TEM1/endosialin/CD248 promotes pathologic scarring and TGF-ß activity through its receptor stability in dermal fibroblasts.

BACKGROUND: Pathologic scars, including keloids and hypertrophic scars, represent a common form of exaggerated cutaneous scarring that is difficult to prevent or treat effectively. Additionally, the pathobiology of pathologic scars remains poorly understood. We aim at investigating the impact of TEM1 (also known as endosialin or CD248), which is a glycosylated type I transmembrane protein, on development of pathologic scars. METHODS: To investigate the expression of TEM1, we utilized immunofluorescence staining, Western blotting, and single-cell RNA-sequencing (scRNA-seq) techniques. We conducted in vitro cell culture experiments and an in vivo stretch-induced scar mouse model to study the involvement of TEM1 in TGF-ß-mediated responses in pathologic scars. RESULTS: The levels of the protein TEM1 are elevated in both hypertrophic scars and keloids in comparison to normal skin. A re-analysis of scRNA-seq datasets reveals that a major profibrotic subpopulation of keloid and hypertrophic scar fibroblasts greatly expresses TEM1, with expression increasing during fibroblast activation. TEM1 promotes activation, proliferation, and ECM production in human dermal fibroblasts by enhancing TGF-ß1 signaling through binding with and stabilizing TGF-ß receptors. Global deletion of Tem1 markedly reduces the amount of ECM synthesis and inflammation in a scar in a mouse model of stretch-induced pathologic scarring. The intralesional administration of ontuxizumab, a humanized IgG monoclonal antibody targeting TEM1, significantly decreased both the size and collagen density of keloids. CONCLUSIONS: Our data indicate that TEM1 plays a role in pathologic scarring, with its synergistic effect on the TGF-ß signaling contributing to dermal fibroblast activation. Targeting TEM1 may represent a novel therapeutic approach in reducing the morbidity of pathologic scars.

Dominant dystrophic epidermolysis bullosa is associated with glycolytically active GATA3+ T helper 2 cells which may contribute to pruritus in lesional skin.

BACKGROUND: Dominant dystrophic epidermolysis bullosa (DDEB) is characterized by trauma-induced blisters and, in some individuals, intense pruritus. Precisely what causes itch in DDEB and optimal ways to reduce it have not been fully determined. OBJECTIVES: To characterize DDEB skin transcriptomes to identify therapeutic targets to reduce pruritus in patients. METHODS: Using bulk RNA sequencing, we evaluated affected and unaffected skin biopsy samples from six patients with DDEB (all with the very itchy pruriginosa subtype) and four healthy individuals. Single-cell transcriptomes of affected (n = 2) and unaffected (n = 1) DDEB skin and healthy skin (n = 2) were obtained. Dupilumab treatment was provided for three patients. RESULTS: The skin bulk transcriptome showed significant enrichment of T helper (Th)1/2 and Th17 pathways in affected DDEB skin compared with nonlesional DDEB skin and healthy skin. Single-cell transcriptomics showed an association of glycolytically active GATA3+ Th2 cells in affected DDEB skin. Treatment with dupilumab in three people with DDEB led to significantly reduced visual analogue scale (VAS) itch scores after 12 weeks (mean VAS 3.83) compared with pretreatment (mean VAS 7.83). Bulk RNAseq and quantitative polymerase chain reaction showed that healthy skin and dupilumab-treated epidermolysis bullosa (EB) pruriginosa skin have similar transcriptomic profiles and reduced Th1/Th2 and Th17 pathway enrichment. CONCLUSIONS: Single-cell RNAseq helps define an enhanced DDEB-associated Th2 profile and rationalizes drug repurposing of anti-Th2 drugs in treating DDEB pruritus.

Dominant dystrophic epidermolysis bullosa (DDEB) is a rare inherited skin disease that causes fragile skin that blisters easily, often triggered by minor injuries. These blisters are accompanied by intense itching, which can be distressing. The underlying cause of DDEB lies in genetic mutations in a gene called COL7A1. This gene encodes 'type VII collagen', a protein crucial for attaching the outer skin layer (epidermis) to the layer beneath (dermis). Although the genetic basis of DDEB is understood, the causes of itch are not known. As well as this, effective treatments for DDEB are lacking, which has driven scientists to explore innovative approaches like repurposing existing drugs. Drug repurposing involves using medications that have already been approved for other health conditions. One such drug is dupilumab, which is used for severe atopic dermatitis (eczema). Dupilumab targets immune cells called Th2 cells, which play a role in inflammation and allergies. While dupilumab has shown promise in relieving DDEB itching, the way it works in this condition is unclear. This study, carried out by a group of researchers in Taiwan, looked at gene expression in DDEB-affected and unaffected skin, and compared it to gene expression in healthy skin samples. We found heightened activity in Th2 immune cells and abnormal gene signals related to itching, similar to atopic dermatitis. These findings support using dupilumab and other anti-inflammatory drugs to alleviate itching in DDEB. Clinical trials will be crucial to evaluate the effectiveness of these drugs for managing DDEB symptoms. This research opens doors for enhanced treatment options and improving the quality of life of people living with DDEB.

Tofacitinib ameliorates skin inflammation in a patient with severe autosomal recessive congenital ichthyosis.

Autosomal recessive congenital ichthyosis (ARCI) is a genetically heterogeneous disorder with aberrant skin scaling and increased transepidermal water loss (TEWL). Current treatments for ARCI are limited and suboptimal. We present the case of a 27-year-old man with ARCI resulting from a homozygous missense variant in TGM1. RNA-sequencing of lesional skin revealed aberrant Janus kinase-signal transducer and activator of transcription signalling, providing a rationale for innovative treatment with a Janus kinase inhibitor. We prescribed oral tofacitinib (11 mg daily) for 26 weeks. Rapid improvements in erythema and fissuring occurred within the first month. Sustained reductions in 5-D itch scale and Dermatology Life Quality Index scores were also observed. TEWL decreased for the first 10 weeks but increased thereafter. Tofacitinib downregulated inflammatory genes and pathways, while enhancing skin barrier markers. Moreover, transglutaminase 1 distribution was normalized although enzymatic activity remained deficient. This study suggests that oral tofacitinib may be a useful therapy to consider for patients with ARCI.

Targeting CK1δ and CK1ε as a New Therapeutic Approach for Clear Cell Renal Cell Carcinoma.

INTRODUCTION: Kidney cancer ranks as the ninth most common cancer in men and the fourteenth in women globally, with renal cell carcinoma (RCC) being the most prevalent type. Despite advances in therapeutic strategies targeting angiogenesis and immune checkpoints, the absence of reliable markers for patient selection and limited duration of disease control underline the need for innovative approaches. CK1δ and CK1ε are highly conserved serine/threonine kinases involved in cell cycle regulation, apoptosis, and circadian rhythm. While CK1δ dysregulation is reportedly associated with breast and bladder cancer progression, their role in RCC remains elusive. This study aimed to investigate the feasibility of CK1δ/ε as new therapeutic targets for RCC patients. METHODS: The relationship between CK1δ/ε and RCC progression was evaluated by the analysis of microarray dataset and TCGA database. The anticancer activity of CK1δ/ε inhibitor was examined by MTT/SRB assay, and apoptotic cell death was analyzed by flow cytometry and Western blotting. RESULTS: Our data demonstrate that the gene expression of CSNK1D and CSNK1E is significantly higher in clear cell RCC (ccRCC) tissues compared to normal kidney samples, which is correlated with lower survival rates in ccRCC patients. SR3029, a selective inhibitor targeting CK1δ/ε, significantly suppresses the viability and proliferation of ccRCC cell lines regardless of the status of VHL deficiency. Importantly, the inhibitor promotes the population of subG1 cells and induces apoptosis, and ectopically expression of CK1δ partially rescued SR3029-induced apoptosis in ccRCC cells. CONCLUSION: These findings underscore the crucial role of CK1δ and CK1ε in ccRCC progression, suggesting CK1δ/ε inhibitors as new therapeutic options for ccRCC patients.

Development of automated metabolite control using mid-infrared probe for bioprocesses and vaccine manufacturing.

Automation of metabolite control in fermenters is fundamental to develop vaccine manufacturing processes more quickly and robustly. We created an end-to-end process analytical technology and quality by design-focused process by replacing manual control of metabolites during the development of fed-batch bioprocesses with a system that is highly adaptable and automation-enabled. Mid-infrared spectroscopy with an attenuated total reflectance probe in-line, and simple linear regression using the Beer-Lambert Law, were developed to quantitate key metabolites (glucose and glutamate) from spectral data that measured complex media during fermentation. This data was digitally connected to a process information management system, to enable continuous control of feed pumps with proportional-integral-derivative controllers that maintained nutrient levels throughout fed-batch stirred-tank fermenter processes. Continuous metabolite data from mid-infrared spectra of cultures in stirred-tank reactors enabled feedback loops and control of the feed pumps in pharmaceutical development laboratories. This improved process control of nutrient levels by 20-fold and the drug substance yield by an order of magnitude. Furthermore, the method is adaptable to other systems and enables soft sensing, such as the consumption rate of metabolites. The ability to develop quantitative metabolite templates quickly and simply for changing bioprocesses was instrumental for project acceleration and heightened process control and automation. ONE-SENTENCE SUMMARY: Intelligent digital control systems using continuous in-line metabolite data enabled end-to-end automation of fed-batch processes in stirred-tank reactors.

Impact of Perception Errors in Vision-Based Detection and Tracking Pipelines on Pedestrian Trajectory Prediction in Autonomous Driving Systems.

Pedestrian trajectory prediction is crucial for developing collision avoidance algorithms in autonomous driving systems, aiming to predict the future movement of the detected pedestrians based on their past trajectories. The traditional methods for pedestrian trajectory prediction involve a sequence of tasks, including detection and tracking to gather the historical movement of the observed pedestrians. Consequently, the accuracy of trajectory prediction heavily relies on the accuracy of the detection and tracking models, making it susceptible to their performance. The prior research in trajectory prediction has mainly assessed the model performance using public datasets, which often overlook the errors originating from detection and tracking models. This oversight fails to capture the real-world scenario of inevitable detection and tracking inaccuracies. In this study, we investigate the cumulative effect of errors within integrated detection, tracking, and trajectory prediction pipelines. Through empirical analysis, we examine the errors introduced at each stage of the pipeline and assess their collective impact on the trajectory prediction accuracy. We evaluate these models across various custom datasets collected in Taiwan to provide a comprehensive assessment. Our analysis of the results derived from these integrated pipelines illuminates the significant influence of detection and tracking errors on downstream tasks, such as trajectory prediction and distance estimation.

An Edge Computing System with AMD Xilinx FPGA AI Customer Platform for Advanced Driver Assistance System.

The convergence of edge computing systems with Field-Programmable Gate Array (FPGA) technology has shown considerable promise in enhancing real-time applications across various domains. This paper presents an innovative edge computing system design specifically tailored for pavement defect detection within the Advanced Driver-Assistance Systems (ADASs) domain. The system seamlessly integrates the AMD Xilinx AI platform into a customized circuit configuration, capitalizing on its capabilities. Utilizing cameras as input sensors to capture road scenes, the system employs a Deep Learning Processing Unit (DPU) to execute the YOLOv3 model, enabling the identification of three distinct types of pavement defects with high accuracy and efficiency. Following defect detection, the system efficiently transmits detailed information about the type and location of detected defects via the Controller Area Network (CAN) interface. This integration of FPGA-based edge computing not only enhances the speed and accuracy of defect detection, but also facilitates real-time communication between the vehicle's onboard controller and external systems. Moreover, the successful integration of the proposed system transforms ADAS into a sophisticated edge computing device, empowering the vehicle's onboard controller to make informed decisions in real time. These decisions are aimed at enhancing the overall driving experience by improving safety and performance metrics. The synergy between edge computing and FPGA technology not only advances ADAS capabilities, but also paves the way for future innovations in automotive safety and assistance systems.

Change in Nutrition and Physical Activity Practices in Early Childcare and Education Settings in Illinois During the COVID-19 Pandemic.

CONTEXT: For many young children, early childcare and education (ECE) programs are the only source of nutritious meals and physical activity (PA); however, the COVID-19 pandemic led to program closures, restrictions, and changed practices. OBJECTIVE: To examine changes in nutrition and PA-related best practices in ECE settings in Illinois from 2019, just prior to the pandemic, as compared to 2022. We also examined how changes over time varied by program type (ie, centers vs homes), Child and Adult Care Food Program (CACFP) status, and/or Head Start/Early Head Start status. DESIGN: The study design is a repeated cross-sectional survey administered in December 2019 and October 2022. SETTING: State of Illinois. PARTICIPANTS: A total of 888 and 1162 ECE providers completed initial and follow-up surveys, respectively. INTERVENTION: NA. MAIN OUTCOME MEASURE: Provider report of meeting 14 nutrition and 9 PA-related best practices. RESULTS: Overall, 9 nutrition-related best practices were maintained and 5 declined over time. Centers, CACFP, and Head Start providers reported significant declines in meeting nutrition-related practices over time. A total of 8 PA-related best practices were maintained and 1 declined over time. Centers reported a significant decline in 5 of the PA-related best practices over time, and these declines were significantly different than in homes over time. Similarly, Head Start programs reported a decline in 4 PA-related best practices over time, and the change was significantly different from non-Head Start programs in 3 of the 4 practices. CONCLUSION: The findings of this study should be considered a new baseline for ECE nutrition and PA-related best practices in Illinois and should serve as a wake-up call for advocates nationwide with regard to the provision of nutrition and PA-related best practices in centers and by CACFP and Head Start providers postpandemic.

Cucurbitacin E Exerts Anti-Proliferative Activity via Promoting p62-Dependent Apoptosis in Human Non-Small-Cell Lung Cancer A549 Cells.

EGFR tyrosine kinase inhibitors (TKIs) are the first-line treatment for advanced EGFR-mutated non-small-cell lung cancer (NSCLC). However, NSCLC patients with wild-type EGFR and KRAS mutation are ineligible for EGFR-TKIs. Therefore, the discovery of new therapeutic agents is urgently needed for NSCLC patients who cannot receive targeted therapies. Natural products possess tremendous chemical diversity and have been extensively investigated for their anticancer activity. In this study, we found that Cucurbitacin E (Cu E), a triterpene of cucurbitacins widely presented in the edible plants of the Cucurbitaceae family, significantly inhibits the viability and proliferation of A549 cells that harbor wild-type EGFR and KRAS mutation. Our results revealed that Cu E increases cell-cycle arrest at G2/M and subG1 phase. Mechanistically, Cu E significantly inhibits the phosphorylation and protein levels of regulatory proteins and hinders G2/M cell-cycle progression. Meanwhile, the treatment of Cu E resulted in DNA damage response and apoptosis. For the first time, we observed that Cu E induces incomplete autophagy as evidenced by increased LC3B-II expression and p62-accumulation. Knockdown of p62 rescued the cells from Cu E-mediated anti-proliferative effect, apoptosis, DNA damage, and ROS production. These findings suggest that Cu E is a promising drug candidate for NSCLC.

Derivation and External Validation of Machine Learning-Based Model for Detection of Pancreatic Cancer.

INTRODUCTION: There is currently no widely accepted approach to screening for pancreatic cancer (PC). We aimed to develop and validate a risk prediction model for pancreatic ductal adenocarcinoma (PDAC), the most common form of PC, across 2 health systems using electronic health records. METHODS: This retrospective cohort study consisted of patients aged 50-84 years having at least 1 clinic-based visit over a 10-year study period at Kaiser Permanente Southern California (model training, internal validation) and the Veterans Affairs (VA, external testing). Random survival forests models were built to identify the most relevant predictors from >500 variables and to predict risk of PDAC within 18 months of cohort entry. RESULTS: The Kaiser Permanente Southern California cohort consisted of 1.8 million patients (mean age 61.6) with 1,792 PDAC cases. The 18-month incidence rate of PDAC was 0.77 (95% confidence interval 0.73-0.80)/1,000 person-years. The final main model contained age, abdominal pain, weight change, HbA1c, and alanine transaminase change (c-index: mean = 0.77, SD = 0.02; calibration test: P value 0.4, SD 0.3). The final early detection model comprised the same features as those selected by the main model except for abdominal pain (c-index: 0.77 and SD 0.4; calibration test: P value 0.3 and SD 0.3). The VA testing cohort consisted of 2.7 million patients (mean age 66.1) with an 18-month incidence rate of 1.27 (1.23-1.30)/1,000 person-years. The recalibrated main and early detection models based on VA testing data sets achieved a mean c-index of 0.71 (SD 0.002) and 0.68 (SD 0.003), respectively. DISCUSSION: Using widely available parameters in electronic health records, we developed and externally validated parsimonious machine learning-based models for detection of PC. These models may be suitable for real-time clinical application.

Transcriptomic responses of peripheral blood mononuclear cells to cyclosporin and etanercept in a female infant with juvenile generalized pustular psoriasis.

Generalized pustular psoriasis (GPP) is a rare but severe form of psoriasis. An early onset of the diseases is correlated with mutations among IL36RN, CARD14, AP1S3, MPO and SERPINA3 genes. Systemic biological agents including anti-TNF-α, anti-IL-17, anti-IL-12/IL-23, anti-IL1R, anti-IL1ß and anti-IL-36R act as novel treatment methods for GPP. Herein we report a female infant clinically diagnosed with GPP since she was 10-month-old. Results of whole-exome sequencing (WES) and Sanger sequencing revealed a reported heterozygous IL36RN (c.115+6T>C) and another reported heterozygous SERPINA3 frame-shifting variant (c.1247_1248del). Initial cyclosporin treatment for the patient led to a partial remission of the symptoms. However, the patient reached nearly total remission of pustules and erythema after anti-TNF-α inhibitor etanercept treatment. Results of further RNA sequencing (RNA-seq) done on peripheral blood mononuclear cells correlated with the clinical responses, showing that cyclosporin suppressed a portion of the neutrophil-related genes, while most genes associated with neutrophil activation, neutrophil-mediated immunity and degranulation were downregulated by the subsequent etanercept treatment. We report this case to demonstrate WES and RNA-seq in combination could come in handy in reaching a precise diagnosis and in evaluating or even predicting the molecular alterations underlying clinical treatment effectiveness.

Machine learning versus regression for prediction of sporadic pancreatic cancer.

BACKGROUND/OBJECTIVES: There is currently no widely accepted approach to identify patients at increased risk for sporadic pancreatic cancer (PC). We aimed to compare the performance of two machine-learning models with a regression-based model in predicting pancreatic ductal adenocarcinoma (PDAC), the most common form of PC. METHODS: This retrospective cohort study consisted of patients 50-84 years of age enrolled in either Kaiser Permanente Southern California (KPSC, model training, internal validation) or the Veterans Affairs (VA, external testing) between 2008 and 2017. The performance of random survival forests (RSF) and eXtreme gradient boosting (XGB) models were compared to that of COX proportional hazards regression (COX). Heterogeneity of the three models were assessed. RESULTS: The KPSC and the VA cohorts consisted of 1.8 and 2.7 million patients with 1792 and 4582 incident PDAC cases within 18 months, respectively. Predictors selected into all three models included age, abdominal pain, weight change, and glycated hemoglobin (A1c). Additionally, RSF selected change in alanine transaminase (ALT), whereas the XGB and COX selected the rate of change in ALT. The COX model appeared to have lower AUC (KPSC: 0.737, 95% CI 0.710-0.764; VA: 0.706, 0.699-0.714), compared to those of RSF (KPSC: 0.767, 0.744-0.791; VA: 0.731, 0.724-0.739) and XGB (KPSC: 0.779, 0.755-0.802; VA: 0.742, 0.735-0.750). Among patients with top 5% predicted risk from all three models (N = 29,663), 117 developed PDAC, of which RSF, XGB and COX captured 84 (9 unique), 87 (4 unique), 87 (19 unique) cases, respectively. CONCLUSIONS: The three models complement each other, but each has unique contributions.

Are the sensorimotor control capabilities of the hands the factors influencing hand function in people with schizophrenia?

BACKGROUND: Previous works reported people with schizophrenia experienced inferior hand functions which influence their daily participation and work efficiency. Sensorimotor capability is one of indispensable elements acting in a well-executed feed-forward and feedback control loop to contribute to hand performances. However, rare studies investigated contribution of sensorimotor ability to hand functions for people with schizophrenia. This study aimed to explore hand function in people with schizophrenia based on the perspective of the sensorimotor control capabilities of the hands. METHODS: Twenty-seven people at the chronic stage of schizophrenia were enrolled. The following assessment tools were used: the Purdue Pegboard Test (PPT) and the VALPAR Component Work Sample-8 (VCWS 8) system for hand function; the Self-Reported Graphic version of the Personal and Social Performance (SRG-PSP) scale for functionality; and the Semmes-Weinstein Monofilaments (SWM), the pinch-holding-up-activity (PHUA) test and the Manual Tactile Test (MTT) for the sensory and sensorimotor parameters. The Clinical Global Impression-Severity (CGI-S) scale and the Extrapyramidal Symptom Rating Scale (ESRS) were used to grade the severity of the illness and the side-effects of the drugs. Spearman's rank correlation coefficient was used to analyze associations among hand function, functionality, and sensorimotor capabilities. A multiple linear regression analysis was used to identify the determinants of hand function. RESULTS: The results indicated that both hand function and sensorimotor capability were worse in people with schizophrenia than in healthy people, with the exception of the sensory threshold measured with the SWM. Moreover, the sensorimotor abilities of the hands were associated with hand function. The results of the regression analysis showed that the MTT measure of stereognosis was a determinant of the PPT measure of the dominant hand function and of the performance on the VCWS 8, and that the ESRS and the MTT measure of barognosis were determinants of the performance on the assembly task of the PPT. CONCLUSIONS: The findings suggested that sensorimotor capabilities, especially stereognosis and barognosis, are crucial determinants of hand function in people with schizophrenia. The results also revealed that the side effects of drugs and the duration of the illness directly affect hand function. CLINICAL TRAIL REGISTRATION: ClinicalTrials.gov , identifier NCT04941677, 28/06/2021.

Internet of Things (IoT) Enables Robot-Assisted Therapy as a Home Program for Training Upper Limb Functions in Chronic Stroke: A Randomized Control Crossover Study.

OBJECTIVE: To compare the effects of using an Internet of things (IoT)-assisted tenodesis-induced-grip exoskeleton robot (TIGER) and task-specific motor training (TSMT) as home programs for the upper-limb (UL) functions of patients with chronic stroke to overturn conventional treatment modes for stroke rehabilitation. DESIGN: A randomized 2-period crossover study. SETTING: A university hospital. PARTICIPANTS: Eighteen chronic stroke patients were recruited and randomized to receive either the IoT-assisted TIGER first or TSMT first at the beginning of the experiment (N=18). INTERVENTION: In addition to the standard hospital-based therapy, participants were allocated to receive a 30-minute home-based, self-administered program of either IoT-assisted TIGER first or TSMT first twice daily for 4 weeks, with the order of both treatments reversed after a 12-week washout period. The exercise mode of the TIGER training included continuous passive motion and the functional mode of gripping pegs. The TSMT involved various movement components of the wrist and hand. MAIN OUTCOME MEASURES: The outcome measures included the box and block test (BBT), the Fugl-Meyer assessment for upper extremity (FMA-UE), the motor activity log, the Semmes-Weinstein Monofilament test, the range of motion (ROM) of the wrist joint, and the modified Ashworth scale. RESULTS: Significant treatment-by-time interaction effects emerged in the results for the BBT (F(1.31)=5.212 and P=.022), the FMA-UE (F(1.31)=6.807 and P=.042), and the ROM of the wrist extension (F(1.31)=8.618 and P=.009). The participants who trained at home with the IoT-assisted TIGER showed more improvement of their UL functions. CONCLUSIONS: The IoT-assisted TIGER training has the potential for restoring the UL functions of stroke patients.

A novel XPA splice-site mutation identified in a 4-year-old Filipino girl with xeroderma pigmentosum.

We herein report a case of a 4-year-old Filipino girl initially seen through online consultation from a general physician. She was born to a 22-year-old primigravid mother, with no birth complications nor a history of consanguinity in the family. During the 1st month of life, she developed hyperpigmented macules over the face, neck, upper back, and limbs, which were exacerbated by sun exposure. At 2 years old, she developed a solitary erythematous papule on the nasal area, which gradually enlarged within one year and developed into an exophytic ulcerating tumor extending to the right supra-alar crease. Xeroderma pigmentosum and squamous cell carcinoma were confirmed by whole-exome sequencing and skin biopsy, respectively.

Modular evolution of secretion systems and virulence plasmids in a bacterial species complex.

BACKGROUND: Many named species as defined in current bacterial taxonomy correspond to species complexes. Uncertainties regarding the organization of their genetic diversity challenge research efforts. We utilized the Agrobacterium tumefaciens species complex (a.k.a. Agrobacterium biovar 1), a taxon known for its phytopathogenicity and applications in transformation, as a study system and devised strategies for investigating genome diversity and evolution of species complexes. RESULTS: We utilized 35 genome assemblies, including 14 newly generated ones, to achieve a phylogenetically balanced sampling of A. tumefaciens. Our genomic analysis suggested that the 10 genomospecies described previously are distinct biological species and supported a quantitative guideline for species delineation. Furthermore, our inference of gene content and core-genome phylogeny allowed for investigations of genes critical in fitness and ecology. For the type VI secretion system (T6SS) involved in interbacterial competition and thought to be conserved, we detected multiple losses and one horizontal gene transfer. For the tumor-inducing plasmids (pTi) and pTi-encoded type IV secretion system (T4SS) that are essential for agrobacterial phytopathogenicity, we uncovered novel diversity and hypothesized their involvement in shaping this species complex. Intriguingly, for both T6SS and T4SS, genes encoding structural components are highly conserved, whereas extensive diversity exists for genes encoding effectors and other proteins. CONCLUSIONS: We demonstrate that the combination of a phylogeny-guided sampling scheme and an emphasis on high-quality assemblies provides a cost-effective approach for robust analysis in evolutionary genomics. We show that the T6SS VgrG proteins involved in specific effector binding and delivery can be classified into distinct types based on domain organization. The co-occurrence patterns of VgrG-associated domains and the neighboring genes that encode different chaperones/effectors can be used to infer possible interacting partners. Similarly, the associations between plant host preference and the pTi type among these strains can be used to infer phenotype-genotype correspondence. Our strategies for multi-level investigations at scales that range from whole genomes to intragenic domains and phylogenetic depths from between- to within-species are applicable to other bacteria. Furthermore, modularity observed in the molecular evolution of genes and domains is useful for inferring functional constraints and informing experimental works.

Incontinentia pigmenti in a male infant and a proposed diagnostic algorithm.

It is extremely rare for males with incontinentia pigmenti to survive. We summarize a diagnostic evaluation protocol for such individuals to provide an explanation for male survival.

Outcomes of active cervical therapeutic exercise on dynamic intervertebral foramen changes in neck pain patients with disc herniation.

BACKGROUND: To better understand biomechanical factors that affect intervertebral alignment throughout active therapeutic exercise, it is necessary to determine spinal kinematics when subjects perform spinal exercises. This study aims to investigate the outcomes of active cervical therapeutic exercise on intervertebral foramen changes in neck pain patients with disc herniation. METHODS: Thirty diagnosed C4/5 and/or C5/6 disc-herniated patients receiving an 8-week cervical therapeutic exercise program were followed up with videofluoroscopic images. The dynamic changes in the foramen were computed at different timepoints, including the neutral position, end-range positions in cervical flexion-extension, protrusion-retraction, and lateral flexion movements. RESULTS: The results showed that the active cervical flexion, retraction, and lateral flexion away from the affected side movements increased the area of the patients' intervertebral foramen; while the active extension, protrusion, and lateral flexion toward the affected side reduced the areas of intervertebral foramen before treatment. After the treatment, the active cervical flexion significantly increased the C2/3, C3/4, and C6/7 foramen area by 5.02-8.67% (p = 0.001 ~ 0.029), and the extension exercise significantly reduced the C2/3 and C4/5 area by 5.12-9.18% (p = 0.001 ~ 0.006) compared to the baseline. Active retraction movement significantly increased the foramen area from C2/3 to C6/7 by 3.82-8.66% (p = 0.002 ~ 0.036 with exception of C5/6). Active lateral flexion away from the affected side significantly increased the foramen by 3.71-6.78% (p = 0.007 ~ 0.046 with exception of C6/7). CONCLUSIONS: The 8-week therapeutic exercises including repeated cervical retraction, extension, and lateral flexion movements to the lesion led to significant changes and improvements in intervertebral foramen areas of the patients with disc herniation. TRIAL REGISTRATION: ISRCTN61539024.

Community-based screening by Anti-HCV reflex HCV Ag test and accessible post-screening care toward elimination of hepatitis C in two hyperendemic townships.

BACKGROUND: Hyperendemic townships of hepatitis C virus (HCV) infection should devote extra efforts to eliminate HCV. We aimed to evaluate efficacy of the screening and linkage to care in two HCV hyperendemic townships. METHODS: Village-to-village HCV screening using anti-HCV reflex HCV Ag test was conducted in two HCV hyperendemic rural townships (Lioujiao and Yijhu). All residents aged 30 years or older were invited. Those patients detected as infected were referred to nearby hospitals or clinics in Lioujiao and to an accessible outreach hepatology clinic in Yijhu. RESULTS: The populations of Lioujiao and Yijhu townships at time of survey were 18,389 and 14,787 with 6086 (33.1%) and 4604 (31.1%) having ever been previously screened, and 1517 and 1071 responded to this screening respectively. Their crude screening coverage rates were 41.5% and 38.5%, and adjusted screening coverage rates were 54.3% and 94.6% respectively. The prevalence rates of anti-HCV and HCV Ag were 17.9% and 11.9% in Lioujiao, and 9.2% and 5.6% in Yijhu respectively, with their rates of antigenemia (HCV Ag/anti-HCV) being 62.1% and 60.6% respectively. Numbers needed to test (NNT) to find a candidate for anti-viral treatment were 9 and 18. For linkage to care, treatment rate by referral (Lioujiao) was slightly lower than by accessible outreach hepatology clinic (Yijhu) (84.9% vs. 93.3%, p = 0.093). Overall successful sustained virological response rate at week 12 was 98.2% (161/164) in outreach hepatology clinic. CONCLUSION: Since NNT was low, it was worthwhile conducting intensive screening in these hyperendemic townships. For high treatment rate, accessible outreach hepatology clinic is feasible especially in areas without adequate medical resources.

Supervised Object-Specific Distance Estimation from Monocular Images for Autonomous Driving.

Accurate distance estimation is a requirement for advanced driver assistance systems (ADAS) to provide drivers with safety-related functions such as adaptive cruise control and collision avoidance. Radars and lidars can be used for providing distance information; however, they are either expensive or provide poor object information compared to image sensors. In this study, we propose a lightweight convolutional deep learning model that can extract object-specific distance information from monocular images. We explore a variety of training and five structural settings of the model and conduct various tests on the KITTI dataset for evaluating seven different road agents, namely, person, bicycle, car, motorcycle, bus, train, and truck. Additionally, in all experiments, a comparison with the Monodepth2 model is carried out. Experimental results show that the proposed model outperforms Monodepth2 by 15% in terms of the average weighted mean absolute error (MAE).