CD81 Controls Beige Fat Progenitor Cell Growth and Energy Balance via FAK Signaling.

Adipose tissues dynamically remodel their cellular composition in response to external cues by stimulating beige adipocyte biogenesis; however, the developmental origin and pathways regulating this process remain insufficiently understood owing to adipose tissue heterogeneity. Here, we employed single-cell RNA-seq and identified a unique subset of adipocyte progenitor cells (APCs) that possessed the cell-intrinsic plasticity to give rise to beige fat. This beige APC population is proliferative and marked by cell-surface proteins, including PDGFRα, Sca1, and CD81. Notably, CD81 is not only a beige APC marker but also required for de novo beige fat biogenesis following cold exposure. CD81 forms a complex with αV/ß1 and αV/ß5 integrins and mediates the activation of integrin-FAK signaling in response to irisin. Importantly, CD81 loss causes diet-induced obesity, insulin resistance, and adipose tissue inflammation. These results suggest that CD81 functions as a key sensor of external inputs and controls beige APC proliferation and whole-body energy homeostasis.

PTP1B mediates the inhibitory effect of MFGE8 on insulin signaling through the ß5 integrin.

Integrins are cell adhesion receptors that dimerize to mediate cell-cell interactions and regulate processes, including proliferation, inflammation, and tissue repair. The role of integrins in regulating insulin signaling is incompletely understood. We have previously shown that binding of the integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) to the αvß5 integrin promotes termination of insulin receptor signaling in mice. Upon ligation of MFGE8, integrin ß5 complexes with the insulin receptor beta (IRß) in skeletal muscle, resulting in dephosphorylation of IRß and reduction of insulin-stimulated glucose uptake. Here, we investigate the mechanism by which the interaction between ß5 and IRß impacts IRß phosphorylation status. We show in in vitro and in vivo in skeletal muscle in mice that antibody-mediated blockade of the ß5 integrin inhibits and recombinant MFGE8 promotes PTP1B binding to and dephosphorylation of IRß resulting in increased or reduced insulin-stimulated glucose uptake, respectively. The ß5-PTP1B complex is recruited by MFGE8 to IRß leading to termination of canonical insulin signaling. ß5 blockade enhances insulin-stimulated glucose uptake in wildtype but not Ptp1b KO mice indicating that PTP1B functions downstream of MFGE8 in modulating insulin receptor signaling. Furthermore, in a human cohort, we report serum MFGE8 levels correlate with indices of insulin resistance. These data provide mechanistic insights into the role of MFGE8 and ß5 in regulating insulin signaling.

Autoregulation of insulin receptor signaling through MFGE8 and the αvß5 integrin.

The role of integrins, in particular αv integrins, in regulating insulin resistance is incompletely understood. We have previously shown that the αvß5 integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) regulates cellular uptake of fatty acids. In this work, we evaluated the impact of MFGE8 on glucose homeostasis. We show that acute blockade of the MFGE8/ß5 pathway enhances while acute augmentation dampens insulin-stimulated glucose uptake. Moreover, we find that insulin itself induces cell-surface enrichment of MFGE8 in skeletal muscle, which then promotes interaction between the αvß5 integrin and the insulin receptor leading to dampening of skeletal-muscle insulin receptor signaling. Blockade of the MFGE8/ß5 pathway also enhances hepatic insulin sensitivity. Our work identifies an autoregulatory mechanism by which insulin-stimulated signaling through its cognate receptor is terminated through up-regulation of MFGE8 and its consequent interaction with the αvß5 integrin, thereby establishing a pathway that can potentially be targeted to improve insulin sensitivity.

Optical Control of Slow Topological Electrons in Moiré Systems.

Floquet moiré materials possess optically-induced flat-electron bands with steady-states sensitive to drive parameters. Within this regime, we show that strong interaction screening and phonon bath coupling can overcome enhanced drive-induced heating. In twisted bilayer graphene (TBG) irradiated by a terahertz-frequency continuous circularly polarized laser, the extremely slow electronic states enable the drive to control the steady state occupation of high-Berry curvature electronic states. In particular, above a critical field amplitude, high-Berry-curvature states exhibit a slow regime where they decouple from acoustic phonons, allowing the drive to control the anomalous Hall response. Our work shows that the laser-induced control of topological and transport physics in Floquet TBG are measurable using experimentally available probes.

Control becomes habitual early on when learning a novel motor skill.

When people perform the same task repeatedly, their behavior becomes habitual, or inflexible to changes in the goals or structure of a task. Although habits have been hypothesized to be a key aspect of motor skill acquisition, there has been little empirical work investigating the relationship between skills and habits. To better understand this relationship, we examined whether and when people's behavior would become habitual as they learned a challenging new motor skill: maneuvering an on-screen cursor with a nonintuitive bimanual mapping from hand to cursor position. After participants practiced using this mapping for up to 10 days, we altered the mapping between the hands and the cursor to assess whether participants could flexibly adjust their behavior or would habitually persist in performing the task the way they had originally learned. We found that participants' behavior became habitual within 2 days of practice, at which point they were still relatively unskilled. Further practice led to improved skill but did not alter the strength of habitual behavior. These data demonstrate that motor skills become habitual after relatively little training but can nevertheless further improve with practice. We suggest that building habits early in learning may be a crucial step in acquiring new motor skills.NEW & NOTEWORTHY Habits and motor skills have often been thought to be deeply related, but very few studies have empirically examined the relationship between the two. We present evidence that habits emerge early in learning, long before a motor skill has been fully learned. Our results suggest that habits may play an integral role in the learning and performance of motor skills from even the early stages of acquiring a new skill.

De novo motor learning of a bimanual control task over multiple days of practice.

Although much research on motor learning has focused on how we adapt our movements to maintain performance in the face of imposed perturbations, in many cases, we must learn new skills from scratch or de novo. Compared with adaptation, relatively little is known about de novo learning. In part, this is because learning a new skill can involve many challenges, including learning to recognize new patterns of sensory input and generate new patterns of motor output. However, even with familiar sensory cues and well-practiced movements, the problem of quickly selecting the appropriate actions in response to the current state is challenging. Here, we devised a bimanual hand-to-cursor mapping that isolates this control problem. We find that participants initially struggled to control the cursor under this bimanual mapping, despite explicit knowledge of the mapping. Performance improved steadily over multiple days of practice, however. Participants exhibited no aftereffects when reverting to a veridical cursor, confirming that participants learned the new task de novo, rather than through adaptation. Corrective responses to mid-movement perturbations of the target were initially weak, but with practice, participants gradually became able to respond rapidly and robustly to perturbations. After 4 days of practice, participants' behavior under the bimanual mapping almost matched performance using a veridically mapped cursor. However, there remained a small but persistent difference in performance level. Our findings illustrate the dynamics and limitations of learning a novel controller and introduce a promising paradigm for tractably investigating this aspect of motor skill learning.NEW & NOTEWORTHY We examine motor learning in a novel task in which participants must use both hands to control an on-screen cursor via a nonintuitive interface. Participants gradually improved their ability to control the cursor over multiple practice sessions, but their control was worse than baseline even after 4 days. These results reveal the timescale and limitations of de novo learning-an important but understudied form of learning.

Ultrasound-assisted ocular drug delivery: A review of current evidence.

Efficient ocular drug delivery is a challenging clinical problem with various therapeutic options but no clearly preferred methodology. Given the ubiquity of ultrasound as a diagnostic technique, the safety profile of ultrasound in an ocular context, and the prospect of custom-made ultrasound-sensitive contrast agents, ultrasound presents an attractive ocular drug delivery modality. In this review, we evaluate our present understanding of ultrasound as it relates to ocular drug delivery and significant knowledge gaps in the field. In doing so, we hope to call attention to a potentially novel drug delivery pathway that could be manipulated to treat or cure ocular diseases.

Connectedness Based on Shared Engagement Predicts Remote Biochemically Verified Quit Status Within Smoking Cessation Treatment Groups on Facebook.

INTRODUCTION: Engagement with online content and online social network integration are associated with smoking behavior change, but less is known about social dynamics of shared engagement between participants in group-based social media interventions. METHODS: Participants were 251 young adult smokers aged 18 to 25 assigned to one of 29 secret Facebook groups tailored to their readiness to quit smoking ("pre-contemplation," "contemplation," and "preparation"). Groups varied in size and were randomly assigned to receive monetary incentives for engagement. All groups received daily posts for 90 days and were assessed for remote biochemically verified smoking abstinence at the end of the intervention. Across 29 groups, we examined associations between group features (group size, incentive condition, readiness to quit) with how connected members were within the group based on shared engagement with the same content (measured by density). At the individual level, we examined associations between 7-day biochemically verified smoking abstinence and how connected an individual was within the group (measured by degree centrality). RESULTS: After adjusting for comment volume, being in a contemplation group (vs. pre-contemplation group) was associated with a decrease in comment-based density. Individual degree centrality was significantly associated with biochemically verified smoking abstinence for both comments and likes. CONCLUSIONS: Future group-based social media interventions for smoking cessation may want to focus on promoting connected engagement between participants, rather than simply quantity of engagement. IMPLICATIONS: Participants in a smoking cessation intervention delivered through Facebook groups were more likely to have biochemically verified smoking abstinence if they were more connected to the rest of the group via shared engagement. Promoting shared engagement between participants may be more likely to promote behavior change than volume of engagement alone.

Identifying Self-Management Support Needs for Pregnant Women With Opioid Misuse in Online Health Communities: Mixed Methods Analysis of Web Posts.

BACKGROUND: The current opioid crisis in the United States impacts broad population groups, including pregnant women. Opioid use during pregnancy can affect the health and wellness of both mothers and their infants. Understanding women's efforts to self-manage opioid use or misuse in pregnancy is needed to identify intervention points for improving maternal outcomes. OBJECTIVE: This study aims to identify the characteristics of women in an online health community (OHC) with opioid use or misuse during pregnancy and the self-management support needs of these mothers. METHODS: A total of 200 web posts by pregnant women with opioid use participating in an OHC were double coded. Concepts and their thematic connections were identified through an inductive process until theoretical saturation was reached. Statistical tests were performed to identify patterns. RESULTS: The majority of pregnant women (150/200, 75.0%) in the OHC exhibited signs of misuse, and 62.5% (125/200) of the participants were either contemplating or pursuing dosage reduction. Self-managed withdrawal was more common (P<.001) than professional treatment among the population. A total of 5 themes of self-management support needs were identified as women sought information about the potential adverse effects of gestational opioid use, protocols for self-managed withdrawal, pain management safety during pregnancy, hospital policies and legal procedures related to child protection, and strategies for navigating offline support systems. In addition, 58.5% (117/200) of the pregnant women expressed negative emotions, of whom only 10.2% (12/117) sought to address their emotional needs with the help of the OHC. CONCLUSIONS: OHCs provide vital self-management support for pregnant women with opioid use or misuse. Women pursuing self-managed dosage reduction are prone to misinformation and repeated relapses, which can result in extreme measures to avoid testing positive for drug use at labor. The study findings provide evidence for public policy considerations, including universal screening of substance use for pregnant women, emphasis on treatment rather than legal punishment, and further expansion of the Drug Addiction Treatment Act waiver training program. The improvement of web-based platforms that can organize geo-relevant information, dispense clinically validated withdrawal schedules, and offer structured peer support is envisioned for harm reduction among pregnant women who opt for self-management of opioid misuse.

Topics and Sentiments of Public Concerns Regarding COVID-19 Vaccines: Social Media Trend Analysis.

BACKGROUND: As a number of vaccines for COVID-19 are given emergency use authorization by local health agencies and are being administered in multiple countries, it is crucial to gain public trust in these vaccines to ensure herd immunity through vaccination. One way to gauge public sentiment regarding vaccines for the goal of increasing vaccination rates is by analyzing social media such as Twitter. OBJECTIVE: The goal of this research was to understand public sentiment toward COVID-19 vaccines by analyzing discussions about the vaccines on social media for a period of 60 days when the vaccines were started in the United States. Using the combination of topic detection and sentiment analysis, we identified different types of concerns regarding vaccines that were expressed by different groups of the public on social media. METHODS: To better understand public sentiment, we collected tweets for exactly 60 days starting from December 16, 2020 that contained hashtags or keywords related to COVID-19 vaccines. We detected and analyzed different topics of discussion of these tweets as well as their emotional content. Vaccine topics were identified by nonnegative matrix factorization, and emotional content was identified using the Valence Aware Dictionary and sEntiment Reasoner sentiment analysis library as well as by using sentence bidirectional encoder representations from transformer embeddings and comparing the embedding to different emotions using cosine similarity. RESULTS: After removing all duplicates and retweets, 7,948,886 tweets were collected during the 60-day time period. Topic modeling resulted in 50 topics; of those, we selected 12 topics with the highest volume of tweets for analysis. Administration and access to vaccines were some of the major concerns of the public. Additionally, we classified the tweets in each topic into 1 of the 5 emotions and found fear to be the leading emotion in the tweets, followed by joy. CONCLUSIONS: This research focused not only on negative emotions that may have led to vaccine hesitancy but also on positive emotions toward the vaccine. By identifying both positive and negative emotions, we were able to identify the public's response to the vaccines overall and to news events related to the vaccines. These results are useful for developing plans for disseminating authoritative health information and for better communication to build understanding and trust.

You Say You Want a Resolution (of Fibrosis).

In pathological fibrosis, aberrant tissue remodeling with excess extracellular matrix leads to organ dysfunction and eventual morbidity. Diseases of fibrosis create significant global health and economic burdens and are often deadly. Although fibrosis has traditionally been thought of as an irreversible process, a growing body of evidence demonstrates that organ fibrosis can reverse in certain circumstances, especially if an underlying cause of injury can be removed. This body of evidence has uncovered more and more contributors to persistent and nonresolving tissue fibrosis. Here, we review the present knowledge on resolution of organ fibrosis and restoration of near-normal tissue architecture. We emphasize three critical areas of tissue homeostasis that are necessary for fibrosis resolution, namely, the elimination of matrix-producing cells, the clearance of excess matrix, and the regeneration of normal tissue constituents. In so doing, we also highlight how profibrotic pathways interact with one another and where there may be therapeutic opportunities to intervene and remediate pathological persistent fibrosis.

Drug Repositioning to Accelerate Drug Development Using Social Media Data: Computational Study on Parkinson Disease.

BACKGROUND: Due to the high cost and low success rate in new drug development, systematic drug repositioning methods are exploited to find new indications for existing drugs. OBJECTIVE: We sought to propose a new computational drug repositioning method to identify repositioning drugs for Parkinson disease (PD). METHODS: We developed a novel heterogeneous network mining repositioning method that constructed a 3-layer network of disease, drug, and adverse drug reaction and involved user-generated data from online health communities to identify potential candidate drugs for PD. RESULTS: We identified 44 non-Parkinson drugs by using the proposed approach, with data collected from both pharmaceutical databases and online health communities. Based on the further literature analysis, we found literature evidence for 28 drugs. CONCLUSIONS: In summary, the proposed heterogeneous network mining repositioning approach is promising for identifying repositioning candidates for PD. It shows that adverse drug reactions are potential intermediaries to reveal relationships between disease and drug.

LysRS serves as a key signaling molecule in the immune response by regulating gene expression.

Lysyl-tRNA synthetase (LysRS) was found to produce diadenosine tetraphosphate (Ap(4)A) in vitro more than two decades ago. Here, we used LysRS silencing in mast cells in combination with transfected normal and mutated LysRS to demonstrate in vivo the critical role played by LysRS in the production of Ap(4)A in response to immunological challenge. Upon such challenge, LysRS was phosphorylated on serine 207 in a MAPK-dependent manner, released from the multisynthetase complex, and translocated into the nucleus. We previously demonstrated that LysRS forms a complex with MITF and its repressor Hint-1, which is released from the complex by its binding to Ap(4)A, enabling MITF to transcribe its target genes. Here, silencing LysRS led to reduced Ap(4)A production in immunologically activated cells, which resulted in a lower level of MITF inducible genes. Our data demonstrate that specific LysRS serine 207 phosphorylation regulates Ap(4)A production in immunologically stimulated mast cells, thus implying that LysRS is a key mediator in gene regulation.

The Malleable Implant Salvage Technique: Infection Outcomes after Mulcahy Salvage Procedure and Replacement of Infected Inflatable Penile Prosthesis with Malleable Prosthesis.

PURPOSE: Since its introduction in 1996 Mulcahy salvage has significantly improved outcomes for the removal and replacement of infected inflatable penile prostheses. Long-term followup data of Mulcahy salvage show an infection-free rate of 82%. A multicenter retrospective analysis of the malleable implant salvage technique was conducted to assess infection outcomes and the feasibility of conversion from malleable device back to inflatable penile prosthesis. MATERIALS AND METHODS: This is a retrospective, institutional review board exempt, multi-institution study of 58 patients who underwent Mulcahy salvage with inflatable penile prosthesis removal and replacement with malleable prosthesis. Patient operative notes and charts were extensively reviewed to compile study data. RESULTS: Between 2002 and 2014 a total of 58 patients underwent infected inflatable penile prosthesis removal and replacement with a malleable prosthesis via Mulcahy salvage. Of these patients 54 (93%) have remained infection-free postoperatively. Average patient age was 56.4 years and average operative time was 148 minutes. Postoperative followup (as of May 2015) ranged from 1 month to 84 months. Of the 54 patients 37 retained the malleable prosthesis and 17 (31%) subsequently underwent replacement with an inflatable penile prosthesis. This occurred on average 6.7 months after Mulcahy salvage. Four patients had persistent infection after Mulcahy salvage with the malleable prosthesis and underwent explantation. CONCLUSIONS: This retrospective analysis of Mulcahy salvage procedure and replacement of inflatable penile prosthesis with malleable prosthesis shows a high infection-free rate. Additionally, 17 of the 54 patients who remained infection-free were able to successfully undergo subsequent removal of the malleable prosthesis and replacement with an inflatable penile prosthesis. Further prospective studies are needed to compare salvage with malleable vs inflatable penile prosthesis.

Symptom clusters in women with breast cancer: an analysis of data from social media and a research study.

PURPOSE: User-generated content on social media sites, such as health-related online forums, offers researchers a tantalizing amount of information, but concerns regarding scientific application of such data remain. This paper compares and contrasts symptom cluster patterns derived from messages on a breast cancer forum with those from a symptom checklist completed by breast cancer survivors participating in a research study. METHODS: Over 50,000 messages generated by 12,991 users of the breast cancer forum on MedHelp.org were transformed into a standard form and examined for the co-occurrence of 25 symptoms. The k-medoid clustering method was used to determine appropriate placement of symptoms within clusters. Findings were compared with a similar analysis of a symptom checklist administered to 653 breast cancer survivors participating in a research study. RESULTS: The following clusters were identified using forum data: menopausal/psychological, pain/fatigue, gastrointestinal, and miscellaneous. Study data generated the clusters: menopausal, pain, fatigue/sleep/gastrointestinal, psychological, and increased weight/appetite. Although the clusters are somewhat different, many symptoms that clustered together in the social media analysis remained together in the analysis of the study participants. Density of connections between symptoms, as reflected by rates of co-occurrence and similarity, was higher in the study data. CONCLUSIONS: The copious amount of data generated by social media outlets can augment findings from traditional data sources. When different sources of information are combined, areas of overlap and discrepancy can be detected, perhaps giving researchers a more accurate picture of reality. However, data derived from social media must be used carefully and with understanding of its limitations.

Testosterone Therapy after Radiation Therapy for Low, Intermediate and High Risk Prostate Cancer.

PURPOSE: Limited literature exists regarding the safety of testosterone therapy in men treated for prostate cancer. We present multi-institutional data on testosterone therapy in hypogonadal men with prostate cancer treated with radiation therapy. MATERIALS AND METHODS: We retrospectively reviewed the records of hypogonadal men treated with testosterone therapy after radiation therapy for prostate cancer at 4 institutions. Serum testosterone, free testosterone, estradiol, sex hormone-binding globulin, prostate specific antigen, prostate specific antigen velocity and prostate biopsy findings were analyzed. RESULTS: A total of 98 men were treated with radiation therapy. Median age was 70.0 years (range 63.0 to 74.3) at initiation of testosterone therapy. Median baseline testosterone was 209 ng/dl (range 152 to 263) and median baseline prostate specific antigen was 0.08 ng/ml (range 0.00 to 0.33). In the cohort the tumor Gleason score was 5 in 3 men (3.1%), 6 in 44 (44.9%), 7 in 28 (28.6%), 8 in 7 (7.1%) and 9 in 4 (4.1%). Median followup was 40.8 months (range 1.5 to 147). Serum testosterone increased to a median of 420 ng/dl (range 231 to 711) during followup (p <0.001). Overall a nonsignificant increase in mean prostate specific antigen was observed from 0.08 ng/ml at baseline to 0.09 ng/ml (p = 0.05). Among patients at high risk prostate specific antigen increased from 0.10 to 0.36 ng/ml (p = 0.018). Six men (6.1%) met criteria for biochemical recurrence. CONCLUSIONS: Testosterone therapy in men following radiation therapy for prostate cancer was associated with a minor increase in serum prostate specific antigen and a low rate of biochemical recurrence.

Partial Priapism Treated with Pentoxifylline.

MAIN FINDINGS: A 26-year-old man suffering from partial priapism was successfully treated with a regimen including pentoxifylline, a nonspecific phosphodiesterase inhibitor that is often used to conservatively treat Peyronie's disease. CASE HYPOTHESIS: Partial priapism is an extremely rare urological condition that is characterized by thrombosis within the proximal segment of a single corpus cavernosum. There have only been 36 reported cases to date. Although several factors have been associated with this unusual disorder, such as trauma or bicycle riding, the etiology is still not completely understood. Treatment is usually conservative and consists of a non-steroidal anti-inflammatory and anti-thrombotic. Promising future implications: This case report supports the utilization of pentoxifylline in patients with partial priapism due to its anti-fibrogenic and anti-thrombotic properties.

Reduction corporoplasty.

OBJECTIVE: Here we present the first video demonstration of reduction corporoplasty in the management of phallic disfigurement in a 17 year old man with a history sickle cell disease and priapism. INTRODUCTION: Surgical management of aneurysmal dilation of the corpora has yet to be defined in the literature. MATERIALS AND METHODS: We preformed bilateral elliptical incisions over the lateral corpora as management of aneurysmal dilation of the corpora to correct phallic disfigurement. RESULTS: The patient tolerated the procedure well and has resolution of his corporal disfigurement. CONCLUSIONS: Reduction corporoplasty using bilateral lateral elliptical incisions in the management of aneurysmal dilation of the corpora is a safe an feasible operation in the management of phallic disfigurement.

Penile artery shunt syndrome: a novel cause of erectile dysfunction after penile revascularization surgery.

INTRODUCTION: Penile revascularization is a surgical treatment option for erectile dysfunction (ED) in healthy individuals due to a focal arterial occlusion in the absence of generalized vascular disease. Most described failures have been attributed to graft stenosis or disruption of the anastomosis. AIM: We report a novel phenomenon called Penile Artery Shunt Syndrome that contributed to persistent ED in a patient after penile microvascular arterial bypass surgery. METHODS: A 26-year-old man presented for evaluation of long-standing ED, which was attributed to trauma sustained 12 years earlier. He had difficulty obtaining and maintaining erections despite oral pharmacotherapy. Clinical data related to the case were studied, analyzed, and reviewed with urologic and radiologic specialists at multiple centers that collaborated in the care of this patient. MAIN OUTCOME MEASURES: Penile duplex ultrasound peak systolic velocities and five-item International Index for Erectile Function questionnaire scores were the main outcome measures. RESULTS: Initial diagnostic workup of the patient confirmed severe insufficiency of the left cavernosal artery, with no evidence of venous leak. The patient underwent penile microvascular arterial bypass surgery with anastomosis of the left inferior epigastric artery to the left dorsal penile artery. The patient had persistence of severe ED despite patent anastomosis by penile duplex ultrasound. Subsequent arteriography revealed an arterial shunt due to an aberrant obturator artery arising from the donor inferior epigastric artery. The patient underwent embolization of the aberrant obturator artery, with resolution of the shunt and marked improvement in erectile function. CONCLUSIONS: The presence of an aberrant obturator artery arising from the inferior epigastric artery may predispose to persistent ED after revascularization due to the creation of a shunt phenomenon. Pelvic arteriography may be useful in identifying anomalous anatomic considerations prior to penile revascularization and to evaluate patients with persistent postoperative ED.