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The simulation data presented in this paper describes the formation and growth of an elongated bubble induced by a long-pulsed laser. The simulation is performed using the M2C solver, which is a recently developed three-dimensional finite volume Navier-Stokes CFD solver. The solver is used to simulate the fluid dynamics of the liquid water, the laser radiation, the laser-induced vaporization, and the fluid dynamics of the bubble after its formation. The data presented in this paper corresponds to a representative case of the cavitation induced by a narrow Gaussian beam (cf. [1]). Simulation data include laser radiance, fluid velocity, pressure, temperature, and bubble dynamics. The input files and the workflow to perform this simulation are also provided. With the information provided in this paper, researchers can repeat this simulation, and use it as a starting point to study related problems involving laser-induced cavitation, continuous vaporization, and bubble dynamics in general.

Introduction: The aim of this study was to find the most appropriate variables to input into machine learning algorithms to identify those patients with primary lung malignancy with high risk for metastasis to the bone. Patient Inclusion: Patients with either histological or radiological diagnoses of lung cancer were included in this study. Results: The patient cohort comprised 1864 patients diagnosed from 2016 to 2021. A total of 25 variables were considered as potential risk factors. These variables have been identified in previous studies as independent risk factors for bone metastasis. Treatment methods for lung cancer were taken into account during model development. The outcome variable was binary, (presence or absence of bone metastasis) with follow‐up until death or 12‐month survival, whichever is the sooner. Results showed that American Joint Committee on Cancer staging, the use of EGFR inhibitor, age, T‐staging, and lymphovascular invasion were the five input features contributing the most to the model algorithm. High AJCC staging (OR 1.98; p < 0.05), the use of EGFR inhibitor (OR 6.14; p < 0.05), high T‐staging (OR 1.47; p < 0.05), and the presence of lymphovascular invasion (OR 4.92; p < 0.05) increase predicted risk of bone metastasis. Conversely, older age reduces predicted bone metastasis risk (OR 0.98; p < 0.05). Conclusion: The machine learning model developed in this study can be easily incorporated into the hospital's Clinical Management System so that input variables can be immediately utilized to give an accurate prediction of bone metastatic risk, therefore informing clinicians on the best treatment strategy for that individual patient. [ABSTRACT FROM AUTHOR]

Metastasis frequently targets bones, where cancer cells from the primary tumour migrate to the bone marrow, initiating new tumour growth. Not only is bone the most common site for metastasis, but it also often marks the first site of metastatic recurrence. Despite causing over 90% of cancer-related deaths, effective treatments for bone metastasis are lacking, with current approaches mainly focusing on palliative care. Circulating tumour cells (CTCs) are pivotal in metastasis, originating from primary tumours and circulating in the bloodstream. They facilitate metastasis through molecular interactions with the bone marrow environment, involving direct cell-to-cell contacts and signalling molecules. CTCs infiltrate the bone marrow, transforming into disseminated tumour cells (DTCs). While some DTCs remain dormant, others become activated, leading to metastatic growth. The presence of DTCs in the bone marrow strongly correlates with future bone and visceral metastases. Research on CTCs in peripheral blood has shed light on their release mechanisms, yet investigations into bone marrow DTCs have been limited. Challenges include the invasiveness of bone marrow aspiration and the rarity of DTCs, complicating their isolation. However, advancements in single-cell analysis have facilitated insights into these elusive cells. This review will summarize recent advancements in understanding bone marrow DTCs using single-cell analysis techniques. [ABSTRACT FROM AUTHOR]

ABSTRACT sRNAs are noncoding transcripts that play critical roles in posttranscriptional regulation in prokaryotes. In the intracellular bacterium Chlamydia, sRNAs have been identified, but functional studies have been limited to an E. coli heterologous system. We have developed an inducible sRNA overexpression system in Chlamydia trachomatis and used it to screen putative sRNAs for effects on the Chlamydia developmental cycle, which involves conversion between replicating (RB) and infectious (EB) chlamydial forms. Overexpression of 4 of 13 C. trachomatis sRNAs decreased production of infectious EBs. We performed detailed characterization of CtrR3 and CtrR7, the two sRNAs that caused the largest progeny defects in our screen. By quantifying chlamydial number and infectious progeny, and by visualizing chlamydial forms using electron microscopy, we showed that overexpression of CtrR3 prevented RB-to-EB conversion, whereas CtrR7 overexpression blocked bacterial replication. We also describe a workflow that allowed us to identify the mRNA targets of CtrR3 in Chlamydia. We first used MS2 aptamer affinity purification coupled with RNA sequencing as an unbiased approach to isolate interacting mRNAs. We then prioritized candidates based on sequence complementarity to the CtrR3 target recognition sequence, which we had identified with bioinformatic and mutational analyses. Finally, we tested putative targets with translational fusion assays in E. coli and C. trachomatis. Using this integrated approach, we provide experimental evidence that YtgB and CTL0389 are mRNA targets of CtrR3 in Chlamydia. These findings demonstrate how our C. trachomatis sRNA overexpression system can be used to investigate the functions and mRNA targets of chlamydial sRNAs. IMPORTANCE Small RNAs (sRNAs) are a class of regulatory RNAs that play important roles in bacterial physiology and pathogenesis. In the intracellular bacterium Chlamydia, however, sRNAs are poorly understood, and functional studies have been limited to a heterologous system. In this study, we developed a genetic system for studying sRNAs in Chlamydia trachomatis and used it to identify four chlamydial sRNAs whose overexpression decreased the production of infectious bacteria. We also successfully utilized this genetic system to determine the target recognition sequence and mRNA targets of an uncharacterized, chlamydial sRNA named CtrR3. Overall, this work offers a generalizable approach for investigating the role of chlamydial sRNAs in their native organism.

The simulation data presented in this paper describes the interaction between a thin-walled aluminum cylinder and a gas bubble in a near-field underwater explosion. The simulation is performed using the AERO-F/S solvers. The finite element AERO-S solver is used to simulate the structural dynamics of the cylinder, including its yielding and collapse. The AERO-F solver is used to simulate the fluid dynamics of the explosion bubble, the surrounding liquid water, and the air inside the cylinder. The two solvers are coupled using an embedded boundary method and the FInite Volume method with Exact two-material Riemann problems (FIVER). The data presented in this paper corresponds to a representative case with initial pressure p0=12.5MPa inside the bubble (cf. [1]). Simulation data include structural stress and deformation, fluid velocity, pressure and bubble dynamics. The input files and the workflow to perform this simulation are also provided. With the information provided in this paper, researchers can repeat this simulation, and use it as a starting point to study related problems involving cavitation bubbles, underwater explosion, and fluid-structure interaction in general.

Recently, the development and application of lane line departure warning systems have been in the market. For any of the systems, the key part of lane line tracking, lane line identification, or lane line departure warning is whether it can accurately and quickly detect lane lines. Since 1990s, they have been studied and implemented for the situations defined by the good viewing conditions and the clear lane markings on road. After then, the accuracy for particular situations, the robustness for a wide range of scenarios, time efficiency and integration into higher-order tasks define visual lane line detection and tracking as a continuing research subject. At present, these kinds of lane marking line detection methods based on machine vision and image processing can be divided into two categories: the traditional image processing and semantic segmentation (includes deep learning) methods. The former mainly involves feature-based and model-based steps, and which can be classified into similarity- and discontinuity-based ones; and the model-based step includes different parametric straight line, curve or pattern models. The semantic segmentation includes different machine learning, neural network and deep learning methods, which is the new trend for the research and application of lane line departure warning systems. This paper describes and analyzes the lane line departure warning systems, image processing algorithms and semantic segmentation methods for lane line detection.

Abstract Folate receptor (FR)-targeted small molecule drug conjugates (SMDCs) have shown promising results in early stage clinical trials with microtubule destabilizing agents, such as vintafolide and EC1456. In our effort to develop FR-targeted SMDCs with varying mechanisms of action, we synthesized EC2629, a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety. This agent was found to be extremely potent with an in vitro IC50 ~ 100× lower than folate SMDCs constructed with various microtubule inhibitors. EC2629 treatment of nude mice bearing FR-positive KB human xenografts led to cures in 100% of the test animals with very low dose levels (300 nmol/kg) following a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing). Complete responses were also observed against FR-positive paclitaxel (KB-PR) and cisplatin (KB-CR) resistant models. When evaluated against FR-positive patient derived xenograft (PDX) models of ovarian (ST070), endometrial (ST040) and triple negative breast cancers (ST502, ST738), EC2629 showed significantly greater anti-tumor activity compared to their corresponding standard of care treatments. Taken together, these studies thus demonstrated that EC2629, with its distinct DNA reacting mechanism, may be useful in treating FR-positive tumors, including those that are classified as drug resistant.

Repetitive subconcussive head impact exposure has been associated with clinical and MRI changes in some non-concussed contact sport athletes over the course of a season. However, analysis of human tolerance for repeated head impacts is complicated by concussion and head impact exposure history, genetics, and other personal factors. Therefore, the objective of the current study was to develop a rodent model for repetitive subconcussive head impact exposure that can be used to understand injury mechanisms and tolerance in the human. This study incorporated the Medical College of Wisconsin Rotational Injury Model to expose rats to multiple low-level head accelerations per day over a 4-week period. The peak magnitude of head accelerations were scaled from our prior human studies of contact sport athletes and the number of exposures per day were based on the median (moderate exposure) and 95th percentile (high exposure) number of exposures per day across the human sample. Following the exposure protocol, rats were assessed for cognitive deficits, emotional changes, blood serum levels of axonal injury biomarkers, and histopathological evidence of injury. High exposure rats demonstrated cognitive deficits and evidence of anxiety-like behaviors relative to shams. Moderate exposure rats did not demonstrate either of those behaviors. Similarly, high exposure rats had histopathological evidence of gliosis [i.e., elevated Iba1 intensity and glial fibrillary acidic protein (GFAP) volume relative to shams] in the basolateral amygdala and other areas. Blood serum levels of neurofilament light (NFL) demonstrated a dose response relationship with increasing numbers of low-level head acceleration exposures with a higher week-to-week rate of NFL increase for the high exposure group compared to the moderate exposure group. These findings demonstrate a cumulative effect of repeated low-level head accelerations and provide a model that can be used in future studies to better understand mechanisms and tolerance for brain injury resulting from repeated low-level head accelerations, with scalable biomechanics between the rat and human.

Purpose: To describe a case of bilateral infectious scleritis secondary to Histoplasma capsulatum in the setting of a locally and systemically immunosuppressed patient. Observations: A 45-year-old man with HLA-B27 associated ankylosing spondylitis and anterior uveitis on systemic secokinumab, underwent bilateral cataract extraction which required extensive peri-operative steroids, including intravitreal triamcinolone, topical prednisolone, and oral prednisone. Six weeks after cataract surgery, the patient presented with mild eye irritation and was found to have bilateral subconjunctival purulence and necrosis. Histoplasma capsulatum was identified on fungal cultures and confirmed by DNA probe. The patient was treated with fortified amphotericin drops and oral itraconazole with complete resolution of scleritis. Conclusion and importance: H. capsulatum is a rare cause of infectious scleritis that must be considered in our immunosuppressed and post-surgical patients.

The extraction of pavement cracks is always a hard task in image processing. In airport and road construction, cracking is the main factor for pavement damage, which can decrease the quality of pavement and affect transportation seriously. Cracks also exist in other artificial or natural objects, such as buildings, bridges, tunnels, etc. Among all the object images, pavement crack images are the most complex, so the image processing and analysis for them is harder than other crack images. From the early image acquisition based on photography technology to the current 3D laser scanning technology, the pavement crack image acquisition technology is becoming more convenient and efficient, but there are still challenges in the automatic processing and recognition of cracks in images. From the early global thresholding to deep learning algorithms, the research for crack extraction has been developed for about 40 years. There are many methods and algorithms that are satisfactory in pavement crack applications, but there is no standard until today. Therefore, in order to know the developing history and the advanced research, we have collected a number of literature in this research topic for summarizing the research artwork status, and giving a review of the pavement crack image acquisition methods and 2D crack extraction algorithms. Also, for image acquisition methods and pavement crack image segmentation, more detailed comparison and discussions are made. Keywords: Highway engineering, Pavement crack, Image acquisition, Image processing, Crack extraction

Mitochondrial complex I can produce large quantities of reactive oxygen species (ROS) by reverse electron transfer (RET) from the ubiquinone (UQ) pool. Glutathionylation of complex I does induce increased mitochondrial superoxide/hydrogen peroxide (O2●−/H2O2) production, but the source of this ROS has not been identified. Here, we interrogated the glutathionylation of complex I subunit NDUFS1 and examined if its modification can result in increased ROS production during RET from the UQ pool. We also assessed glycerol-3-phosphate dehydrogenase (GPD) and proline dehydrogenase (PRODH) glutathionylation since both flavoproteins have measurable rates for ROS production as well. Induction of glutathionylation with disulfiram induced a significant increase in O2●−/H2O2 production during glycerol-3-phosphate (G3P) and proline (Pro) oxidation. Treatment of mitochondria with inhibitors for complex I (rotenone and S1QEL), complex III (myxothiazol and S3QEL), glycerol-3-phosphate dehydrogenase (iGP), and proline dehydrogenase (TFA) confirmed that the sites for this increase were complexes I and III, respectively. Treatment of liver mitochondria with disulfiram (50–1000 nM) did not induce GPD or PRODH glutathionylation, nor did it affect their activities, even though disulfiram dose-dependently increased the total number of protein glutathione mixed disulfides (PSSG). Immunocapture of complex I showed disulfiram incubations resulted in the modification of NDUFS1 subunit in complex I. Glutathionylation could be reversed by reducing agents, restoring the deglutathionylated state of NDUFS1 and the activity of the complex. Reduction of glutathionyl moieties in complex I also significantly decreased ROS production by RET from GPD and PRODH. Overall, these findings demonstrate that the modification of NDUFS1 can result in increased ROS production during RET from the UQ pool, which has implications for understanding the relationship between mitochondrial glutathionylation reactions and induction of oxidative distress in several pathologies

Mitochondria critically regulate a range of cellular processes including bioenergetics, cellular metabolism, apoptosis, and cellular Ca2+ signaling. The voltage-dependent anion channel (VDAC) functions as a passageway for the exchange of ions, including Ca2+, across the outer mitochondrial membrane. In cardiomyocytes, genetic or pharmacological activation of isoform 2 of VDAC (VDAC2) effectively potentiates mitochondrial Ca2+ uptake and suppresses Ca2+ overload-induced arrhythmogenic events. However, molecular mechanisms by which VDAC2 controls mitochondrial Ca2+ transport and thereby influences cardiac rhythmicity remain elusive. Vertebrates express three highly homologous VDAC isoforms. Here, we used the zebrafish tremblor/ncx1h mutant to dissect the isoform-specific roles of VDAC proteins in Ca2+ handling. We found that overexpression of VDAC1 or VDAC2, but not VDAC3, suppresses the fibrillation-like phenotype in zebrafish tremblor/ncx1h mutants. A chimeric approach showed that moieties in the N-terminal half of VDAC are responsible for their divergent functions in cardiac biology. Phylogenetic analysis further revealed that a glutamate at position 73, which was previously described to be an important regulator of VDAC function, is sevolutionarily conserved in VDAC1 and VDAC2, whereas a glutamine occupies position 73 (Q73) of VDAC3. To investigate whether E73/Q73 determines VDAC isoform-specific anti-arrhythmic effect, we mutated E73 to Q in VDAC2 (VDAC2E73Q) and Q73 to E in VDAC3 (VDAC3Q73E). Interestingly, VDAC2E73Q failed to restore rhythmic cardiac contractions in ncx1 deficient hearts, while the Q73E conversion induced a gain of function in VDAC3. In HL-1 cardiomyocytes, VDAC2 knockdown diminished the transfer of Ca2+ from the SR into mitochondria and overexpression of VDAC2 or VDAC3Q73E restored SR-mitochondrial Ca2+ transfer in VDAC2 deficient HL-1 cells, whereas this rescue effect was absent for VDAC3 and drastically compromised for VDAC2E73Q. Collectively, our findings demonstrate a critical role for the evolutionary conserved E73 in determining the anti-arrhythmic effect of VDAC isoforms through modulating Ca2+ cross-talk between the SR and mitochondria in cardiomyocytes.

Asthma is the most common non-communicable pulmonary condition, affecting prepubertal boys more often than girls. This study explored how maternal and perinatal risk factors are linked to poorly controlled childhood asthma in a sex dependent manner. This single centre study was performed at a metropolitan teaching hospital in Western Sydney, Australia, using electronical obstetric records from 2000 to 2017 and electronical pediatric records from 2007 to 2018. The data of 1694 children with complete entries were retrospectively analysed. Risk factors for multiple hospital admission for asthma were selected by backward-eliminated Poisson regression modelling. Selection stability of these parameters was independently confirmed using approximated exhaustive search. Sex-specific regression models indicated that most notably parity (RR[95%CI] for parity = 3; 1.85[1.22-2.81]), birth length z-score (1.45[1.23-1.70]) and birth weight z-score (0.77[0.65-0.90]) contributed to multiple asthma admissions in girls, while boys were affected most prominently by maternal BMI (e.g. BMI 35-39.9; 1.92[1.38-2.67]) and threatened preterm labor (1.68[1.10-2.58]). Allergic status was a risk factors for both boys and girls (1.47[1.18-1.83] and 1.46[1.13-1.89]). Applying ROC analysis, the predictive modelling of risk factors for hospital admissions showed an incremental increase with an AUC of 0.84 and 0.75 for girls and boys respectively for >3 hospital admissions. Multiple hospital admissions for asthma are associated with maternal and perinatal risk factors in a sex and birth order dependent manner. Hence, prospective risk stratification studies aiming to improve childhood asthma control are warranted to test the clinical utility of these parameters. Furthermore, the influence of the early in utero environment on male-female differences in other communicable and non-communicable respiratory conditions should be considered.

Operation brain trauma therapy (OBTT) is a drug- and biomarker-screening consortium intended to improve the quality of preclinical studies and provide a rigorous framework to increase the translational potential of experimental traumatic brain injury (TBI) treatments. Levetiracetam (LEV) is an antiepileptic agent that was the fifth drug tested by OBTT in three independent rodent models of moderate to severe TBI. To date, LEV has been the most promising drug tested by OBTT and was therefore advanced to testing in the pig. Adult male micro pigs were subjected to a mild central fluid percussion brain injury followed by a post-injury intravenous infusion of either 170 mg/kg LEV or vehicle. Systemic physiology was assessed throughout the post-injury period. Serial serum samples were obtained pre-injury as well as at 1 min, 30 min, 1 h, 3 h, and 6 h post-injury for a detailed analysis of the astroglial biomarker glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1. Tissue was collected 6 h following injury for histological assessment of diffuse axonal injury using antibodies against the amyloid precursor protein (APP). The animals showed significant increases in circulating GFAP levels from baseline to 6 h post-injury; however, LEV treatment was associated with greater GFAP increases compared to the vehicle. There were no differences in the numbers of APP+ axonal swellings within the pig thalamus with LEV treatment; however, significant alterations in the morphological properties of the APP+ axonal swellings, including reduced swelling area and increased swelling roundness, were observed. Additionally, expression of the neurite outgrowth marker, growth-associated protein 43, was reduced in axonal swellings following LEV treatment, suggesting potential effects on axonal outgrowth that warrant further investigation.

Objective. Dysphagia after pneumonectomy is uncommon but concerning. The purpose of this paper is to present a case of dysphonia secondary to postpneumonectomy syndrome. Case Report. A 66-year-old female with stage IIIa adenocarcinoma of the lung was treated with a left pneumonectomy. Three years later, she presented with severe dysphagia, dyspnea, and dysphonia. Esophagram demonstrated severely deviated esophagus to the left of midline, attributed to prior left-sided pneumonectomy, without clear evidence of any external compression. Chest CT scan showed associated leftward mediastinal shift. This patient was treated with voice therapy and an exclusion diet, as the patient elected not to have surgery. Conclusion. This is the first reported case of dysphonia accompanying severe dysphagia following left pneumonectomy. While postpneumonectomy syndrome is rare, a high degree of clinical suspicion is recommended when treating patients with history of pneumonectomy.

Background. An estimated 25% of primary and secondary syphilis, a sexually transmitted infection caused by the spirochete bacterium Treponema pallidum, occurs in patients coinfected with human immunodeficiency virus (HIV) (Chesson et al., 2005). This association is especially evident in men who have sex with men (MSM). In HIV-positive patients, primary syphilis infection may progress more rapidly to the tertiary, and most destructive, stage and reinfection can start with the latent or tertiary stage; in such patients, advanced syphilis may arise without clinical warning signs (Kenyan et al., 2018). It is important to note that neurosyphilis can occur during any stage of infection in all patients, regardless of immunocompetence status (CDC, 2021). Case Presentation. A 56-year-old male with a past medical history of well-controlled HIV with a CD4 count of 700 cells/mm3 and an undetectable viral load, psoriasis, and a remote episode of treated syphilis, presented with a two-week history of a diffuse desquamating rash, alopecia, sinusitis, unilateral conjunctivitis, and blurred vision. His last sexual encounter was over ten months ago. The diagnosis of syphilis was confirmed by microhemagglutination assay, and he was treated for presumed neuro-ocular infection with a two-week course of intravenous Penicillin G. Conclusion. Syphilis has acquired a reputation as “the great masquerader” due to its protean manifestations. It may follow an unpredictable course, especially in HIV-positive patients, including those whose treatment has achieved undetectable serology. For example, ocular syphilis may present in an otherwise asymptomatic individual (Rein, 2020) and alopecia may arise as the sole indication of acute syphilitic infection (Doche et al., 2017). Therefore, a high index of suspicion is warranted in order to prevent severe and irreversible complications.

Background: Lesbian, gay, bisexual, transgender, and queer (LGBTQ) individuals face considerable health disparities, often due to a lack of LGBTQ-competent care. Such disparities and lack of access to informed care are even more staggering in rural settings. As the state medical school for the Washington, Wyoming, Alaska, Montana, and Idaho (WWAMI) region, the University of Washington School of Medicine (UWSOM) is in a unique position to train future physicians to provide healthcare that meets the needs of LGBTQ patients both regionally and nationally. Objective: To describe our methodology of developing a student-driven longitudinal, region-wide curriculum to train medical students to provide high-quality care to LGBTQ patients. Methods: A 4-year LGBTQ Health Pathway was developed and implemented as a student-led initiative at the UWSOM. First- and second-year medical students at sites across the WWAMI region are eligible to apply. Accepted Pathway students complete a diverse set of pre-clinical and clinical components: online modules, didactic courses, longitudinal community service/advocacy work, a scholarly project, and a novel clinical clerkship in LGBTQ health developed specifically for this Pathway experience. Students who complete all requirements receive a certification of Pathway completion. This is incorporated into the Medical Student Performance Evaluation as part of residency applications. Results: The LGBTQ Health Pathway is currently in its fourth year. A total of 43 total students have enrolled, of whom 37.3% are based in the WWAMI region outside of Seattle. Pathway students have completed a variety of scholarly projects on LGBTQ topics, and over 1000 hours of community service/advocacy. The first cohort of 8 students graduated with a certificate of Pathway completion in spring 2020. Conclusions: The LGBTQ Health Pathway at UWSOM is a novel education program for motivated medical students across the 5-state WWAMI region. The diverse milestones, longitudinal nature of the program, focus on rural communities, and opportunities for student leadership are all strengths and unique aspects of this program. The Pathway curriculum and methodology described here serve as a model for student involvement and leadership in medical education. This program enables medical students to enhance their training in the care of LGBTQ patients and provides a unique educational opportunity for future physicians who strive to better serve LGBTQ populations.

Background Human Papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC) is one of the fastest growing cancers in the Western world. When compared to OPSCCs induced by smoking or alcohol, patients with HPV+ OPSCC, have better survival and the mechanisms remain unclear.Methods The Cancer Genome Atlas (TCGA) database was examined for genes associated with tissue-resident CD8+ T cells. Multiplex immunohistochemistry (IHC) staining was performed on tumor specimen taken from 35 HPV+ and 27 HPV- OPSCC patients.Results TCGA database revealed that the expression of genes encoding CD103 and CD69 were significantly higher in HPV+ head and neck SCCs (HNSCC) than in HPV- HNSCC. Higher expression levels of these two genes were also associated with better overall survival. IHC staining showed that the proportion of CD103+ tumor-resident CD8+ T cells were significantly higher in HPV+ OPSCCs when compared to HPV- OPSCC. This higher level was also associated with both lower risk of loco-regional failure, and better overall survival. Importantly, patients with HPV- OPSCC who had comparable levels of CD103+ tumor-resident CD8+ T cells to those with HPV+ OPSCC demonstrated similar survival as those with HPV+OPSCC.Conclusion Our results show that CD103+ tumor-resident CD8+ T cells are critical for protective immunity in both types of OPSCCs. Our data further suggest that the enhanced local protective immunity provided by tumor-resident T cell responses is the underlying factor driving favorable clinical outcomes in HPV+ OPSCCs over HPV- OPSCCs.

Traumatic brain injury (TBI) is a heterogeneous disease in its origin, neuropathology, and prognosis, with no FDA-approved treatments. The pathology of TBI is complicated and not sufficiently understood, which is the reason why more than 30 clinical trials in the past three decades turned out unsuccessful in phase III. The multifaceted pathophysiology of TBI involves a cascade of metabolic and molecular events including inflammation, oxidative stress, excitotoxicity, and mitochondrial dysfunction. In this study, an open head TBI mouse model, induced by controlled cortical impact (CCI), was used to investigate the chronic protective effects of mitoquinone (MitoQ) administration 30 days post-injury. Neurological functions were assessed with the Garcia neuroscore, pole climbing, grip strength, and adhesive removal tests, whereas cognitive and behavioral functions were assessed using the object recognition, Morris water maze, and forced swim tests. As for molecular effects, immunofluorescence staining was conducted to investigate microgliosis, astrocytosis, neuronal cell count, and axonal integrity. The results show that MitoQ enhanced neurological and cognitive functions 30 days post-injury. MitoQ also decreased the activation of astrocytes and microglia, which was accompanied by improved axonal integrity and neuronal cell count in the cortex. Therefore, we conclude that MitoQ has neuroprotective effects in a moderate open head CCI mouse model by decreasing oxidative stress, neuroinflammation, and axonal injury.

Since procedural justice was proposed, this vein of research has gained much popularity in scholarship, empirical supports, and theoretical advancement. Yet, research on the procedural fairness within police organizations, particularly on the underlying and mediating mechanisms between internal and external procedural justice, remains understudied. Relying on survey data collected from Taiwanese police officers, this study expands the current literature by testing the direct relationships between supervisor, organizational, and social supports and external procedural justice and their indirect connections through supervisor trustworthiness and self-legitimacy. Supervisor and social supports were found to directly boost officers' commitment to external procedural justice. Perceived organizational support promotes external procedural justice through cultivating officer self-legitimacy. This study concludes by discussing cross-border research and pragmatic implications for police training and management. [ABSTRACT FROM AUTHOR]

Summary: Given its role as the source of definitive hematopoietic cells, we sought to determine whether mutations initiated in the hemogenic endothelium would yield hematopoietic abnormalities or malignancies. Here, we find that endothelium-specific transposon mutagenesis in mice promotes hematopoietic pathologies that are both myeloid and lymphoid in nature. Frequently mutated genes included previously recognized cancer drivers and additional candidates, such as Pi4ka, a lipid kinase whose mutation was found to promote myeloid and erythroid dysfunction. Subsequent validation experiments showed that targeted inactivation of the Pi4ka catalytic domain or reduction in mRNA expression inhibited myeloid and erythroid cell differentiation in vitro and promoted anemia in vivo through a mechanism involving deregulation of AKT, MAPK, SRC, and JAK-STAT signaling. Finally, we provide evidence linking PI4KAP2, previously considered a pseudogene, to human myeloid and erythroid leukemia. : Using transposon mutagenesis that targets the endothelium, Ziyad et al. identify Pi4ka as an important regulator of hematopoiesis. Loss of Pi4ka inhibits myeloid and erythroid cell differentiation. Previously considered a pseudogene in humans, PI4KAP2 is shown to be protein-coding and a negative regulator of PI4KA signaling. Keywords: erythropoiesis, myelopoiesis, hematopoiesis, leukemia, hemogenic endothelium, lipid kinase, Pi4ka, PI4KAP2, Akt, Erk

Our data suggest that, after a myocardial infarction, integrin-associated protein CD47 on cardiac myocytes is elevated. In culture, increased CD47 on the surface of dying cardiomyocytes impairs phagocytic removal by immune cell macrophages. After myocardial ischemia and reperfusion, acute CD47 inhibition with blocking antibodies enhanced dead myocyte clearance by cardiac phagocytes and also improved the resolution of cardiac inflammation, reduced infarct size, and preserved cardiac contractile function. Early targeting of CD47 in the myocardium after reperfusion may be a new strategy to enhance wound repair in the ischemic heart.

Abstract Efficient thermal management at the nanoscale is important for reducing energy consumption and dissipation in electronic devices, lab-on-a-chip platforms and energy harvest/conversion systems. For many of these applications, it is much desired to have a solid-state structure that reversibly switches thermal conduction with high ON/OFF ratios and at high speed. Here we describe design and implementation of a novel, all-solid-state thermal switching device by nanostructured phase transformation, i.e., modulation of contact pressure and area between two poly-silicon surfaces activated by microstructural change of a vanadium dioxide (VO2) thin film. Our solid-state devices demonstrate large and reversible alteration of cross-plane thermal conductance as a function of temperature, achieving a conductance ratio of at least 2.5. Our new approach using nanostructured phase transformation provides new opportunities for applications that require advanced temperature and heat regulations.

Abstract The development of molecular genetics has greatly enhanced the study of the biology and pathology associated with parasites of the phylum Apicomplexa. We have established a system specifically designed for Neospora caninum, and used this system as a heterologous platform for the expression of foreign genes. Plasmid constructs containing fluorescent proteins or targeted genes of Toxoplasma gondii, driven by N. caninum promoters, have yielded robust expression and correct trafficking of target gene products as assessed by immunofluorescence assays and Western blot analyses. Using this approach, we here demonstrated that N. caninum expressing T. gondii’s GRA15 and ROP16 kinase are biologically active and induced immunological phenotypes consistent with T. gondii strains. N. caninum expressing TgGRA15 differentially disturbed the NF-κB pathway, inducing an increased IL-12 production. On the other hand, N. caninum expressing TgROP16 induced host STAT3 phosphorylation and consequent reduction of IL-12 synthesis. These results indicate that heterologous gene expression in N. caninum is a useful tool for the study of specific gene functions and may allow the identification of antigenic targets responsible for the phenotypic differences observed between these two closely related apicomplexan parasites. Additionally, these observations may prove to be useful for the development of vaccine protocols to control toxoplasmosis and/or neosporosis.

Abstract Studies in vivo and in vitro have suggested that the mechanism underlying Alzheimer’s disease (AD) neuropathogenesis is initiated by an interaction between the cellular prion protein (PrPC) and amyloid-β oligomers (Aβo). This PrPC-Aβo complex activates Fyn kinase which, in turn, hyperphosphorylates tau (P-Tau) resulting in synaptic dysfunction, neuronal loss and cognitive deficits. AD transgenic mice lacking PrPC accumulate Aβ, but show normal survival and no loss of spatial learning and memory suggesting that PrPC functions downstream of Aβo production but upstream of intracellular toxicity within neurons. Since AD and traumatic brain injury (TBI)-linked chronic traumatic encephalopathy are tauopathies, we examined whether similar mechanistic pathways are responsible for both AD and TBI pathophysiologies. Using transgenic mice expressing different levels of PrPC, our studies investigated the influence and necessity of PrPC on biomarker (total-tau [T-Tau], P-Tau, GFAP) levels in brain and blood as measured biochemically following severe TBI in the form of severe closed head injury (sCHI). We found that following sCHI, increasing levels of T-Tau and P-Tau in the brain were associated with the PrPC expression levels. A similar relationship between PrPC expression and P-Tau levels following sCHI were found in blood in the absence of significant T-Tau changes. This effect was not seen with GFAP which increased within 24 h following sCHI and progressively decreased by the 7 day time point regardless of the PrPC expression levels. Changes in the levels of all biomarkers were independent of gender. We further enhanced and expanded the quantitation of brain biomarkers with correlative studies using immunohisochemistry. We also demonstrate that a TBI-induced calpain hyperactivation is not required for the generation of P-Tau. A relationship was demonstrated between the presence/absence of PrPC, the levels of P-Tau and cognitive dysfunction. Our studies suggest that PrPC is important in mediating TBI related pathology.

Abstract Background Congenital hydrocephalus (CH) is a highly morbid disease that features enlarged brain ventricles and impaired cerebrospinal fluid homeostasis. Although early linkage or targeted sequencing studies in large multigenerational families have localized several genes for CH, the etiology of most CH cases remains unclear. Recent advances in whole exome sequencing (WES) have identified five new bona fide CH genes, implicating impaired regulation of neural stem cell fate in CH pathogenesis. Nonetheless, in the majority of CH cases, the pathological etiology remains unknown, suggesting more genes await discovery. Methods WES of family members of a sporadic and familial form of severe L1CAM mutation‐negative CH associated with aqueductal stenosis was performed. Rare genetic variants were analyzed, prioritized, and validated. De novo copy number variants (CNVs) were identified using the XHMM algorithm and validated using qPCR. Xenopus oocyte experiments were performed to access mutation impact on protein function and expression. Results A novel inherited protein‐damaging mutation (p.Pro605Leu) in SLC12A6, encoding the K+‐Cl− cotransporter KCC3, was identified in both affected members of multiplex kindred CHYD110. p.Pro605 is conserved in KCC3 orthologs and among all human KCC paralogs. The p.Pro605Leu mutation maps to the ion‐transporting domain, and significantly reduces KCC3‐dependent K+ transport. A novel de novo CNV (deletion) was identified in SLC12A7, encoding the KCC3 paralog and binding partner KCC4, in another family (CHYD130) with sporadic CH. Conclusion These findings identify two novel, related genes associated with CH, and implicate genetically encoded impairments in ion transport for the first time in CH pathogenesis.