense HetNet applications, motivating the usage of machine learning techniques for adaptive cell switching. Graph neural networks (GNNs) are powerful deep learning models with strong generalization abilities but receive little attention for cell switching. This paper proposes a GNN-based cell switching solution (GBCSS) that has a smaller computational complexity than existing heuristic algorithms. The presented performance evaluation uses the Milan telecommunication dataset based on real-world call detail records, comparing GBCSS with a traditional exhaustive search (ES) algorithm, a state-of-the-art learning-based algorithm, and the baseline without cell switching. Results indicate that GBCSS achieves a 10.41% energy efficiency gain when compared with the baseline and achieves 75.76% of the optimal performance obtained with ES algorithm. The results also demonstrate GBCSS' significant scalability and generalization abilities to differing load conditions and the number of BSs, suggesting this approach is well-suited to ultra-dense HetNet deployment.

Impact of clinical placement sites on general practice as a career preference for Australian medical students.

OBJECTIVE: This study investigates whether General Practice placement experience or locations (urban/metropolitan vs non-metropolitan) promote student interest in pursuing general practice. DESIGN: SurveyMonkey was used in the design of the survey. SETTING: The study was conducted online. PARTICIPANTS: A total of 520 and 705 clinical-year students were surveyed in 2009 and 2019, respectively. The study was conducted online, using SurveyMonkey, and the participants were mostly non-indigenous Australian medical students, between the ages of 18 and 30. INTERVENTIONS: Students were recruited from the General Practice Students' Network membership database to complete the survey online. Chi-squared testing, Pearson's correlation and a multivariate logistic regression analysis were used to investigate the correlation between general practice placements and intention to become a general practice. MAIN OUTCOME MEASURES: The association and causation between general practice placement location, student experience and students' intended career outcomes. RESULTS: In 2009, majority of students rated their general practice experience 'mostly positive' while most metropolitan participants and majority of non-metropolitan placement participants in the 2019 survey responded with 'mostly positive' in 2019. Based on 2009 and 2019 data, general practice placement location had no association with the likelihood of pursuing general practice as a career, while student experience had a stronger positive correlation with the likelihood of pursuing general practice as a career. CONCLUSION: Our study shows that students' overall experience with their general practice placements significantly encourages medical students to pursue the general practice pathway. As such, increasing both metropolitan and non-metropolitan placement experiences can potentially overcome general practice shortage.

Fine Mapping of a New Major QTL-qGLS8 for Gray Leaf Spot Resistance in Maize.

Gray leaf spot (GLS), caused by different species of Cercospora, is a fungal, non-soil-borne disease that causes serious reductions in maize yield worldwide. The identification of major quantitative trait loci (QTLs) for GLS resistance in maize is essential for developing marker-assisted selection strategies in maize breeding. Previous research found a significant difference (P < 0.01) in GLS resistance between T32 (highly resistant) and J51 (highly susceptible) genotypes of maize. Initial QTL analysis was conducted in an F2 : 3 population of 189 individuals utilizing genetic maps that were constructed using 181 simple sequence repeat (SSR) markers. One QTL (qGLS8) was detected, defined by the markers umc1130 and umc2354 in three environments. The qGLS8 QTL detected in the initial analysis was located in a 51.96-Mb genomic region of chromosome 8 and explained 7.89-14.71% of the phenotypic variation in GLS resistance in different environments. We also developed a near isogenic line (NIL) BC3F2 population with 1,468 individuals and a BC3F2-Micro population with 180 individuals for fine mapping. High-resolution genetic and physical maps were constructed using six newly developed SSRs. The QTL-qGLS8 was narrowed down to a 124-kb region flanked by the markers ym20 and ym51 and explained up to 17.46% of the phenotypic variation in GLS resistance. The QTL-qGLS8 contained seven candidate genes, such as an MYB-related transcription factor 24 and a C 3 H transcription factor 347), and long intergenic non-coding RNAs (lincRNAs). The present study aimed to provide a foundation for the identification of candidate genes for GLS resistance in maize.

[Spatial and temporal variations of hydrogen and oxygen isotopes and sources of water vapour indicated from satellite precipitation products along the transection of 38°north latitude in North China]. / 基于卫星降水产品的华北北纬38°å¸¦é™æ°´æ°¢æ°§åŒä½ç´ 时空特征及水汽来源.

The variations of hydrogen and oxygen isotopes in rainfall are critical for understanding the sources of rainfall and the influence of local evaporation. Satellite precipitation products with high time resolution (for instance 1 h) could be helpful for testifying the accuracy of water sources, as it can clearly illustrate the route of cloud movement. In this study, we analyzed the composition of hydrogen and oxygen isotopes in different rainfall events in three stations from 2015 to 2018 along the transection of 38° N latitude from Taihang Mountains to the coastal region in North China, Taihang Mountain Station (mountainous area), Luancheng Station (pre-mountain plain) and Nanpi Station (coastal low plain). By selecting typical rainfall events, water vapor sources and its influence rainfall on hydrogen and oxygen isotopes were analyzed with hourly available CMORPH satellite precipitation products. Results showed that the hydrogen and oxygen isotopes of precipitation were cha-racterized by enrichment in the rainy season and depletion in the dry season. The hydrogen and oxygen isotopes in the rainy season showed a tendency of depletion with the increases of precipitation. The slope and intercept of the fitted relationship of hydrogen and oxygen isotopes in the piedmont region of the mountains were the lowest, indicating that precipitation in the piedmont plain was significantly affected by secondary evaporation fractionation. The effect of evaporation resulted in the largest variations of isotope ratio in the dry year. In the mountainous station, due to the heavy rainfall, large isotopic variation was found in rich precipitation year. Based on the route analysis of sate-llite precipitation products, dominant water vapor in the region was inland and northwest-oriented water vapor, while water vapor in the rainy season was from southwest and from the Pacific Ocean. There was a significant difference in the hydrogen and oxygen isotopes of precipitation in the mountainous and plain stations in 2016, owing to water vapor sources and effects of rainfall for the mountainous and evaporation for plain. The results from HYSPLIT model showed that during the rainstorm on 19th July in 2016, water vapor at the mountainous station was mainly from the southwest, while that in the coastal plain was a mixture of southwest and southeast sources. Overall, our results showed that spatial and temporal variations of hydrogen and oxygen isotopes were controlled by both water sources and evaporation processes along the transection of 38° north latitude in North China.

Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp3 papain-like protease.

The COVID-19 pandemic has emerged as the biggest life-threatening disease of this century. Whilst vaccination should provide a long-term solution, this is pitted against the constant threat of mutations in the virus rendering the current vaccines less effective. Consequently, small molecule antiviral agents would be extremely useful to complement the vaccination program. The causative agent of COVID-19 is a novel coronavirus, SARS-CoV-2, which encodes at least nine enzymatic activities that all have drug targeting potential. The papain-like protease (PLpro) contained in the nsp3 protein generates viral non-structural proteins from a polyprotein precursor, and cleaves ubiquitin and ISG protein conjugates. Here we describe the expression and purification of PLpro. We developed a protease assay that was used to screen a custom compound library from which we identified dihydrotanshinone I and Ro 08-2750 as compounds that inhibit PLpro in protease and isopeptidase assays and also inhibit viral replication in cell culture-based assays.

Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp5 main protease.

The coronavirus 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spread around the world with unprecedented health and socio-economic effects for the global population. While different vaccines are now being made available, very few antiviral drugs have been approved. The main viral protease (nsp5) of SARS-CoV-2 provides an excellent target for antivirals, due to its essential and conserved function in the viral replication cycle. We have expressed, purified and developed assays for nsp5 protease activity. We screened the nsp5 protease against a custom chemical library of over 5000 characterised pharmaceuticals. We identified calpain inhibitor I and three different peptidyl fluoromethylketones (FMK) as inhibitors of nsp5 activity in vitro, with IC50 values in the low micromolar range. By altering the sequence of our peptidomimetic FMK inhibitors to better mimic the substrate sequence of nsp5, we generated an inhibitor with a subnanomolar IC50. Calpain inhibitor I inhibited viral infection in monkey-derived Vero E6 cells, with an EC50 in the low micromolar range. The most potent and commercially available peptidyl-FMK compound inhibited viral growth in Vero E6 cells to some extent, while our custom peptidyl FMK inhibitor offered a marked antiviral improvement.

Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp14 RNA cap methyltransferase.

The COVID-19 pandemic has presented itself as one of the most critical public health challenges of the century, with SARS-CoV-2 being the third member of the Coronaviridae family to cause a fatal disease in humans. There is currently only one antiviral compound, remdesivir, that can be used for the treatment of COVID-19. To identify additional potential therapeutics, we investigated the enzymatic proteins encoded in the SARS-CoV-2 genome. In this study, we focussed on the viral RNA cap methyltransferases, which play key roles in enabling viral protein translation and facilitating viral escape from the immune system. We expressed and purified both the guanine-N7 methyltransferase nsp14, and the nsp16 2'-O-methyltransferase with its activating cofactor, nsp10. We performed an in vitro high-throughput screen for inhibitors of nsp14 using a custom compound library of over 5000 pharmaceutical compounds that have previously been characterised in either clinical or basic research. We identified four compounds as potential inhibitors of nsp14, all of which also showed antiviral capacity in a cell-based model of SARS-CoV-2 infection. Three of the four compounds also exhibited synergistic effects on viral replication with remdesivir.

Rictor Is a Novel Regulator of TRAF6/TRAF3 in Osteoclasts.

Tumor necrosis factor receptor-associated factors (TRAFs) are crucial for receptor activator of nuclear factor-κB (RANK) activation in osteoclasts. However, the upstream mechanisms of TRAF members in the osteoclastic lineage remain largely unknown. Here, we demonstrated that Rictor, a key component of mechanistic target of rapamycin complex 2 (mTORC2), was crucial for TRAF6/TRAF3 expression in osteoclasts. Our ex vivo and in vivo studies showed that Rictor ablation from the osteoclastic lineage reduced osteoclast numbers and increased bone mass in mice. Mechanistically, we found that Rictor ablation restricted osteoclast formation, which disrupted TRAF6 stability and caused autophagy block in a manner distinct from mTORC1, resulting in reduced TRAF3 degradation. Boosting TRAF6 expression or knockdown of TRAF3 levels in Rictor-deficient cells could both overcome the defect. Moreover, Rictor could interact with TRAF6 upon RANK ligand (RANKL) stimulation and loss of Rictor impaired TRAF6 stability and promoted its ubiquitinated degradation. These findings established an innovative link between Rictor, TRAF protein levels, and autophagic block. More importantly, mTOR complexes in the osteoclastic lineage are likely switches for coordinating TRAF6 and TRAF3 protein levels, and Rictor may function as an essential upstream regulator of TRAF6/TRAF3 that is partially independent of mTORC1 activity. Inhibitors targeting Rictor may therefore be valuable for preventing or treating osteoclast-related diseases. © 2021 American Society for Bone and Mineral Research (ASBMR).

Correlating the Performance of a Fire-Retardant Coating across Different Scales of Testing.

Material-scale tests involving milligrams of samples are used to optimize fire-retardant coating formulations, but actual applications of these coatings require them to be assessed with structural-scale fire tests. This significant difference in the scale of testing (milligrams to kilograms of sample) raises many questions on the relations between the inherent flammability and thermal characteristics of the coating materials and their "performance" at the structural scale. Moreover, the expected "performance" requirements and the definition of "performance" varies at different scales. In this regard, the pathway is not established when designing and formulating fire-retardant coatings for structural steel sections or members. This manuscript explores the fundamental relationships across different scales of testing with the help of a fire-protective system based on acrylic resin with a typical combination of intumescent additives, viz. ammonium polyphosphate, pentaerythritol, and expandable graphite. One of the main outcomes of this work dictates that higher heat release rate values and larger amounts of material participating in the pyrolysis process per unit time will result in a rapid rise in steel substrate temperature. This information is very useful in the design and development of generic fire-retardant coatings.

Survival outcomes following laparoscopic vs open surgery for non-metastatic rectal cancer: a two-center cohort study with propensity score matching.

BACKGROUND?>: Laparoscopic surgery for rectal cancer is commonly performed in China. However, compared with open surgery, the effectiveness of laparoscopic surgery, especially the long-term survival, has not been sufficiently proved. METHODS?>: Data of eligible patients with non-metastatic rectal cancer at Nanfang Hospital of Southern Medical University and Guangdong Provincial Hospital of Chinese Medicine between 2012 and 2014 were retrospectively reviewed. Long-term survival outcomes and short-term surgical safety were analysed with propensity score matching between groups. RESULTS: Of 430 cases collated from two institutes, 103 matched pairs were analysed after propensity score matching. The estimated blood loss during laparoscopic surgery was significantly less than that during open surgery (P = 0.019) and the operative time and hospital stay were shorter in the laparoscopic group (both P < 0.001). The post-operative complications rate was 9.7% in the laparoscopic group and 10.7% in the open group (P = 0.818). No significant difference was observed between the laparoscopic group and the open group in the 5-year overall survival rate (75.7% vs 80.6%, P = 0.346), 5-year relapse-free survival rate (74.8% vs 76.7%, P = 0.527), or 5-year cancer-specific survival rate (79.6% vs 87.4%, P = 0.219). An elevated carcinoembryonic antigen, <12 harvested lymph nodes, and perineural invasion were independent prognostic factors affecting overall survival and relapse-free survival. CONCLUSIONS?>: Our findings suggest that open surgery should still be the priority recommendation, but laparoscopic surgery is also an acceptable treatment for non-metastatic rectal cancer.

Single-nucleotide polymorphisms of HLA and Polygonum multiflorum-induced liver injury in the Han Chinese population.

BACKGROUND: Polygonum multiflorum is one of the leading causes of herb-induced liver injury in China. HLA-B*35:01 is reported to be a potential biomarker of Polygonum multiflorum-induced liver injury (PM-DILI). However, little is known about the relationship between single-nucleotide polymorphisms (SNPs) and PM-DILI. AIM: To identify SNPs that indicate susceptibility to PM-DILI. METHODS: We conducted a systematic study enrolling 382 participants from four independent hospitals, including 73 PM-DILI patients, 118 patients with other drug-induced liver injury (other-DILI) and 191 healthy controls. Whole-exome sequencing was performed for 8 PM-DILI patients and 8 healthy controls who were randomly selected from the above subjects. Nineteen SNPs that showed high frequencies in the 8 PM-DILI patients were selected as candidate SNPs and then screened in 65 PM-DILI patients, 118 other-DILI patients and 183 healthy controls using the MassARRAY system. HLA-B high-resolution genotyping was performed for the 73 PM-DILI and 118 other-DILI patients. The Han-MHC database was selected as a population control for HLA-B analysis. P < 6.25 × 10-3 after Bonferroni correction was considered significant. RESULTS: The frequencies of rs111686806 in the HLA-A gene, rs1055348 in the HLA-B gene, and rs202047044 in the HLA-DRB1 gene were significantly higher in the PM-DILI group than in the control group [27.2% vs 11.6%, P = 1.72 × 10-5, odds ratio (OR) = 3.96, 95% confidence interval (CI): 2.21-7.14; 42.5% vs 8.6%, P = 1.72 × 10-19, OR = 13.62, 95%CI: 7.16-25.9; 22.9% vs 8.1%, P = 4.64 × 10-6, OR = 4.1, 95%CI: 2.25-7.47]. Only rs1055348 showed a significantly higher frequency in the PM-DILI group than in the other-DILI group (42.5% vs 13.6%, P = 1.84 × 10-10, OR = 10.06, 95%CI: 5.06-20.0), which suggested that it is a specific risk factor for PM-DILI. rs1055348 may become a tag for HLA-B*35:01 with 100% sensitivity and 97.7% specificity in the PM-DILI group and 100% sensitivity and 98.1% specificity in the other-DILI group. Furthermore, HLA-B*35:01 was confirmed to be associated with PM-DILI with a frequency of 41.1% in the PM-DILI group compared with 11.9% (P = 4.30 × 10-11, OR = 11.11, 95%CI: 5.57-22.19) in the other-DILI group and 2.7% (P = 6.22 × 10-166, OR = 62.62, 95%CI: 35.91-109.20) in the Han-MHC database. CONCLUSION: rs111686806, rs1055348, and rs202047044 are associated with PM-DILI, of which, rs1055348 is specific to PM-DILI. As a tag for HLA-B*35:01, rs1055348 may become an alternative predictive biomarker of PM-DILI.

Evaluation and improvement the safety of total marrow irradiation with helical tomotherapy using repeat failure mode and effects analysis.

BACKGROUND & PURPOSE: Helical tomotherapy has been applied to total marrow irradiation (HT-TMI). Our objective was to apply failure mode and effects analysis (FMEA) two times separated by 1 year to evaluate and improve the safety of HT-TMI. MATERIALS AND METHODS: A multidisciplinary team was created. FMEA consists of 4 main steps: (1) Creation of a process map; (2) Identification of all potential failure mode (FM) in the process; (3) Evaluation of the occurrence (O), detectability (D) and severity of impact (S) of each FM according to a scoring criteria (1-10), with the subsequent calculation of the risk priority number (RPN=O*D*S) and (4) Identification of the feasible and effective quality control (QC) methods for the highest risks. A second FMEA was performed for the high-risk FMs based on the same risk analysis team in 1 year later. RESULTS: A total of 39 subprocesses and 122 FMs were derived. First time RPN ranged from 3 to 264.3. Twenty-five FMs were defined as being high-risk, with the top 5 FMs (first RPN/ second RPN): (1) treatment couch movement failure (264.3/102.8); (2) section plan dose junction error in delivery (236.7/110.4); (3) setup check by megavoltage computed tomography (MVCT) failure (216.8/94.6); (4) patient immobilization error (212.5/90.2) and (5) treatment interruption (204.8/134.2). A total of 20 staff members participated in the study. The second RPN value of the top 5 high-risk FMs were all decreased. CONCLUSION: QC interventions were implemented based on the FMEA results. HT-TMI specific treatment couch tests; the arms immobilization methods and strategy of section plan dose junction in delivery were proved to be effective in the improvement of the safety.

The migration direction of hair cell nuclei is closely related to the perinuclear actin filaments in Arabidopsis.

Nuclear migration in Arabidopsis root hairs is bidirectional and relies on actin filaments. However, how actin filaments regulate the bidirectional movement of nuclei remains unclear. Here, we discovered that nuclei migrate forward and backward according to the developmental stage of the hair cells. In addition, the migration direction of nuclei was not constant but reversed occasionally, accompanied by nuclear shape changes. Confocal microscopic analysis revealed that perinuclear actin bundles were closely related to the migration and shape of hair cell nuclei. Pharmacological studies showed that SMIFH2, an inhibitor of the actin nucleator-formin, inhibited nuclear backward migration probably by impairing the perinuclear actin filaments. These data indicate that nuclear migration in hair cells is likely motivated by the competition of mechanical forces acting on the nucleus. Furthermore, the perinuclear actin filaments are closely related to the migration direction of hair cell nuclei.