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Nanofiber-porous systems comprising a porous substrate overlaid with nanofiber weave offer the potential for higher acoustic absorption than the substrate alone with negligible increase in thickness. The characterization of nanofibers from acoustic measurements is investigated in this work, and a regression model for predicting their acoustic properties from a single physical parameter is proposed to enable the design of nanofiber-porous systems directly from fabrication parameters. Characterization as a resistive screen via Johnson–Champoux–Allard and lumped element models for transfer matrix computations of absorption coefficient for nanofiber-porous systems exhibited good agreement with the measured spectra. The lumped element model was chosen as it was defined by fewer parameters and did not require nanofiber layer thickness measurements, eliminating the associated uncertainty. A regression model for lumped element parameters vs areal density established a design tool based on a single, easily measured physical property for optimized absorption at target frequencies without prior acoustic characterization of the nanofiber layer, enabling the analysis of complex acoustic networks incorporating nanofiber-porous systems. Practical considerations of applying adhesives at the nanofiber-porous interface were studied to evaluate possible enhancement of acoustic performance. For comparison with prior work by others, flow resistances from physical measurement and acoustic characterization were compared.

This study examines the spread of politically related information on Twitter, following the immediate wake of the 2014 Thai coup. The role and use of Twitter cannot be underestimated as it plays a significant and growing impact in conflicts and crises. In specific, this study assessed the use of Twitter in a country like Thailand, where political coups often occur. Furthermore, the incorporation of two perspectives—rumor theory and elaboration likelihood model (ELM)—add value in the assessment of political information dissemination during political turmoil. The study applied both content analysis and survey with rigorous analyses that had tremendous contributions in the course of 2014 Thai coup by understanding the way people behave and use Twitter to spread rumors. Overall, this study sheds vital insights into the ways in which political dissemination is crucial and for people to understand and interpret political coup events.

Y-box binding protein 1 (YBX1 or YB1) is a therapeutically relevant oncoprotein capable of RNA and DNA binding and mediating protein–protein interactions that drive proliferation, stemness, and resistance to platinum-based therapies. Given our previously published findings, the potential for YB1-driven cisplatin resistance in medulloblastoma (MB), and the limited studies exploring YB1-DNA repair protein interactions, we chose to investigate the role of YB1 in mediating radiation resistance in MB. MB, the most common pediatric malignant brain tumor, is treated with surgical resection, cranio-spinal radiation, and platinum-based chemotherapy, and could potentially benefit from YB1 inhibition. The role of YB1 in the response of MB to ionizing radiation (IR) has not yet been studied but remains relevant for determining potential anti-tumor synergy of YB1 inhibition with standard radiation therapy. We have previously shown that YB1 drives proliferation of cerebellar granular neural precursor cells (CGNPs) and murine Sonic Hedgehog (SHH) group MB cells. While others have demonstrated a link between YB1 and homologous recombination protein binding, functional and therapeutic implications remain unclear, particularly following IR-induced damage. Here we show that depleting YB1 in both SHH and Group 3 MB results not only in reduced proliferation but also synergizes with radiation due to differential response dynamics. YB1 silencing through shRNA followed by IR drives a predominantly NHEJ-dependent repair mechanism, leading to faster γH2AX resolution, premature cell cycle re-entry, checkpoint bypass, reduced proliferation, and increased senescence. These findings show that depleting YB1 in combination with radiation sensitizes SHH and Group 3 MB cells to radiation.

We argue that the compelling critical perspective put forward by Michael Sandel in The Tyranny of Merit could benefit from the account of power that Cut Loose advanced in its earlier typology. First, the ways that principles of meritocracy serve the interests of particular social groups become clearer when we consider more fully the tensions that inherently exist between merit and other conceptions of the good. Second, the allure of these competing moral perspectives – above all, fraternal morality – helps us make sense of the turn toward nativist populism that we have seen in the United States and elsewhere. Amid the steady unraveling of religious and republican ties, a White working class has responded to its relative economic decline, in part, by seeking solace in ethnocentrism. Third, we argue that the morality of grace can offer an alternative source of existential meaning, which meritocracy – with its focus on contentless excellence – lacks, and which egalitarianism – with its materialist and secular viewpoint – often struggles to cultivate. Here, we turn to Sandel’s earlier book, What Money Can’t Buy, for inspiration, seeing grace as not just the absence of a meritocratic ethic of merciless competition, but a source of value, fulfillment, and connection in itself. We end our essay with a description of what such an economy and politics of grace might look like.

Purpose of Review In this review, we aim to summarize the evolution of care for the solid organ transplant recipient (SOTR) with COVID-19 disease, based on the current published guidelines and our center’s experience. Recent Findings Oral antiviral medications and monoclonal antibodies are now used with the goal to prevent severe disease. Immunomodulating drugs in addition to antivirals have been used in the treatment of severe COVID-19. Summary With the ongoing pandemic and unique challenges posed by the SOTR, understanding the risk and advancing management and treatment of COVID-19 infections are imperative to the successful care of a transplant recipient. There are many ongoing clinical trials being conducted in hopes of developing novel therapeutics towards COVID-19.

Accurate precipitation monitoring is crucial for understanding climate change and rainfall-driven hazards at a local scale. However, the current suite of monitoring approaches have different insufficiencies, including low spatial and temporal resolutions, and the inability to monitor potentially destructive precipitation events such as hailstorms. In this study, we develop an array-based solution to monitor rainfall with seismic nodal stations, offering both high spatial and high temporal resolutions. We analyze seismic records from densely spaced, high-frequency seismometers in Oklahoma, and identify signals from all 9 precipitation events that occurred during the one-month station deployment in 2016. After removing anthropogenic noise and Earth structure response, the obtained precipitation spatial pattern mimics the one from an operational weather radar, while offering higher spatial and temporal resolutions. We further show the potential of this approach to monitor hail with joint analysis of seismic intensity and independent precipitation rate measurements, and advocate for coordinated seismological-meteorological field campaign design.

Chemoproteomics of bile acid-protein targets reveals a bile salt hydrolase in Enterococcus faecium.

This study quantifies the number of estimates involved in firms’ accruals and examines whether it is informative about the relation between accruals and future earnings. We measure the number of estimates using the frequency of the use of the word estimate in the qualitative portions of a firm’s Notes to the Financial Statements (footnotes). Motivated by arguments regarding the impact of estimation errors in accruals, we hypothesize and find that the accruals of firms that have more estimates have a lower relation with future earnings (i.e., lower persistence) and a lower association with their past, current, and future cash flows. This paper was accepted by Suraj Srinivasan, accounting. Funding: This work was supported by Zijiang Endowment. H. Chen acknowledges the financial support from the National Natural Science Foundation of China [Grants 72150710550, 71790591, and 72121002]. J. V. Chen acknowledges the financial support from the University of Michigan, University of Illinois at Chicago, Paton Accounting Fellowship, and Harry Jones Endowment. F. Li acknowledges the financial support from SJTU SAIF Zijiang Discipline Development Fund, sponsored by the Zijiang Foundation. Supplemental Material: The internet appendix and data are available at https://doi.org/10.1287/mnsc.2022.4659 .

Background Despite multiple studies indicating a low prevalence of bacterial coinfection in coronavirus disease 2019 (COVID-19) patients, the majority of hospitalized COVID-19 patients receive one or more antibiotics. Patients with coinfection usually have multiple risk factors and poor clinical outcomes. Methods A retrospective case control study was conducted comparing clinical characteristics and antimicrobial use in hospitalized adult COVID-19 patients with bacterial co-infections vs. randomly selected patients without co-infections (matched on month of admission). The study was conducted at three hospitals within the Montefiore Medical Center, Bronx, NY between March 1, 2020 and October 31, 2020. A multivariable logistic regression model was developed to assess the relationship of each predictor variable with coinfection status. Secondary outcomes included hospital mortality, antibiotic days of therapy (DOT), and C. difficile infection. Results A total of 150 patients with coinfection and 150 patients without co-infection were included in the analysis. Table 1 summarized baseline characteristics and risk factors. The multivariable logistic regression model indicated that presence of a central line (OR=5.4, 95% CI: 2.7-11.1), prior antibiotic exposure within 30 days (OR=5.3, 95% CI: 2.8-10.0), prior ICU admission (OR=3.6, 95% CI: 1.7-7.6), steroid use (OR=2.7, 95% CI: 1.4-4.9), and any comorbid condition (OR=2.7, 95% CI: 1.4-5.2) were significantly associated with the development of coinfection (table 2). Mortality was higher in patients with coinfection (56% vs. 11%, p < 0.0001) (table 3). Average antibiotic DOT was 10.5 in coinfected patients compared to 4 in non-coinfected patients, (p < 0.0001). Forty-one percent of coinfected patients had a multidrug resistant organism isolated. C. difficile rate was higher in coinfected patients (4% vs. 0%, p=0.03). Conclusion As the healthcare community contends with a 3rd year of COVID-19 pandemic, understanding risk factors most predictive of bacterial coinfection can guide empiric antimicrobial therapy and targeted stewardship interventions. Ideally, co-infection risk scores are developed which may be useful for future inpatient surges. Disclosures Yi Guo, PharmD, BCIDP, Merck: Grant/Research Support Kelsie Cowman, MPH, Merck: Grant/Research Support.

Understanding the interplay between phenotypic plasticity and genetic adaptation is a long-standing focus of evolutionary biology. In bacteria, the oxidative stress response limits the formation of mutagenic reactive oxygen species (ROS) under diverse stress conditions. This suggests that the dynamics of the oxidative stress response are closely tied to the timing of the mutation supply that fuels genetic adaptation to stress. Here, we explored how mutation rates change in real-time in Escherichia coli cells during continuous hydrogen peroxide treatment in microfluidic channels. By visualising nascent DNA replication errors, we uncovered that sudden oxidative stress causes a burst of mutations. We developed a range of single-molecule and single-cell microscopy assays to determine how these mutation dynamics arise from phenotypic adaptation mechanisms. Signalling of peroxide stress by the transcription factor OxyR rapidly induces ROS scavenging enzymes. However, an adaptation delay leaves cells vulnerable to the mutagenic and toxic effects of hydroxyl radicals generated by the Fenton reaction. Resulting DNA damage is counteracted by a spike in DNA repair activities during the adaptation delay. Prior stress exposure or constitutive OxyR induction allowed cells to avoid the burst of mutations. Similar observations for alkylation stress show that mutation bursts are a general phenomenon associated with adaptation delays.

Over the last ten years, there has been considerable progress in using digital behavioral phenotypes, captured passively and continuously from smartphones and wearable devices, to infer mood and diagnose major depressive disorder. However, most digital phenotype studies suffer from poor replicability, often fail to detect clinically relevant events, and use measures of depression that are not validated or suitable for collecting large and longitudinal data. Here, we report high-quality longitudinal validated assessments of mood from computerized adaptive testing paired with continuous digital assessments of behavior from smartphone sensors for up to 40 weeks on 183 individuals experiencing mild to severe symptoms of depression. We apply a novel combination of cubic spline interpolation and idiographic models to generate individualized predictions of future mood from the digital behavioral phenotypes, achieving high prediction accuracy of depression severity up to three weeks in advance (R2≥ 80%). We show that the passive behavioral phenotypes enhance prediction of future mood over and above a baseline model which predicts future mood based on past depression severity alone for 52% of individuals in our cohort. In conclusion, our study verified the feasibility of obtaining high-quality longitudinal assessments of mood from a clinical population and predicting symptom severity weeks in advance using passively collected digital behavioral data. Our results indicate the possibility of expanding the repertoire of patient-specific behavioral measures to enable future psychiatric research.

Introduction: Women with Polycystic Ovary Syndrome (PCOS) have classic risk factors for cardiovascular disease such as obesity, hypertension, hypercholesterolemia, insulin resistance, and metabolic syndrome. Studies have demonstrated that they have increased markers of cardiovascular disease, including endothelial dysfunction, coronary artery calcification, and increased arterial stiffness leading to myocardial infarction, angina, stroke, and rarely coronary artery dissection. We present a case of a young female with PCOS without any other major classic cardiovascular risk factors except hypertension who presented with chest pain, later found to have myocardial infarction due to dissection of the right coronary artery. Case: A 33year old female presented with lightheadedness and intermittent dull mid-sternal chest pain. It became progressively worse in 5-6 hours. Past medical history was relevant for hypertension, insulin resistance, PCOS, and overweight. She was noncompliant with her medications. Family history was significant for hypertension, diabetes, coronary artery disease, and negative for any connective tissue disorders. Electrocardiogram showed ST-T elevation in leads II, III, and aVF and depression in leads I and aVL. Troponin level was significantly high at 0.378 ng/ml. Dual antiplatelet therapy was initiated. The patient underwent an emergency cardiac catheterization that revealed focal 85% flow limiting dissection in the proximal right coronary artery with a long 35% lesion in the mid right coronary artery and 40% focal lesion in the right posterior descending artery. Percutaneous intervention with a drug-eluting stent was placed successfully. She was discharged later with dual antiplatelet therapy, beta-blocker, angiotensin receptor blocker, and statin. Conclusion: Spontaneous coronary artery dissection in young females is usually associated with hormonal therapy or in the postpartum state. However, our case report highlights that physicians should have a high index of suspicion for spontaneous coronary artery dissection in a young female with PCOS.

The value of anti-CTLA-4 antibodies in cancer therapy is well established. However, the broad application of currently available anti-CTLA-4 therapeutic antibodies is hampered by their narrow therapeutic index. It is therefore challenging and attractive to develop the next generation of anti-CTLA-4 therapeutics with improved safety and efficacy. To this end, we generated fully human heavy chain-only antibodies (HCAbs) against CTLA-4. The hIgG1 Fc domain of the top candidate, HCAb 4003-1, was further engineered to enhance its regulatory T (T

Bile acids are important gut microbiota metabolites that regulate both host and microbial functions. To identify the direct protein targets of bile acids in

Along with the popularity of social network site, social commerce such as Facebook has rapidly become a promising platform to conduct online advertisings and business activities. Drawing from Latent State Trait theory (LST), we conducted an online experiment to empirically investigate the impact of information quality, picture of product presentation, the number of people’s “Like”, and impulsiveness on female customer’s urge to buy impulsively as well as the interaction effect of environmental cues and individual trait. The results showed that information quality, picture of product presentation, impulsiveness positively affected urge to buy impulsively. Contrary to our expectation, only information quality was found to interact with impulsiveness to jointly influence impulsive buying behavior, while the interaction of impulsiveness with product presentation and the number of like was insignificant. The findings not only help to enrich our understanding about important factors influencing impulse buying within Facebook B2C social commerce but also offer social commerce practitioners better strategy in selling their products and services, specifically for female customers.

Teachers’ consideration may affect their intention to implement learner-centred pedagogy. Literature showed that aspects such as task goal, students’ characteristics, teachers’ ability, learning en...

Background Acquired hemophilia A is a disorder caused by autoantibodies against coagulation factor VIII that may present with severe bleeding. We report a rare case of acquired hemophilia A presenting with coexisting lupus anticoagulant. Case presentation An 81-year-old Caucasian female presented with large ecchymoses over the torso and extremities in the setting of an enoxaparin bridge to warfarin. Anticoagulation was held, but she continued to develop bruises with significant anemia and prolonged coagulation studies that failed to correct with mixing. Workup revealed factor VIII activity Conclusions Diagnosis of acquired hemophilia A can be confounded by other causes of abnormal coagulation studies and may require specialized testing, such as a chromogenic Bethesda assay, to confirm the presence of a factor VIII inhibitor.

PurposeTo provide better services to customers, especially immediate responses and 24/7 availability, businesses are implementing text-based automated conversational agents, i.e. chatbots on their social platforms and websites. Chatbots are required to not only provide customers with necessary consultancy and guidance but also communicate friendly and socially. Based on the cognitive fit theory, this study attempts to examine the role of chatbot as a decision aid and how the match between information presentation in forms of decisional guidance and communication style and the shopping task influences consumers' perceived cognitive fit and decision performance outcomes.Design/methodology/approachA 2 x 2 x 2 between subject online experiment was conducted to identify which kind of decisional guidance (suggestive and informative guidance) and communication style (task-oriented vs social-oriented style) are the most appropriate for each type of shopping task (searching vs browsing task).FindingsThe findings show that when customers interact with chatbots, they will perceive higher cognitive fit if the chatbots provide them with suggestive guidance and communicate in a friendly style especially when they perform a searching task.Originality/valueThis study is the first attempt to understand the role of chatbots as a decision aid to customers using the communicative language. This study also tries to explore the cognitive fit theory in a novel way, and we propose the information presentation in forms of communicative language rather than matrices, tables and graphs.

Understanding team viability -- a team's capacity for sustained and future success -- is essential for building effective teams. In this study, we aggregate features drawn from the organizational behavior literature to train a viability classification model over a dataset of 669 10-minute text conversations of online teams. We train classifiers to identify teams at the top decile (most viable teams), 50th percentile (above a median split), and bottom decile (least viable teams), then characterize the attributes of teams at each of these viability levels. We find that a lasso regression model achieves an accuracy of .74--.92 AUC ROC under different thresholds of classifying viability scores. From these models, we identify the use of exclusive language such as `but' and `except', and the use of second person pronouns, as the most predictive features for detecting the most viable teams, suggesting that active engagement with others' ideas is a crucial signal of a viable team. Only a small fraction of the 10-minute discussion, as little as 70 seconds, is required for predicting the viability of team interaction. This work suggests opportunities for teams to assess, track, and visualize their own viability in real time as they collaborate., Comment: CSCW 2020 Honorable Mention Award

Intelligent Virtual Assistants (IVA) such as Apple Siri, Google Assistant, are increasingly being used to assist users with performing different tasks. However, their characteristics also raise use...

This paper proposes an end-to-end deep learning framework, termed as motion-aid feature calibration network (MFCN), for video object detection. The key idea is to leverage on the temporal coherence of video features while considering their motion patterns as captured by optical flow. To boost detection accuracy, the framework aggregates the calibrated features both at pixel and instance levels across frames to achieve improved robustness despite appearance variations. The aggregation and calibration are efficiently and adaptively conducted based on an integrated optical flow network. Meanwhile, the entire architecture of the proposed method is end-to-end, thus significantly improving its training and inference efficiency when compared to multi-stage methods for video object detection. Evaluations on KITTI and ImageNet VID indicate that MFCN can improve the results of a strong still-image detector by 11.2% and 7.31% respectively. MFCN also outperforms other competitive video object detectors and achieves a better trade-off between accuracy and runtime speed, demonstrating its potential for use in autonomous driving systems.

Despite excellent oncologic outcomes, the management of localized prostate cancer remains complex and is dependent on multiple factors, including patient life expectancy, medical comorbidities, tumor characteristics, and genetic risk factors. Decades of iterative clinical trials have improved the optimization and utilization of surgical and radiation-based modalities, as well as their combinatorial use with anti-androgen and systemic therapies. While cure rates are high and converging on equivalent disease control should an upfront surgical or radiotherapeutic approach be optimized, the long-term side effects of surgical and radiation-based treatments can differ significantly in nature. Decisions regarding the selection of therapy are therefore best made in an informed and shared medical decision-making process between clinician and patient with respect to cancer control as well as adverse effects. We outline in this narrative review an understanding regarding implications of surgical and radiation treatment on quality of life after treatment, and how these data may be considered in the context of advising patients regarding the selection of therapy. This narrative review largely focuses on the quality of life data obtained from prospective randomized trials of men treated for prostate cancer. We believe this provides the best assessment of the quality of life and can be used to inform patients when making treatment decisions.

We observed bacterial or fungal coinfections in COVID-19 patients admitted between March 1 and April 18, 2020 (152 of 4,267, 3.6%). Among these patients, mortality was 57%; 74% were intubated; 51% with bacteremia had central venous catheters. Time to culture positivity was 6–7 days, and 79% had received prior antibiotics. Metallo-β-lactamase–producing E. cloacae coinfections occurred in 5 patients.

PurposeThis study aims at investigating the effects of two-way review system and how reach and richness of information influence the perceptions of risks and benefits among service providers and their intention to continue sharing their property on sharing economy.Design/methodology/approachTo generate the variance, a 2 × 2 × 2 full factorial experiment was conducted to collect data. The research model was then tested using the structural equation model technique.FindingsThe study finds that reach of information predicts the social and economic benefits among service providers, while richness of information negatively relates to perceived informational privacy risks, which, in turn, significantly influence the decision of the service providers to continue sharing. The results also suggest that the existence of the two-way review system weakens the effects of reach on perceived social benefits and of richness on perceived informational privacy risks.Originality/valueThe present study investigates the two-way review system as the intervention of platforms to protect the service providers. Also, the emphasis is on the service providers rather than on consumers on sharing economy platforms to investigate their behavioral intention as customers on such platforms.

There are numerous opportunities for antimicrobial stewardship programs (ASPs) to utilize technology to maximize their impact on patient care. Herein we describe different technology platforms, strengths and limitations of each, and provide some examples of their use in clinical settings. Electronic medical record (EMR) upgrades and clinical decision support tools can enhance existing stewardship functions such as audit and feedback, de-escalation, “time-outs” among others. Antimicrobial utilization and resistance data reporting enables a deeper understanding of local trends in the context of benchmarked national data. User-friendly smartphone apps are prescriber-oriented platforms which house stewardship guidelines, antibiograms, and other information which can potentially reach thousands of prescribers. Finally, harnessing social media platforms can increase the visibility of stewardship and infection prevention research. There are multiple options for consuming stewardship technology, from free social media and online resources to costly EMR upgrades and clinical decision support tools. There are multiple benefits to incorporating technology into daily stewardship operations, but costs, design, and implementation challenges must be considered. Stewardship programs should evaluate the strengths and limitations of each type of technology to understand which will best suit their needs and goals.

Background Pre-exposure prophylaxis for COVID-19 with tixagevimab/cilgavimab (T/C) received Emergency Use Authorization (EUA) based on results of a clinical trial conducted prior to the emergence of the Omicron variant. The clinical effectiveness of T/C has not been well described in the Omicron era. We examined the incidence of symptomatic illness and hospitalizations among T/C recipients when Omicron accounted for virtually all local cases. Methods Through retrospective electronic medical record chart review, we identified patients who received T/C between January 1 –July 31, 2022 within our quaternary referral health system. We determined the incidence of symptomatic COVID-19 infections and hospitalizations due to or presumed to be caused by early Omicron variants before and after receiving T/C (pre-T/C and post-T/C). Chi square and Mann-Whitney Wilcoxon two-sample tests were used to examine differences between the characteristics of those who got COVID-19 before or after T/C prophylaxis, and rate ratios (RR) and 95% confidence intervals (CI) were calculated to assess differences in hospitalization rates for the two groups. Results Of 1295 T/C recipients, 105 (8.1%) developed symptomatic COVID-19 infection before receiving T/C, and 102 (7.9%) developed symptomatic disease after receiving it. Of the 105 patients who developed symptomatic infection pre-T/C, 26 (24.8%) were hospitalized, compared with six of the 102 patients (5.9%) who were diagnosed with COVID-19 post-T/C (RR = 0.24; 95% CI = 0.10–0.55; p = 0.0002). Seven of the 105 (6.7%) patients infected pre-T/C, but none of the 102 infected post-T/C required ICU care. No COVID-related deaths occurred in either group. The majority of COVID-19 cases among those infected pre-T/C treatment occurred during the Omicron BA.1 surge, while the majority of post-T/C cases occurred when Omicron BA.5 was predominant. In both groups, having at least one dose of vaccine strongly protected against hospitalization (pre-T/C group RR = 0.31, 95% CI = 0.17–0.57, p = 0.02; post-T/C group RR = 0.15; 95% CI = 0.03–0.94; p = 0.04). Conclusion We identified COVID-19 infections after T/C prophylaxis. Among patients who received T/C at our institution, COVID-19 Omicron cases occurring after T/C were one-fourth as likely to require hospitalization compared to those with Omicron prior to T/C. However, due to the presence of changing vaccine coverage, multiple therapies, and changing variants, the effectiveness of T/C in the Omicron era remains difficult to assess.

The Nation’s Report Card reveals that lower performing students exhibited greater achievement decline than their average/high performing peers based on 2022 long-term trend mathematics assessments for age 9 students. Technology including computer-assisted instruction plays an important role in today’s dynamic learning environments. Currently, there is a lack of computer-assisted intervention programs that systematically teach generalized word problem-solving skills that is driven by mathematical models. Model-based problem solving (MBPS) is one of the essential emphases in the Common Core mathematical practice standards. This study investigated the effects of a web-based computer tutor, MBPS, on enhancing word problem-solving performance of elementary students who are struggling in mathematics. The MBPS tutor incorporates best practices that are identified by the Institute of Educational Sciences’ (IES) latest practice guide including providing systematic instruction, visual and verbal supports, and teaching of precise mathematical language. Findings indicate that the MBPS tutor boosted participants’ performance above and beyond the business-as-usual comparison group.

The microbiota generates diverse metabolites that can engage multiple pathways to modulate host physiology and disease, but their protein targets and mechanism(s) of action have not been fully elucidated. To address this challenge, we focused on indole-3-acetic acid (IAA), a prominent microbiota metabolite, and developed IAA-based chemical reporters for proteomic studies. We discovered that IAA interacts with many proteins in host cells, including small-molecule transporters, receptors and metabolic enzymes. Notably, our functional studies revealed that IAA binds to orphan G protein-coupled receptors such as GPRC5A, but only aromatic monoamines were capable of inducing GPRC5A signaling. Functional profiling of microbiota uncovered specific bacterial species and enzymes that generate GPRC5A agonists. Finally, biochemical characterization of GPRC5A activation identified more potent synthetic agonists as well as key amino acid residues involved in ligand binding. These studies highlight the utility of chemoproteomics to dissect protein targets and mechanisms of action for microbiota metabolites.

BACKGROUND Medulloblastoma (MB) is the most common pediatric brain tumor. MB can be dividing into 4 genetically distinct subgroups (Sonic Hedgehog (SHH), Wingless (WNT), Group 3, and Group 4). Most patients receive radiation and cisplatin backbone therapy. SHH and Group3 patients demonstrate poor prognosis, especially in cases of MYC amplification or p53 mutation. Given the continued reliance on DNA damage therapies, and our groups previous findings that YB1 regulates IGF2 transcription in SHH MB, we chose to investigate the role of YB1 in the DNA damage response and we performed RIPseq to understand mRNAs regulated by YB1 that may be targeted as novel therapeutics. METHODS Cell lines include primary MBCs derived from NeuroD2-SmoA1 SHH mice, ONS-76 human SHH, Daoy human SHH, D341 and D425 Human Group 3. YB1 overexpression or knockdown followed by radiation and assessment of yH2AX (a marker of DNA de-condensation following damage), Comet assay (a marker of physical damage), and proliferation time courses were used to assess effects of YB1 modulation on radiation response. RIPseq and YB1 knockdown were used to assess the effects of YB1 on PLXND1 levels. Scratch assay and western blotting of EMT markers were used to assess effects of PLXND1 silencing on migration. RESULTS (Radiation Studies) Overexpression of YB1 in primary MBCs followed by allograft into BL6 mice results in decreased overall survival. YB1 silencing followed by radiation results in faster resolution of yH2AX, faster resolution of damage, and lack of pRPA32 accumulation. YB1 silencing sensitizes cells to radiation resulting in substantial decreases in proliferation. (RNA Binding Protein Studies) YB1 binds and positively regulates PLXND1 translation. Silencing PLXND1 results in decreased migration and EMT mark expression. CONCLUSIONS YB1 drives a more error prone non-homologous End-Joining based mechanism of repair and binds and regulates PLXND1 post-transcriptionally. PLXND1 drives a migratory phenotype in SHH MB.

INTRODUCTION AND OBJECTIVE:Ideal length of neoadjuvant chemotherapy (NAC) before cystectomy for muscle-invasive bladder cancer (MIBC) is uncertain. Trials initially studied 3 cycles, but 4 cycles a...

Enterococcus faecium is a ubiquitous Gram-positive bacterium that has been recovered from the environment, food, and microbiota of mammals. Commensal strains of E. faecium can confer beneficial effects on host physiology and immunity, but antibiotic usage has afforded antibiotic-resistant and pathogenic isolates from livestock and humans. However, the dissection of E. faecium functions and mechanisms has been restricted by inefficient gene-editing methods. To address these limitations, here, we report that the expression of E. faecium RecT recombinase significantly improves the efficiency of recombineering technologies in both commensal and antibiotic-resistant strains of E. faecium and other Enterococcus species such as E. durans and E. hirae. Notably, the expression of RecT in combination with clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 and guide RNAs (gRNAs) enabled highly efficient scarless single-stranded DNA recombineering to generate specific gene-editing mutants in E. faecium. Moreover, we demonstrate that E. faecium RecT expression facilitated chromosomal insertions of double-stranded DNA templates encoding antibiotic-selectable markers to generate gene deletion mutants. As a further proof of principle, we use CRISPR-Cas9-mediated recombineering to knock out both sortase A genes in E. faecium for downstream functional characterization. The general RecT-mediated recombineering methods described here should significantly enhance genetic studies of E. faecium and other closely related species for functional and mechanistic studies. IMPORTANCE Enterococcus faecium is widely recognized as an emerging public health threat with the rise of drug resistance and nosocomial infections. Nevertheless, commensal Enterococcus strains possess beneficial health functions in mammals to upregulate host immunity and prevent microbial infections. This functional dichotomy of Enterococcus species and strains highlights the need for in-depth studies to discover and characterize the genetic components underlying its diverse activities. However, current genetic engineering methods in E. faecium still require passive homologous recombination from plasmid DNA. This involves the successful cloning of multiple homologous fragments into a plasmid, introducing the plasmid into E. faecium, and screening for double-crossover events that can collectively take up to multiple weeks to perform. To alleviate these challenges, we show that RecT recombinase enables the rapid and efficient integration of mutagenic DNA templates to generate substitutions, deletions, and insertions in the genomic DNA of E. faecium. These improved recombineering methods should facilitate functional and mechanistic studies of Enterococcus.

Postmastectomy pain syndrome (PMPS) or breast conservation surgery (BCS) pain syndrome could be long-term and lead to disability and impairment on body and social function. The pain syndromes are not uncommon in breast cancer patients. It can affect social, psychological, physical and behavioral aspects of a patient. Surgery, radiation, chemotherapy and psychological factors can all contribute to the development of pain syndromes. Axillary dissection is a strong predictor for pain development. Pain medications, ganglion blocks are typically given to the patient for management. Integrative medicine such as acupuncture and psychological management methods are promising modalities in the management arsenal. In this study, we summarized the up-to-date literature to elucidate the etiology, risk factors and management strategies for PMPS.

There is currently a lack of level 1 evidence regarding the relative efficacy of radical prostatectomy compared with radiotherapy combined with androgen deprivation therapy for high-risk prostate cancer. There has recently been an improved optimization of treatment, achieving superior biochemical outcomes and cancer-specific mortality through the use of combined modality therapy strategies. Combined modality therapies have also increasingly incorporated brachytherapy boost. Although available observational data must be interpreted with caution because of the effects of potential residual confounding, we present here a narrative review of recent advances in understanding the relative efficacy of the principal combined modality approaches for treating high-risk prostate cancer. As the trend has demonstrated approaching equivalence between well-selected combined modality therapies, an increasing emphasis should be placed on selecting therapy tailored toward a patient's goals regarding quality of life. We present here an outline of efforts to date to understand the implications of treatment on functional outcomes and quality-of-life endpoints.