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Background: Sinonasal neoplasms, whether benign and malignant, pose a significant challenge to clinicians and represent a model area for multidisciplinary collaboration in order to optimize patient care. The International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors (ICSNT) aims to summarize the best available evidence and presents 48 thematic and histopathology‐based topics spanning the field. Methods: In accordance with prior International Consensus Statement on Allergy and Rhinology documents, ICSNT assigned each topic as an Evidence‐Based Review with Recommendations, Evidence‐Based Review, and Literature Review based on the level of evidence. An international group of multidisciplinary author teams were assembled for the topic reviews using the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses format, and completed sections underwent a thorough and iterative consensus‐building process. The final document underwent rigorous synthesis and review prior to publication. Results: The ICSNT document consists of four major sections: general principles, benign neoplasms and lesions, malignant neoplasms, and quality of life and surveillance. It covers 48 conceptual and/or histopathology‐based topics relevant to sinonasal neoplasms and masses. Topics with a high level of evidence provided specific recommendations, while other areas summarized the current state of evidence. A final section highlights research opportunities and future directions, contributing to advancing knowledge and community intervention. Conclusion: As an embodiment of the multidisciplinary and collaborative model of care in sinonasal neoplasms and masses, ICSNT was designed as a comprehensive, international, and multidisciplinary collaborative endeavor. Its primary objective is to summarize the existing evidence in the field of sinonasal neoplasms and masses. [ABSTRACT FROM AUTHOR]

The biological effects of densely-ionizing radiations such as neutrons and heavy ions encountered in space travel, nuclear incidents, and cancer radiotherapy, significantly differ from those of sparsely-ionizing photons and necessitate a comprehensive understanding for improved protection measures. Data on lifespan studies of laboratory rodents exposed to fission neutrons, accumulated in the Janus archive, afford unique insights into the impact of densely ionizing radiation on mortality from cancers and various organ dysfunction. We extracted and analyzed data for 21,308 individual B6CF1 mice to investigate the effects of neutron dose, fractionation, protraction, age, and sex on mortality. As Cox regression encountered limitations owing to assumption violations, we turned to Random Survival Forests (RSF), a machine learning algorithm adept at modeling nonlinear relationships. RSF interpretation using Shapley Additive Explanations revealed a dose response for mortality risk that curved upwards at low doses < 20 cGy, became nearly-linear over 20–150 cGy, and saturated at high doses. The response was enhanced by fractionation/protraction of irradiation (exhibiting an inverse dose rate effect), and diminished by older age at exposure. Somewhat reduced mortality was predicted for males vs females. This research expands our knowledge on the long-term effects of densely ionizing radiations on mammal mortality. [ABSTRACT FROM AUTHOR]

The development of physiologically relevant in vitro systems for simulating disease onset and progression and predicting drug metabolism holds tremendous value in reducing drug discovery time and cost. However, many of these platforms lack accuracy in replicating the tissue architecture and multicellular interactions. By leveraging three-dimensional cell culture, biomimetic soft hydrogels, and engineered stimuli, in vitro models have continued to progress. Nonetheless, the incorporation of the microvasculature has been met with many challenges, specifically with the addition of parenchymal cell types. Here, a systematic approach to investigating the initial seeding density of endothelial cells and its effects on interconnected networks was taken and combined with hepatic spheroids to form a liver-on-a-chip model. Leveraging this system, nicotine's effects on microvasculature and hepatic function were investigated. The findings indicated that nicotine led to interrupted adherens junctions, decreased guanosine triphosphate cyclohydrolase 1 expression, impaired angiogenesis, and lowered barrier function, all key factors in endothelial dysfunction. With the combination of the optimized microvascular networks, a vascularized liver-on-a-chip was formed, providing functional xenobiotic metabolism and synthesis of both albumin and urea. This system provides insight into potential hepatotoxicity caused by various drugs and allows for assessing vascular dysfunction in a high throughput manner. [ABSTRACT FROM AUTHOR]

Aims: Diabetic cardiomyopathy (DCM) is a major complication of diabetes and a risk factor for cardiovascular disease. Endothelial dysfunction is central to DCM, and endothelial-to-mesenchymal transition (EndMT) is a key form of endothelial dysfunction in diabetes. EndMT in DCM has been well-studied in model systems and has been found to be epigenetically regulated by non-coding RNAs (ncRNAs). However, EndMT in DCM and its associated epigenetic changes need further characterization in human patients. It is also not known if ncRNAs are affected by changes in DNA methylation in DCM. This study aims to confirm in human hearts, the findings from animal and cell studies, and potentially provide novel insight into interactions between DNA methylation and ncRNAs in EndMT in DCM. Methods and results: Heart tissues were collected from autopsy patients, fixed in formalin, and embedded in paraffin. Thin sections from paraffin-embedded tissues were used for histology and immunofluorescence analyses, where we confirmed that diabetic patients showed increased cardiac fibrosis that EndMT had occurred. Tissue curls from the paraffin-embedded tissues were used for RT-qPCR and methylation analyses. RT-qPCR quantitatively showed that EndMT occurs in the hearts of diabetics, and that EndMT in human hearts corresponded to changes in key ncRNAs. Methylation analysis showed that some of the EndMT-related ncRNAs were regulated by DNA promoter methylation, while others may be regulated through different epigenetic mechanisms. Conclusions: We show that EndMT is a relevant pathological process in human hearts during DCM, and that its occurrence coincides with changes in relevant ncRNAs. We further find that interplay between DNA methylation and certain ncRNAs involved in the regulation of EndMT may contribute to the observed changes in ncRNA expression. These findings reinforce the role of EndMT in patients afflicted with DCM and underscore the complexities and importance of the interactions between different facets of epigenetic regulation. [ABSTRACT FROM AUTHOR]

Background: Quality of life (QOL) for individuals with sinonasal malignancy (SNM) is significantly under‐studied, yet it is critical for counseling and may impact treatment. In this study we evaluated how patient, treatment, and disease factors impact sinonasal‐specific and generalized QOL using validated metrics in a large cohort over a 5‐year posttreatment time frame. Methods: Patients with SNM who underwent definitive treatment with curative intent were enrolled in a prospective, multisite, longitudinal observational study. QOL was assessed using the 22‐item Sino‐Nasal Outcome Test (SNOT‐22) and University of Washington Quality of Life Questionnaire (UWQOL) instruments at pretreatment baseline and multiple follow‐ups through 5 years posttreatment. Multivariable modeling was used to determine demographic, disease, and treatment factors associated with disease‐specific and generalized physical and social/emotional function QOL. Results: One hundred ninety‐four patients with SNM were analyzed. All QOL indices were impaired at pretreatment baseline and improved after treatment. SNOT‐22 scores improved 3 months and UWQOL scores improved 6 to 9 months posttreatment. Patients who underwent open compared with endoscopic tumor resection had worse generalized QOL (p < 0.001), adjusted for factors including T stage. Pterygopalatine fossa (PPF) involvement was associated with worse QOL (SNOT‐22, p < 0.001; UWQOL Physical dimension, p = 0.02). Adjuvant radiation was associated with worse disease‐specific QOL (p = 0.03). Neck dissection was associated with worse generalized physical function QOL (p = 0.01). Positive margins were associated with worse generalized social/emotional function QOL (p = 0.01). Conclusion: Disease‐specific and generalized QOL is impaired at baseline in patients with SNM and improves after treatment. Endoscopic resection is associated with better QOL. PPF involvement, adjuvant radiation, neck dissection, and positive margins were associated with worse QOL posttreatment. [ABSTRACT FROM AUTHOR]

The peptide domain extending from residues 49 to 57 of the HIV-1 Tat protein (TAT) has been widely shown to facilitate cell entry of and blood-brain barrier (BBB) permeability to covalently bound macromolecules; therefore, TAT-linked therapeutic peptides trafficked through peripheral routes have been used to treat brain diseases in preclinical and clinical studies. Although the mechanisms underlying cell entry by similar peptides have been established to be temperature-dependent and cell-type specific and to involve receptor-mediated endocytosis, how these peptides cross the BBB remains unclear. Here, using an in vitro model, we studied the permeability of TAT, which was covalently bound to the fluorescent probe fluorescein isothiocyanate (FITC), and evaluated whether it crossed the "in vitro BBB", a monolayer of brain endothelial cells, and whether the mechanisms were similar to those involved in TAT entry into cells. Our results show that although TAT crossed the monolayer of brain endothelial cells in a temperature-dependent manner, in contrast to the reported mechanism of cell entry, it did not require receptor-mediated endocytosis. Furthermore, we revisited the hypothesis that TAT facilitates brain delivery of covalently bound macromolecules by causing BBB disruption. Our results demonstrated that the dose of TAT commonly used in preclinical and clinical studies did not exert an effect on BBB permeability in vitro or in vivo; however, an extremely high TAT concentration caused BBB disruption in vitro. In conclusion, the BBB permeability to TAT is temperature-dependent, but at treatment-level concentrations, it does not involve receptor-mediated endocytosis or BBB disruption. [ABSTRACT FROM AUTHOR]

Complex regional pain syndrome is a chronic debilitating pain disorder that is difficult to manage, in part due to its heterogeneous clinical presentation and lack of clearly defined pathophysiology. Patients usually require a multidisciplinary approach to treatment, which can entail pharmacotherapy, physical therapy, behavioral therapy, and interventional pain procedures, such as sympathetic nerve blocks, spinal cord stimulation, and dorsal root ganglion stimulation. However, many patients continue to experience pain refractory to these multimodal strategies. Scrambler therapy (ST) is a noninvasive method of neuromodulation that is applied through cutaneous electrodes, and can alleviate chronic neuropathic pain by stimulating C-fibers and replacing endogenous pain signals with synthetic non-nociceptive signals. Although the use of ST has been reported for several types of refractory central and peripheral neuropathic pain, there is a paucity of data regarding the use of ST for complex regional pain syndrome. We present two patients with complex regional pain syndrome of the right lower extremity, who each underwent ST and experienced significant pain relief and improvement in function and quality of life. [ABSTRACT FROM AUTHOR]

The article discusses the use of transcutaneous electrical nerve stimulation (TENS) and scrambler therapy for relief of chronic and neuropathic pain as of July 2023. Topics covered include the physiology and mechanisms of electroanalgesia, the devices in a TENS unit and their use in patients, the heterogenous results with TENS, and the distinctive Scrambler therapy and its differences with TENS. Also noted is the suggested analgesic benefit of scrambler therapy on patients with chronic pain.

The discovery and development of antimicrobial therapies represents one of the most significant advancements in modern medicine. Although the primary therapeutic intent of antimicrobials is to eliminate their target pathogens, several antimicrobials have been shown to provide analgesia as a secondary benefit. Antimicrobials have demonstrated analgesic effects in conditions that involve dysbiosis or potential subclinical infection (e.g., chronic low back pain with Modic type 1 changes; chronic prostatitis/chronic pelvic pain; irritable bowel syndrome; inflammatory bowel disease; functional gastrointestinal disorders/dyspepsia; myalgic encephalomyelitis/chronic fatigue syndrome), and might even prevent the chronification of pain after acute infections that are associated with excessive systemic inflammation (e.g., post COVID-19 condition/long Covid, rheumatic fever). Clinical studies often assess the analgesic effects of antimicrobial therapies in an observational manner, without the ability to identify causative relationships, and significant gaps in the understanding remain regarding the analgesic potential of antimicrobials. Numerous interrelated patient-specific, antimicrobial-specific, and disease-specific factors altogether contribute to the perception and experience of pain, and each of these requires further study. Given worldwide concerns regarding antimicrobial resistance, antimicrobials must continue to be used judiciously and are unlikely to be repurposed as primary analgesic medications. However, when equipoise exists among several antimicrobial treatment options, the potential analgesic benefits of certain antimicrobial agents might be a valuable aspect to consider in clinical decision-making. This article (the second in a two-part series) aims to comprehensively review the evidence on the prevention and treatment of chronic pain using antimicrobial therapies and suggest a framework for future studies on this topic. [ABSTRACT FROM AUTHOR]

There is increasing evidence that the relationship between chronic pain and infections is complex and intertwined. Bacterial and viral infections can cause pain through numerous mechanisms such as direct tissue damage and inflammation, the induction of excessive immunologic activity, and the development of peripheral or central sensitization. Treating infections might relieve pain by attenuating these processes, but a growing body of literature suggests that some antimicrobial therapies confer analgesic effects, including for nociceptive and neuropathic pain symptoms, and affective components of pain. The analgesic mechanisms of antimicrobials are indirect, but might be conceptualized into two broad categories: 1) the reduction of the infectious burden and associated pro-inflammatory processes; and 2) the inhibition of signaling processes (e.g., enzymatic and cytokine activity) necessary for nociception and maladaptive neuroplastic changes via off-target effects (unintended binding sites). For the former, there is evidence that symptoms of chronic low back pain (when associated with Modic type 1 changes), irritable bowel syndrome, inflammatory bowel disease, chronic pelvic pain, and functional dyspepsia might be improved after antibiotic treatment, though significant questions remain regarding specific regimens and dose, and which subpopulations are most likely to benefit. For the latter, there is evidence that several antimicrobial classes and medications exert analgesic effects independent of their reduction of infectious burden, and these include cephalosporins, ribavirin, chloroquine derivatives, rapalogues, minocycline, dapsone, and piscidin-1. This article aims to comprehensively review the existing literature for antimicrobial agents that have demonstrated analgesic efficacy in preclinical or clinical studies. [ABSTRACT FROM AUTHOR]

Permeation of small molecules through membranes is a fundamental biological process, and molecular dynamics simulations have proven to be a promising tool for studying the permeability of membranes by providing a precise characterization of the free energy and diffusivity. In this study, permeation of ethanol through three different membranes of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylserine (POPS), PO-phosphatidylethanolamine (POPE), and PO-phosphatidylcholine (POPC) is studied. Permeabilities are calculated and compared with two different approaches based on Fick's first law and the inhomogeneous solubility-diffusion model. Microsecond simulation of double bilayers of these membranes provided a direct measurement of permeability by a flux-based counting method. These simulations show that a membrane of POPC has the highest permeability, followed by POPE and POPS. Due to the membrane-modulating properties of ethanol, the permeability increases as functions of concentration and saturation of the inner leaflet in a double bilayer setting, as opposed to the customary definition as a proportionality constant. This concentration dependence is confirmed by single bilayer simulations at different ethanol concentrations ranging from 1% to 18%, where permeability estimates are available from transition-based counting and the inhomogeneous solubility-diffusion model. We show that the free energy and diffusion profiles for ethanol lack accuracy at higher permeant concentrations due to non-Markovian kinetics caused by collective behavior. In contrast, the counting method provides unbiased estimates. Finally, the permeabilities obtained from single bilayer simulations are combined to represent natural gradients felt by a cellular membrane, which accurately models the non-equilibrium effects on ethanol permeability from single bilayer simulations in equilibrium. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) causes lifelong infection in over 90% of the world's population. EBV infection leads to several types of B cell and epithelial cancers due to the viral reprogramming of host-cell growth and gene expression. EBV is associated with 10% of stomach/gastric adenocarcinomas (EBVaGCs), which have distinct molecular, pathological, and immunological characteristics compared to EBV-negative gastric adenocarcinomas (EBVnGCs). Publicly available datasets, such as The Cancer Genome Atlas (TCGA), contain comprehensive transcriptomic, genomic, and epigenomic data for thousands of primary human cancer samples, including EBVaGCs. Additionally, single-cell RNA-sequencing data are becoming available for EBVaGCs. These resources provide a unique opportunity to explore the role of EBV in human carcinogenesis, as well as differences between EBVaGCs and their EBVnGC counterparts. We have constructed a suite of web-based tools called the EBV Gastric Cancer Resource (EBV-GCR), which utilizes TCGA and single-cell RNA-seq data and can be used for research related to EBVaGCs. These web-based tools allow investigators to gain in-depth biological and clinical insights by exploring the effects of EBV on cellular gene expression, associations with patient outcomes, immune landscape features, and differential gene methylation, featuring both whole-tissue and single-cell analyses. [ABSTRACT FROM AUTHOR]

Objective The objective was to qualitatively synthesize all reported cases of complications, adverse effects, side effects, or harms arising from the use of scrambler therapy (ST). Methods and Design A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The PubMed, Embase, Scopus, Web of Science, United States National Library of Medicine clinical trials registry, and Cochrane Central Register of Controlled Trials databases were searched from database inception to December 10, 2021. Case reports/series, abstracts, retrospective studies, and prospective studies (e.g. open-label trials, randomized controlled trials) pertaining to ST and any description of a complication, adverse effect, side effect, or harm were screened. The search protocol was developed a priori and registered via the International Prospective Register of Systematic Reviews (PROSPERO ID: CRD42021291838). Results A total of six RCTs, 19 prospective open-label trials, and 11 case series / case reports met the inclusion criteria, comprising 1,152 total patients. Two patients experienced contact dermatitis, and one patient reported minor ecchymosis that resolved without intervention. This yielded a composite complication rate of 0.26% (3/1,152). There were zero reported serious adverse events. Conclusions When used in accordance with the treatment protocols described by the United States Food and Drug Administration and device manual, ST is associated with a reported composite complication rate that is orders of magnitude lower than those of invasive neuromodulation devices. ST neuromodulation is a safe alternative for patients who cannot undergo invasive neuromodulation device implantation because of either risk or preference. [ABSTRACT FROM AUTHOR]

Managing the aging infrastructure of water distribution systems presents a challenge for many utilities. With various asset types competing for limited dollars, designing an effective asset management program is a resource allocation problem. Mobilization of equipment and crew is a significant cost (typically 2%–10%) within any capital improvement program. Therefore, selecting projects that target multiple asset classes together can reduce mobilization and help utilities stretch their budgets further. This research presents a process for modeling the joint renewal planning of multiple asset classes. The problem is framed as a dual‐objective optimization, where the selection of project areas aims to maximize lead service line removal and water meter changeout together. A case study from a Midwest utility is presented, and empirical data suggests the dual‐objective approach effectively reduces duplicate interventions in the same regions. Equity considerations are also examined, where constraints are added to enforce system‐wide project selection. Results show that the sensitivity of the objective toward equity is dependent on the underlying spatial distribution of the target asset itself, where uneven spread of the target asset leads to greater negative impact on model performance. [ABSTRACT FROM AUTHOR]

Pathogenic repeat sequences underlie several human disorders, including amyotrophic lateral sclerosis, Huntington's disease, and myotonic dystrophy. Here, we speak to several researchers about how repeat sequences have been implicated in affecting all aspects of the Central Dogma of molecular biology through their effects on DNA, RNA, and protein. [ABSTRACT FROM AUTHOR]

In Employment Division v. Smith, the Supreme Court famously held that the First Amendment Free Exercise Clause permits neutral laws of general applicability to incidentally burden religion without offering religious exemptions. Today, many people--including Justice Alito in his concurrence in Fulton v. City of Philadelphia--are calling for Smith to be replaced by a jurisprudence that applies strict scrutiny to neutral, generally applicable laws that place a substantial burden on religion. Yet, both before and after Smith, what exactly has constituted a "substantial burden" on religion has been far from clear. While some courts indicate that burdens on religion can only exist when the state threatens penal consequences or the withholding of benefits to coercively pressure religious adherents to forgo their faith, other courts indicate that burdens can also exist when the state-- without coercion or pressure--directly prevents or hinders persons from exercising their faith. While some courts have suggested that the substantiality of a burden on religion hinges on the weight of the penalties or losses that the state attaches to a claimant's exercise of religion, other courts have also measured substantiality by examining whether the religious exercise affected is central, obligatory, or mandated. Not only have existing conceptions of burden conflicted with one another, but some definitions of "substantial burden" also leave room for the state to effectively prevent religious activity without being subject to heightened scrutiny. Other definitions have failed to clarify when burdens cross the threshold of substantiality. Some definitions prompt courts to engage in ill-equipped decision-making that risks violating the Establishment Clause. And still other definitions run afoul of the Free Exercise Clause itself. In the wake of these problems, this Comment proposes a definition of "substantial burden" by starting from the operative verb of the Free Exercise Clause--to prohibit. This Comment argues that the state imposes a substantial burden on religion when it creates a de jure or de facto ban on any form of religious exercise--i.e., when the state legally forbids or effectively prevents the exercise of one's religion. Whenever neutral, generally applicable laws create such a burden, they should be subject to strict scrutiny. The definitional framework proposed by this Comment can exist alongside the existing doctrine that laws (including facially neutral ones) that discriminate against religion, and thus fall outside of Smith, should be subject to strict scrutiny. As this Comment argues, defining substantial burdens (in the context of neutral laws of general applicability) to include de jure and de facto bans on any religious exercise not only better comports with the text of the Free Exercise Clause itself, but also mitigates many of the problems raised by definitions of "substantial burden" used by courts in the past few decades. While this Comment's de jure and de facto framework does not purport to solve all of these problems, it provides a structured way for judges and legislators alike to think more rigorously about constitutionally faithful standards that might replace Smith should it be overturned. [ABSTRACT FROM AUTHOR]

The rise of SARS-CoV-2 variants and the history of outbreaks caused by zoonotic coronaviruses point to the need for next-generation vaccines that confer protection against variant strains. Here, we combined analyses of diverse sequences and structures of coronavirus spikes with data from deep mutational scanning to design SARS-CoV-2 variant antigens containing the most significant mutations that may emerge. We trained a neural network to predict RBD expression and ACE2 binding from sequence, which allowed us to determine that these antigens are stable and bind to ACE2. Thus, they represent viable variants. We then used a computational model of affinity maturation (AM) to study the antibody response to immunization with different combinations of the designed antigens. The results suggest that immunization with a cocktail of the antigens is likely to promote evolution of higher titers of antibodies that target SARS-CoV-2 variants than immunization or infection with the wildtype virus alone. Finally, our analysis of 12 coronaviruses from different genera identified the S2' cleavage site and fusion peptide as potential pan-coronavirus vaccine targets. Author summary: SARS-CoV-2 variants have already emerged and future variants may pose greater threats to the efficacy of current vaccines. Rather than using a reactive approach to vaccine development that would lag behind the evolution of the virus, such as updating the sequence in the vaccine with a current variant, we sought to use a proactive approach that predicts some of the mutations that could arise that could evade current immune responses. Then, by including these mutations in a new vaccine antigen, we might be able to protect against those potential variants before they appear. Toward this end, we used various computational methods including sequence analysis and machine learning to design such antigens. We then used simulations of antibody development, and the results suggest that immunization with our designed antigens is likely to result in an antibody response that is better able to target SARS-CoV-2 variants than current vaccines. We also leveraged our sequence analysis to suggest that a particular site on the spike protein could serve as a useful target for a pan-coronavirus vaccine. [ABSTRACT FROM AUTHOR]

Objective: To determine the utility of monospot testing in the diagnosis of mononucleosis in the collegiate student–athlete clinical setting. Design: Retrospective cohort study. Setting: National Collegiate Athletic Association Division I sports medicine clinic. Patients: All varsity student athletes who had a monospot test and Epstein–Barr virus (EBV) titers obtained from January 1, 2016, through March 31, 2020, (n = 199) were included. Independent Variables: Monospot, EBV antibody titers, and liver transaminase results. Main Outcome Measures: Using EBV titers indicating acute or recent infection as the gold standard for diagnosing infectious mononucleosis (IM), the reliability of a positive monospot test and elevated liver transaminases for the diagnosis of IM were examined. Results: The monospot test had a sensitivity and specificity of 80.0% and 90.6%, respectively, with a positive predictive value of 36.4% and a negative predictive value of 98.5% in this cohort. All athletes diagnosed with IM also had elevated liver transaminases. Conclusions: The specificity of the monospot test is lower than previously reported in the literature, and a positive test is not sufficient to diagnose mononucleosis in this clinical setting. Positive monospot results should be confirmed with EBV antibody testing. Elevated transaminase levels are highly correlated with acute IM and could play a supporting role in the diagnosis. [ABSTRACT FROM AUTHOR]

Intraoperative cerebrospinal fluid (CSF) leaks are associated with increased risk of postoperative CSF leaks despite multilayered reconstruction with vascularized tissue. A recent randomized controlled trial (RCT) examining the use of perioperative lumbar drains (LD) in high-risk skull base defects identified a significant reduction in postoperative CSF leak incidence (21.2 vs. 8.2%; p  = 0.017). This study was conducted to assess the efficacy of the selective use of CSF diversion, for patients with intraoperative CSF leaks involving endoscopic endonasal approaches (EEA) to the skull base. Method  Consecutive endoscopic endonasal surgeries of the skull base from a pre-RCT cohort and post-RCT cohort were compared. The following case characteristics between the two cohorts were examined: patient age, body mass index (BMI), rate of revision surgery, tumor histology, use of CSF diversion, and vascularized reconstruction. The primary measured outcome was postoperative CSF leak. Results  The pre-RCT cohort included 76 patients and the post-RCT cohort included 77 patients, with dural defects in either the anterior or posterior cranial fossa (pituitary and parasellar/suprasellar surgeries excluded). There was a significant reduction in the incidence of postoperative CSF leak in the post-RCT cohort (27.6 vs. 12.9%; p  = 0.04). On subgroup analysis, there was a trend toward improvement in CSF leak rate of the anterior cranial fossa (19.2 vs. 10.5%; p  = 0.27), whereas CSF leak rates of the posterior cranial fossa were significantly reduced compared with the pre-RCT cohort (41.4 vs. 12.8%; p  = 0.02). Conclusion  This study demonstrates that the integration of selective CSF diversion into the reconstructive algorithm improved postoperative CSF leak rates. [ABSTRACT FROM AUTHOR]

In this issue of Cell Chemical Biology , Bonazzi et al. demonstrate that pharmacologically degrading the transcription factor Helios (IKZF2) results in destabilization of regulatory T cells, which normally restrain anti-tumor immunity. These results highlight how molecular glue degraders can selectively target previously undruggable proteins with potential applications in the clinic. [ABSTRACT FROM AUTHOR]

Background: Prognosticating recovery times for individual athletes with a concussion remains a challenge for health care providers. Several preinjury and postinjury factors have been proposed to be predictive of prolonged return-to-play (RTP) times, but the data in this area are still sparse. Purposes: This study aimed to identify risk factors associated with prolonged recovery times and determine which are most predictive of prolonged recovery times in a head-to-head comparison. Study Design: Case-control study; Level of evidence, 3. Methods: All concussions occurring between September 2017 and August 2020 at a single National Collegiate Athletic Association Division I institution were reviewed and included in this study. Preinjury modifiers including age, sex, sport, concussion history, and past medical problems were collected from the electronic medical records. Postinjury modifiers analyzed included initial and follow-up Sport Concussion Assessment Tool 5th Edition scores, vestibular evaluation findings, and eye tracking results. Results: A total of 159 athletes and 187 concussion cases were included. Preinjury factors that were correlated with prolonged RTP times included a history of concussions (P =.015), a history of migraines (P =.013), and whether an athlete participated in an individual sport (P =.009). Postinjury factors correlated with prolonged RTP times included the total number (P =.020) and severity (P =.023) of symptoms as well as abnormal Vestibular Ocular Motor Screening findings (P =.002). Overall, 6 different symptoms (balance problems, difficulty concentrating, light sensitivity, drowsiness, fatigue/low energy, and difficulty remembering) were significantly correlated with prolonged RTP times. The study also found that the number and severity of symptoms were additive in a dose-dependent fashion. On multivariable analysis of all these factors, a history of concussions was found to be the most predictive of prolonged RTP times, while participation in an individual sport had the largest effect on recovery times. Conclusion: Several preinjury and postinjury risk factors were identified as being correlated with prolonged recovery times. Many of these risk factors were also found to be additive in nature. This information provides clinicians with a valuable tool in prognosticating and estimating recovery times for athletes. The study also revealed that athletes participating in individual sports had longer RTP times compared with athletes in team sports, which is a novel finding that requires further research. [ABSTRACT FROM AUTHOR]

With rapid development of voice control technology, making speech recognition more precisely in various IoT domains have been an intractable problem to be solved. Since there are various conversation scenes, understanding the context of a dialog scene is a key issue of voice control systems. However, the reality is available training data for dialog system are always insufficient. In this paper, we mainly solve the problem of data lacking in dialog systems by data augmentation technique. A Generative Adversarial Network(GAN)-based model is proposed and the data are augmented effectively. It can generate from text to text, enhance the original data with text retelling, and improve the robustness of parameter estimation of unknown data by using the sample data generated by GAN model. A new N-gram language model is used to evaluate multiple recognition candidates of speech recognition, and the candidate sentences with the highest evaluation scores are selected as the final result of speech recognition. Our data enhancement algorithm based on the Generative Model is verified by the experiments. In the result of model comparison test, the error rates of data set THCHS30 and AISHELL are 3.3% and 5.1% which are lower than that of the baseline system. [ABSTRACT FROM AUTHOR]

Accidents often occur in the earth—typhoons, floods, earthquakes, traffic accidents and so on. Whether these accidents can be timely and effectively responded to has been an important indicator to judge whether a region is advanced or not. IoT provide a possibility to solve such emergent problems by intelligent monitoring, diagnosis and repair. For example, coastal cities are often attacked by typhoons, if typhoon meteorological identification and early warning can be effectively carried out, many unnecessary property and personnel losses can be reduced. Accurate typhoon prediction has very important practical significance. However, current typhoon monitoring and prediction are mainly based on simulation with meteorological data; the accuracy still needs to be improved. Nowadays, the technology of Internet of Things (IoT) and remote sensing technology become more and more closely linked; many IoT systems in smart cities' can obtain high-resolution remote sensing image data. Therefore, it is possible to use urban IoT system to realize the early warning of typhoon. In this paper, we propose a deep learning method for typhoon cloud recognition and typhoon center location, and design a general algorithm framework, including data preprocessing, model training and parameter selection, test and result analysis. Besides, we implement a typhoon early warning demo system. The experimental results show that our algorithm is better than the traditional methods in recognition accuracy. [ABSTRACT FROM AUTHOR]

This refers to a case of a patient with an irregular carotid cave aneurysm who presented with new recurrent headaches. She was not eligible for a flow diverting stent as she had chronic menometrorrhagia. An endoscopic endonasal clipping was offered. The patient tolerated the procedure well.By Zachary C. Gersey; Bhuvic Patel; Eric Wang and Georgios A. ZenonosReported by Author; Author; Author; Author [Extracted from the article]

Objective: Options for the management of orbital floor fractures continue to evolve offering both potential advantages as well as higher costs. To date, the effect of implant choice on the cost associated with the repair of orbital floor fractures has not been studied. Methods: A retrospective review at a tertiary care, level I trauma center examining all adult, uncomplicated orbital floor fractures that underwent open reduction and internal fixation from 2013 to 2016. Patients with concurrent operative facial fractures were excluded. The main outcomes were overall cost of care from injury to last follow-up and operating room-related costs. Costs were determined using computerized records of charges as well as the hospital Charge Description Master. Kruksal-Wallis rank sum tests were used to analyze for differences between groups. Results: Twenty-eight patients fulfilled the inclusion criteria. Eight different stock, non-patient specific, implants were used for repair. The cost of individual types of implants ranged from $70.25 to $7 718.00. Total cost of care per patient across all implant types averaged $35 585.57 (range $25 586.26 to $49 985.74, P =.34). Operation-related charges accounted for the vast majority (94.4%) of the total cost of care. One complication occurred requiring operative re-positioning of the implant with an additional $13 042.41 in charges. Conclusions: In the setting of uncomplicated orbital floor fractures, surgeons should select an implant that allows them to carry out the repair in a safe, timely fashion. Additional large-scale studies would help to further delineate cost differences. [ABSTRACT FROM AUTHOR]

Indicating trust or distrust of a node is a key issue in the trust management of IoT. However, there are some challenges for the management with anonymous nodes, inaccurate communication, etc. Due to huge number of nodes in IoT, one of the possible solutions is predicting trust and distrust values. In this paper, we propose a dynamic trust model based on direct and indirect trust computation, and the most important part of a model, trust prediction. The prediction method mainly depends on the combination of exponential smoothing and a Markov chain. We employ exponential smoothing to predict trustiness and a Markov chain to fix the deviation of the prediction. To test our scheme, we create a simulation to evaluate its performance and effectiveness. The simulation results are encouraging. [ABSTRACT FROM AUTHOR]

Background: Endoscopic skull‐base surgery (ESBS) is employed in the management of diverse skull‐base pathologies. Paralleling the increased utilization of ESBS, the literature in this field has expanded rapidly. However, the rarity of these diseases, the inherent challenges of surgical studies, and the continued learning curve in ESBS have resulted in significant variability in the quality of the literature. To consolidate and critically appraise the available literature, experts in skull‐base surgery have produced the International Consensus Statement on Endoscopic Skull‐Base Surgery (ICAR:ESBS). Methods: Using previously described methodology, topics spanning the breadth of ESBS were identified and assigned a literature review, evidence‐based review or evidence‐based review with recommendations format. Subsequently, each topic was written and then reviewed by skull‐base surgeons in both neurosurgery and otolaryngology. Following this iterative review process, the ICAR:ESBS document was synthesized and reviewed by all authors for consensus. Results: The ICAR:ESBS document addresses the role of ESBS in primary cerebrospinal fluid (CSF) rhinorrhea, intradural tumors, benign skull‐base and orbital pathology, sinonasal malignancies, and clival lesions. Additionally, specific challenges in ESBS including endoscopic reconstruction and complication management were evaluated. Conclusion: A critical review of the literature in ESBS demonstrates at least the equivalency of ESBS with alternative approaches in pathologies such as CSF rhinorrhea and pituitary adenoma as well as improved reconstructive techniques in reducing CSF leaks. Evidence‐based recommendations are limited in other pathologies and these significant knowledge gaps call upon the skull‐base community to embrace these opportunities and collaboratively address these shortcomings. [ABSTRACT FROM AUTHOR]

Background: Endoscopic skull‐base surgery (ESBS) is a rapidly growing discipline that often combines the expertise of otolaryngology–head and neck surgeons and neurosurgeons to provide care for these challenging conditions. As the field has grown, so too has the literature evaluating this surgical approach and the challenges and complications associated with these interventions. An international, multidisciplinary effort to critically evaluate and grade the current literature on ESBS has resulted in the International Consensus Statement on Endoscopic Skull Base Surgery (ICAR:SB). This Executive Summary highlights the key findings of the ICAR:SB document. Methods: Following the prior methodology of the ICAR statements, the ICAR:SB document consists of 98 topics in ESBS that underwent a systematic review. When sufficient evidence exists, an evidence‐based review with recommendation (EBRR) or evidence‐based review (EBR) was created and then underwent an iterative review process until consensus was achieved. This Executive Summary recapitulates these findings. Results: This summary complies the EBR and EBRR from the ICAR:SB document in the management of numerous skull‐base pathologies including cerebrospinal fluid rhinorrhea, intradural tumors, sinonasal malignancies, and clival tumors, as well as the key issues of reconstruction after and the complications associated with ESBS. Conclusion: The ICAR:SB Executive Summary recaps the evidenced‐based recommendations concerning the advantages, limitations and challenges of ESBS in the management of diverse skull‐base pathologies. Although multifactorial in nature, the overall level of evidence in ESBS is modest. This represents an opportunity to address these knowledge gaps moving forward. [ABSTRACT FROM AUTHOR]

Cyclin‐dependent kinases 4 and 6 (CDK4/6) are key regulators of the cell cycle, and there are FDA‐approved CDK4/6 inhibitors for treating patients with metastatic breast cancer. However, due to conservation of their ATP‐binding sites, development of selective agents has remained elusive. Here, we report imide‐based degrader molecules capable of degrading both CDK4/6, or selectively degrading either CDK4 or CDK6. We were also able to tune the activity of these molecules against Ikaros (IKZF1) and Aiolos (IKZF3), which are well‐established targets of imide‐based degraders. We found that in mantle cell lymphoma cell lines, combined IKZF1/3 degradation with dual CDK4/6 degradation produced enhanced anti‐proliferative effects compared to CDK4/6 inhibition, CDK4/6 degradation, or IKZF1/3 degradation. In summary, we report here the first compounds capable of inducing selective degradation of CDK4 and CDK6 as tools to pharmacologically dissect their distinct biological functions. [ABSTRACT FROM AUTHOR]

Cyclin‐dependent kinases 4 and 6 (CDK4/6) are key regulators of the cell cycle, and there are FDA‐approved CDK4/6 inhibitors for treating patients with metastatic breast cancer. However, due to conservation of their ATP‐binding sites, development of selective agents has remained elusive. Here, we report imide‐based degrader molecules capable of degrading both CDK4/6, or selectively degrading either CDK4 or CDK6. We were also able to tune the activity of these molecules against Ikaros (IKZF1) and Aiolos (IKZF3), which are well‐established targets of imide‐based degraders. We found that in mantle cell lymphoma cell lines, combined IKZF1/3 degradation with dual CDK4/6 degradation produced enhanced anti‐proliferative effects compared to CDK4/6 inhibition, CDK4/6 degradation, or IKZF1/3 degradation. In summary, we report here the first compounds capable of inducing selective degradation of CDK4 and CDK6 as tools to pharmacologically dissect their distinct biological functions. [ABSTRACT FROM AUTHOR]

Objective: To determine the performance of a targeted microarray-based cell-free DNA (cfDNA) test (Harmony Prenatal Test®) for the identification of pregnancies at increased risk for 22q11.2 deletion.Methods: Test performance was determined in 2 steps including a total of 1,953 plasma samples. Analytical validation was performed in 1,736 plasma samples. Clinical verification of performance was performed in an additional 217 prospectively ascertained samples from pregnancies with fetal deletion status determined by diagnostic testing.Results: Analytical sensitivity was 75.4% (95% CI: 67.1-82.2%) based on 122 samples with deletions ranging from 1.96 to 3.25 Mb. In 1,614 presumed unaffected samples, specificity was determined to be at least 99.5% (95% CI: 99.0-99.7%). In the clinical cohort, 5 of 7 samples from pregnancies affected with 22q11.2 deletion were determined to have a high probability of deletion. There were no false positive results in the 210 unaffected samples in this cohort. These clinical data are consistent with the performance demonstrated in the analytical validation.Conclusions: cfDNA testing using a targeted microarray-based technology is able to identify pregnancies at increased risk for 22q11.2 deletions of 3.0 Mb and smaller while maintaining a low false positive rate. [ABSTRACT FROM AUTHOR]

Background Current surgical management of retroperitoneal masses involving major vessels now includes complete en bloc resection with in situ venous, arterial, or combined reconstruction. No studies have investigated preresection arterial bypass for continuous lower extremity perfusion during definitive resection. Here, we characterize and compare the outcomes of surgery for retroperitoneal masses with major vascular involvement by a two-stage approach (femoral-femoral bypass preceding resection) and the traditional one-stage approach (consecutive resection and in situ vascular reconstruction). Materials and methods We retrospectively reviewed patients who underwent resection of retroperitoneal masses and reconstruction of major arterial or venous structures from 2004 to 2016. Outcomes were compared with unpaired t -tests, chi-squared tests, and Kaplan–Meier analysis. Results Eight patients underwent a two-stage procedure, and seven underwent a one-stage procedure for retroperitoneal masses with vascular involvement. Mean (±SD) oncologic resection time (443 ± 215 versus 648 ± 128 min, P = 0.047) and postoperative ICU stay (0.9 ± 1.3 versus 4.4 ± 2.9 d, P = 0.018) were significantly shorter for the two-stage approach. Conclusions To our knowledge, this is the first report of a two-stage approach for resection of retroperitoneal masses with major vessel involvement. Femoral-femoral arterial bypass before definitive resection could be a viable option for improving intraoperative vascular control and decreasing perioperative complications in these complex procedures. [ABSTRACT FROM AUTHOR]

Abstract The lipid composition of bovine and human ocular lens membranes has been probed, and a variety of lipids have been found including phosphatidylcholine (PC), phosphatidylethanolamine (PE), sphingomyelin (SM), and cholesterol (CHOL) with cholesterol being present in particularly high concentrations. In this study, we use the all-atom CHARMM36 force field to simulate binary, ternary, and quaternary mixtures as models of the ocular lens. High concentration of cholesterol, in combination with different and varying diversity of phospholipids (PL) and sphingolipids (SL), affect the structure of the ocular lens lipid bilayer. The following analyses were done for each simulation: surface area per lipid, component surface area per lipid, deuterium order parameters (S CD), electron density profiles (EDP), membrane thickness, hydrogen bonding, radial distribution functions, clustering, and sterol tilt angle distribution. The S CD show significant bilayer alignment and packing in cholesterol-rich bilayers. The EDP show the transition from liquid crystalline to liquid ordered with the addition of cholesterol. Hydrogen bonds in our systems show the tendency for intramolecular interactions between cholesterol and fully saturated lipid tails for less complex bilayers. But with an increased number of components in the bilayer, the acyl chain of the lipids becomes a less important characteristic, and the headgroup of the lipid becomes more significant. Overall, cholesterol is the driving force of membrane structure of the ocular lens membrane where interactions between cholesterol, PL, and SL determine structure and function of the biomembrane. The goal of this work is to develop a baseline for further study of more physiologically realistic ocular lens lipid membranes. This article is part of a Special Issue entitled: Emergence of Complex Behavior in Biomembranes edited by Marjorie Longo. Graphical abstract Image 1 Highlights • Ocular lens membranes are unique with a majority of lipids being cholesterol. • Cow and human sphingolipids differ and affect lipid membrane structure. • Cholesterol is the main driving force for membrane structure. • Lipid interactions and chemical structure influence the physical properties of membranes. [ABSTRACT FROM AUTHOR]

Emergent cell behaviors that drive tissue morphogenesis are the integrated product of instructions from gene regulatory networks, mechanics and signals from the local tissue microenvironment. How these discrete inputs intersect to coordinate diverse morphogenic events is a critical area of interest. Organ-on-chip technology has revolutionized the ability to construct and manipulate miniaturized human tissues with organotypic three-dimensional architectures in vitro. Applications of organ-on-chip platforms have increasingly transitioned from proof-of-concept tissue engineering to discovery biology, furthering our understanding of molecular and mechanical mechanisms that operate across biological scales to orchestrate tissue morphogenesis. Here, we provide the biological framework to harness organ-on-chip systems to study tissue morphogenesis, and we highlight recent examples where organ-on-chips and associated microphysiological systems have enabled new mechanistic insight in diverse morphogenic settings. We further highlight the use of organ-on-chip platforms as emerging test beds for cell and developmental biology. [ABSTRACT FROM AUTHOR]

We propose a repeated review deep learning model for image captioning in image evidence review process. It consists of two subnetworks. One is the convolutional neural network which is employed to extract the image features and the other is the recurrent neural network which is used to decode the image features into captions. Our model combines the advantages of the two subnetworks by recalling visual information different from the traditional model of encoder–decoder, and then introduces multimodal layer to fuse the image and caption effectively. The proposed model has been validated on benchmark datasets (MSCOCO, Flickr). It shows that the proposed model performs well on bleu-3 and bleu-4, even to some extent, beyond the best models available today (such as NIC, m-RNN, etc.). [ABSTRACT FROM AUTHOR]

The barrier function of the stratum corneum (SC) is intimately related to the structure of the lipid matrix, which is composed of ceramides (Cer), cholesterol (Chol), and free fatty acid (FFA). In this study, the all-atom CHARMM36 (C36) force field is used to simulate bilayers of N-palmitoylsphingosine (Cer16), N-lignoceroylsphingosine (Cer24), Chol, and lignoceric acid (LA) as simple models of the SC. Equimolar mixtures of Cer, Chol, and LA are replicated from experiment for comparison and validation of the C36 force field, and the effects of lipid diversity and temperature are studied. The presence of Chol and LA have effects on nearly all membrane properties including surface area per lipid, area compressibility moduli, chain order, Chol tilt, bilayer thickness, interdigitation, hydrogen bonding, and lipid clustering, while temperature has a more moderate effect. In systems containing Cer16, there is a profound difference in interdigitation between pure Cer and mixed systems, while systems containing Cer24 are relatively unaffected. Increasing temperature has the potential to shift hydrogen bonding pairs rather than uniformly decrease bonding, which can lead to greater Cer-Cer bonding at higher temperatures. Comparison with deuterium order parameter experiments demonstrates good agreement, which supports further use of this class of lipids and fatty acids for development of more complex SC models. [ABSTRACT FROM AUTHOR]

Recent studies in lipid raft formation and stratum corneum permeability have focused on the role of ceramides (CER). In this study, we use the all-atom CHARMM36 (C36) force field to simulate bilayers using N-palmitoylsphingosine (CER16) or α-hydroxy-N-stearoyl phytosphingosine (CER[AP]) in 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) or 1-palmitoyl-2-oleoylphosphatidylcholine (POPC), which serve as general membrane models. Conditions are replicated from experimental studies for comparison purposes, and concentration (XCER) is varied to probe the effect of CER on these systems. Comparisons with experiment based on deuterium order parameters and bilayer thickness demonstrate good agreement, thus supporting further use of the C36 force field. CER concentration is shown to have a profound effect on nearly all membrane properties including surface area per lipid, chain order and tilt, area compressibility moduli, bilayer thickness, hydrogen bonding, and lipid clustering. Hydrogen bonding in particular can significantly affect other membrane properties and can even encourage transition to a gel phase. Despite CER's tendency to condense the membrane, an expansion of CER lipids with increasing XCER is possible depending on how the balance between various hydrogen-bond pairs and lipid clustering is perturbed. Based on gel phase transitions, support is given for phytosphingosine's role as a hydrogen-bond bridge between sphingosine ordered domains in the stratum corneum. [ABSTRACT FROM AUTHOR]

Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks), a family of three members in mammals (α, β and γ), have emerged as potential therapeutic targets due to their role in regulating many important cellular signaling pathways. In comparison to the PI5P4Kα and PI5P4Kβ, which usually have similar expression profiles across cancer cells, PI5P4Kγ exhibits distinct expression patterns, and pathological functions for PI5P4Kγ have been proposed in the context of cancer and neurodegenerative diseases. PI5P4Kγ has very low kinase activity and has been proposed to inhibit the PI4P5Ks through scaffolding function, providing a rationale for developing a selective PI5P4Kγ degrader. Here, we report the development and characterization of JWZ-1-80, a first-in-class PI5P4Kγ degrader. JWZ-1-80 potently degrades PI5P4Kγ via the ubiquitin-proteasome system and exhibits proteome-wide selectivity and is therefore a useful tool compound for further dissecting the biological functions of PI5P4Kγ. JWZ-1-80 induces rapid and sustained proteasomal degradation of endogenous PI5P4Kγ through recruitment of the E3 ligase adaptor VHL. JWZ-1-80 exhibits excellent proteome-wide selectivity and does not degrade PI5P4Kα and PI5P4Kβ. [Display omitted] • A first-in-class PI5P4Kγ degrader were developed. • JWZ-1-80 selectively degraded PI5P4Kγwithout affecting PI5P4Kα and PI5P4Kβ. • JWZ-1-80 degraded PI5P4Kγ through the ubiquitin-protease pathway. • JWZ-1-80 exhibits high proteome-wide selectivity. • JWZ-1-80 induced the degradation of PI5P4Kγ in multiple cell lines. [ABSTRACT FROM AUTHOR]

Myotonic dystrophy (DM) is a dominantly-inherited genetic disorder affecting skeletal muscle, heart, brain, and other organs. DM type 1 is caused by expansion of a CTG triplet repeat in DMPK , whereas DM type 2 is caused by expansion of a CCTG tetramer repeat in CNBP . In both cases the DM mutations lead to expression of dominant-acting RNAs. Studies of RNA toxicity have now revealed novel mechanisms and new therapeutic targets. Preclinical data have suggested that RNA dominance is responsive to therapeutic intervention and that DM therapy can be approached at several different levels. Here we review recent efforts to alleviate RNA toxicity in DM. [ABSTRACT FROM AUTHOR]

Myotonic dystrophy (DM) is an autosomal dominant neuromuscular disease primarily characterized by myotonia and progressive muscle weakness. The pathogenesis of DM involves microsatellite expansions in noncoding regions of transcripts that result in toxic RNA gain-of-function. Each successive generation of DM families carries larger repeat expansions, leading to an earlier age of onset with increasing disease severity. At present, diagnosis of DM is challenging and requires special genetic testing to account for somatic mosaicism and meiotic instability. While progress in genetic testing has been made, more rapid, accurate, and cost-effective approaches for measuring repeat lengths are needed to establish clear correlations between repeat size and disease phenotypes. [ABSTRACT FROM AUTHOR]

Topic models, such as probabilistic latent semantic analysis (PLSA) and latent Dirichlet allocation (LDA), have shown impressive success in many fields. Recently, multi-view learning via probabilistic latent semantic analysis (MVPLSA), is also designed for multi-view topic modeling. These approaches are instances of generative model, whereas they all ignore the manifold structure of data distribution, which is generally useful for preserving the nonlinear information. In this paper, we propose a novel multiple graph regularized generative model to exploit the manifold structure in multiple views. Specifically, we construct a nearest neighbor graph for each view to encode its corresponding manifold information. A multiple graph ensemble regularization framework is proposed to learn the optimal intrinsic manifold. Then, the manifold regularization term is incorporated into a multi-view topic model, resulting in a unified objective function. The solutions are derived based on the Expectation Maximization optimization framework. Experimental results on real-world multi-view data sets demonstrate the effectiveness of our approach. [ABSTRACT FROM AUTHOR]

Therapy resistance is a major challenge in the treatment of cancer. Here, we performed CRISPR-Cas9 screens across a broad range of therapies used in acute myeloid leukemia to identify genomic determinants of drug response. Our screens uncover a selective dependency on RNA splicing factors whose loss preferentially enhances response to the BCL2 inhibitor venetoclax. Loss of the splicing factor RBM10 augments response to venetoclax in leukemia yet is completely dispensable for normal hematopoiesis. Combined RBM10 and BCL2 inhibition leads to mis-splicing and inactivation of the inhibitor of apoptosis XIAP and downregulation of BCL2A1 , an anti-apoptotic protein implicated in venetoclax resistance. Inhibition of splicing kinase families CLKs (CDC-like kinases) and DYRKs (dual-specificity tyrosine-regulated kinases) leads to aberrant splicing of key splicing and apoptotic factors that synergize with venetoclax, and overcomes resistance to BCL2 inhibition. Our findings underscore the importance of splicing in modulating response to therapies and provide a strategy to improve venetoclax-based treatments. [Display omitted] • Genome-wide screens identify genomic determinants of drug response in AML • RBM10 loss enhances venetoclax efficacy and is dispensable for hematopoiesis • Inhibition of splicing-dependent kinases overcomes venetoclax resistance • SM09419 synergizes with venetoclax by impairing XIAP and splicing factors Wang et al. perform genetic screens to identify mediators of sensitization and resistance to acute myeloid leukemia therapies. This reveals a unique relationship between expression of RNA splicing factors and response to the BCL2 inhibitor venetoclax, as well as an inhibitor of splicing-dependent kinases, which overcomes venetoclax resistance. [ABSTRACT FROM AUTHOR]

RNA-binding proteins (RBPs) acting at various steps in the post-transcriptional regulation of gene expression play crucial roles in neuronal development and synaptic plasticity. Genetic mutations affecting several RBPs and associated factors lead to diverse neurological symptoms, as characterized by neurodevelopmental and neuropsychiatric disorders, neuromuscular and neurodegenerative diseases, and can often be multisystemic diseases. We will highlight the physiological roles of a few specific proteins in molecular mechanisms of cytoplasmic mRNA regulation, and how these processes are dysregulated in genetic disease. Recent advances in computational biology and genomewide analysis, integrated with diverse experimental approaches and model systems, have provided new insights into conserved mechanisms and the shared pathobiology of mRNA dysregulation in disease. Progress has been made to understand the pathobiology of disease mechanisms for myotonic dystrophy, spinal muscular atrophy, and fragile X syndrome, with broader implications for other RBP-associated genetic neurological diseases. This gained knowledge of underlying basic mechanisms has paved the way to the development of therapeutic strategies targeting disease mechanisms. [ABSTRACT FROM AUTHOR]

Permeation of many small molecules through lipid bilayers can be directly observed in molecular dynamics simulations on the nano- and microsecond timescale. While unbiased simulations provide an unobstructed view of the permeation process, their feasibility for computing permeability coefficients depends on various factors that differ for each permeant. The present work studies three small molecules for which unbiased simulations of permeation are feasible within less than a microsecond, one hydrophobic (oxygen), one hydrophilic (water), and one amphiphilic (ethanol). Permeabilities are computed using two approaches: counting methods and a maximum-likelihood estimation for the inhomogeneous solubility diffusion (ISD) model. Counting methods yield nearly model-free estimates of the permeability for all three permeants. While the ISD-based approach is reasonable for oxygen, it lacks precision for water due to insufficient sampling and results in misleading estimates for ethanol due to invalid model assumptions. It is also demonstrated that simulations using a Langevin thermostat with collision frequencies of 1/ps and 5/ps yield oxygen permeabilities and diffusion constants that are lower than those using Nosé–Hoover by statistically significant margins. In contrast, permeabilities from trajectories generated with Nosé–Hoover and the microcanonical ensemble do not show statistically significant differences. As molecular simulations become more affordable and accurate, calculation of permeability for an expanding range of molecules will be feasible using unbiased simulations. The present work summarizes theoretical underpinnings, identifies pitfalls, and develops best practices for such simulations. [ABSTRACT FROM AUTHOR]

Objectives To identify the prevalence and risk factors for nasal deformities after endoscopic endonasal surgery (EES) of the skull base. Design Retrospective case series. Setting Tertiary referral academic center. Participants EES patients from January 2011 to October 2013. Main Outcome Measures Surgical approach, method of skull base reconstruction, and postoperative nasal deformities. Results Of 328 patients, 19 patients (5.8%) had nasal dorsum collapse, 3 (0.9%) with new septal perforations and 2 (0.6%) with septal deviations requiring surgical correction. Postoperative deformities were only found in the setting of nasoseptal flap reconstruction (p = 0.0001) and were most common in patients who had undergone an approach involving more than one anatomical subsite (p = 0.0021). Patients with nasal deformities were on average 6 years younger (p = 0.08) and were more likely to have a malignant pathology (p = 0.08). Conclusions All deformities were associated with use of a nasoseptal flap for reconstruction and were most common in combined approaches, suggesting that flap size may play a role in the development of nasal deformities. The mechanism of nasal dorsum collapse is unclear but does not appear to be related to septal cartilage necrosis. These findings warrant a prospective analysis to identify risk factors for postoperative nasal deformities and data for counseling of patients. [ABSTRACT FROM AUTHOR]

Summary The intrinsic (mitochondrial) apoptotic pathway is a conserved cell death program crucial for eliminating superfluous, damaged, or incorrectly specified cells [ 1 ], and the multi-domain pro-death BCL-2 family proteins BAX and BAK are required for its activation [ 2, 3 ]. In response to internal damage or developmental signals, BAX and/or BAK permeabilize the mitochondrial outer membrane [ 4, 5 ], resulting in cytochrome c release and activation of effector caspases such as Caspase-3 (Casp3) [ 6 ]. While the mitochondrial apoptotic pathway plays a critical role during late embryonic development in mammals [ 3 ], its role during early development remains controversial [ 7, 8 ]. Here, we show that Bax −/− Bak −/− murine embryonic stem cells (ESCs) display defects during the exit from pluripotency, both in culture and during teratoma formation. Specifically, we find that when ESCs are stimulated to differentiate, a subpopulation fails to do so and instead upregulates FAS in a p53-dependent manner to trigger Bax/Bak-dependent apoptosis. Blocking this apoptotic pathway prevents the removal of these poorly differentiated cells, resulting in the retention of cells that have not exited pluripotency. Taken together, our results provide further evidence for heterogeneity in the potential of ESCs to successfully differentiate and reveal a novel role for apoptosis in promoting efficient ESC differentiation by culling cells that are slow to exit pluripotency. [ABSTRACT FROM AUTHOR]

Phosphatidylinositol 5‐phosphate 4‐kinase, type II, gamma (PIP4K2C) remains a poorly understood lipid kinase with minimal enzymatic activity but potential scaffolding roles in immune modulation and autophagy‐dependent catabolism. Achieving potent and selective agents for PIP4K2C while sparing other lipid and non‐lipid kinases has been challenging. Here, we report the discovery of the highly potent PIP4K2C binder TMX‐4102, which shows exclusive binding selectivity for PIP4K2C. Furthermore, we elaborated the PIP4K2C binder into TMX‐4153, a bivalent degrader capable of rapidly and selectively degrading endogenous PIP4K2C. Collectively, our work demonstrates that PIP4K2C is a tractable and degradable target, and that TMX‐4102 and TMX‐4153 are useful leads to further interrogate the biological roles and therapeutic potential of PIP4K2C. [ABSTRACT FROM AUTHOR]