As a fundamental component of the host cellular cytoskeleton, actin is routinely engaged by infecting viruses. Furthermore, viruses from diverse groups, and infecting diverse hosts, have convergently evolved an array of mechanisms for manipulating the actin cytoskeleton for efifcacious infection. An ongoing chorus of research now indicates that the actin cytoskeleton is critical for viral replication at many stages of the viral life cycle, including binding, entry, nuclear localization, genomic transcription and reverse transcription, assembly, and egress/dissemination. Speciifcally, viruses subvert the force-generating and macromolecular scaffolding properties of the actin cytoskeleton to propel viral surifng, internalization, and migration within the cell. Additionally, viruses utilize the actin cytoskeleton to support and organize assembly sites, and eject budding virions for cell-to-cell transmission. It is the purpose of this review to provide an overview of current research, focusing on the various mechanisms and themes of virus-mediated actin modulation described therein.

Cardiac arrhythmias occur in a wide variety of conditions where increased intracellular Ca2+ is known to occur, including myocardial ischemia, cardiac glycoside toxicity, congestive heart failure, and excessive prolongation of action potential duration. The multifunctional Ca2+/calmodulin dependent protein kinaseⅡ(CaM kinase) is an important physiologic target for intracellular Ca2+ and regulates key control points for intracellular Ca2+ homeostasis, including L-type Ca2+ current, release and uptake of Ca2+ from the sarcoplasmic reticulum. Since CaM kinase is uniquely positioned to affect Ca2+ sensitive ionic currents and resultant arrhythmias, CaM kinase may also be an effective antiarrhythmic drug target. The transient inward current (Iti) triggers delayed afterdepolarizations, which are a likely cause of Ca2+ overload arrhythmias. The identity of Iti is controversial, but appears to result from different ionic currents depending on the experimental conditions. These currents are likely activated by intracellular Ca2+ because Iti always follows excessive intracellular Ca2+ concentrations (［Ca2+］i). The studies from our laboratory indicate that three different ［Ca2+］i sensitive currents, which could contribute to Iti, are present in rabbit ventricular myocytes. These currents are the Na+/Ca2+ exchanger, the Ca2+ activated Cl- current, and the Ca2+ activated non-selective cation current. We also found that Iti was suppressed by CaM kinase inhibitory peptides in the presence of physiologic solutions. These data support the hypothesis: CaM kinase can augment Iti during clinically relevant conditions, which are associated with increased ［Ca2+］i, and thus act as a proarrhythmic signaling molecule.

Objective:To investigate the expression of endoplasmic reticulum stress proteins in photoreceptor apoptosis in light-induced retinal degeneration. Methods: Exposure to excessive levels of light induced photoreceptor apoptosis and had been previously used as a model for the study of retinal degeneration. Photoreceptor apoptosis was detected by terminal dUTP transferase nick end labeling (TUNEL). The protein expression levels of ER stress sensors including glucose-regulated protein-78 (GRP78/BiP), caspase-12, phospho-eukaryotic initiation factor 2? (eIF2?) and phospho-double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK) were examined by immuno-fluorescence and Western blot analysis. Results: Following light exposure, the protein expression levels of GRP78/BiP, caspase-12, phospho-eIF2? and phospho-PERK were up-regulated in a time dependent manner. The up-regulation of these proteins coincided with or preceded the photoreceptor apoptosis. At the peak of their expression, they were mainly located in the photoreceptor inner segments and/or outer nuclear layers (ONL). Conclusion: Activation of endoplasmic reticulum stress proteins appears to play an important role in light-induced retinal degeneration. Therefore endoplasmic reticulum stress modulators could become a strong candidate for a therapeutic agent in treatment of these diseases.

Purpose: Outpatient classified total hip arthroplasty (THA) is a safe option for a select group of patients. An analysis of a national database was conducted to understand the risk factors for unplanned discharge to a skilled nursing facility (SNF) or acute rehabilitation (rehab) after outpatient classified THA. Materials and Methods: A query of the National Surgical Quality Improvement Program (NSQIP) database for THA (Current Procedural Terminology [CPT] 27130) performed from 2015 to 2018 was conducted. Patient demographics, American Society of Anesthesiologists (ASA) classification, functional status, NSQIP morbidity probability, operative time, length of stay (LOS), 30-day reoperation rate, readmission rate, and associated complications were collected. Results: A total of 2,896 patients underwent outpatient classified THA. The mean age of patients was 61.2 years. The mean body mass index (BMI) was 29.6 kg/m 2 with median ASA 2. The results of univariate comparison of SNF/rehab versus home discharge showed that a significantly higher percentage of females (58.7% vs. 46.8%), age >70 years (49.3% vs. 20.9%), ASA ≥3 (58.0% vs. 25.8%), BMI >35 kg/m 2 (23.3% vs. 16.2%), and hypoalbuminemia (8.0% vs. 1.5%) (P<0.0001) were discharged to SNF/rehab. The results of multivariable logistic regression showed that female sex (odds ratio [OR] 1.47; P=0.03), age >70 years (OR 3.08; P=0.001), ASA≥3 (OR 2.56; P=0.001), and preoperative hypoalbuminemia (<3.5 g/dL) (OR 3.76; P=0.001) were independent risk factors for SNF/rehab discharge. Conclusion Risk factors associated with discharge to a SNF/rehab after outpatient classified THA were identified. Surgeons will be able to perform better risk stratification for patients who may require additional postoperative intervention.

The adapter protein Lamellipodin (Lpd) plays an important role in cell migration. In particular, Lpd mediates lamellipodia formation by regulating actin dynamics via interacting with Ena/VASP proteins. Its RA-PH tandem domain configuration suggests that like its paralog RIAM, Lpd may also mediate particular Ras GTPase signaling. We determined the crystal structures of the Lpd RA-PH domains alone and with an N-terminal coiled-coil region (cc-RA-PH). These structures reveal that apart from the anticipated coiled-coil interaction, Lpd may also oligomerize through a second intermolecular contact site. We then validated both oligomerization interfaces in solution by mutagenesis. A fluorescence-polarization study demonstrated that Lpd binds phosphoinositol with low affinity. Based on our crystallographic and biochemical data, we propose that Lpd and RIAM serve diverse functions: Lpd plays a predominant role in regulating actin polymerization, and its function in mediating Ras GTPase signaling is largely suppressed compared to RIAM.
Actins ; metabolism ; Amino Acid Sequence ; Binding Sites ; Carrier Proteins ; chemistry ; genetics ; metabolism ; Crystallography, X-Ray ; Humans ; Membrane Proteins ; chemistry ; genetics ; metabolism ; Molecular Sequence Data ; Mutagenesis ; Phosphatidylinositols ; metabolism ; Polymerization ; Protein Binding ; Protein Structure, Tertiary ; Recombinant Proteins ; biosynthesis ; chemistry ; genetics ; Signal Transduction ; ras Proteins ; metabolism

Purpose: The number of obese patients seeking total hip arthroplasty (THA) continues to expand despite body mass index (BMI) cutoffs. We sought to determine the outcomes of THA in the morbidly obese patient, and hypothesized they would have comparable outcomes to two cohorts of obese, and normal weight patients. Materials and Methods: THA performed on morbidly obese patients (BMI >40 kg/m2 ) at a single academic center from 2010 until 2020 were retrospectively reviewed. Eighty morbidly obese patients were identified, and matched in a 1:3:3 ratio to control cohorts with BMI 30-40 kg/m2 and BMI <30 kg/m2 . Acute postoperative outcomes and BMI change after surgery were evaluated for clinical significance with univariate and regression analyses. Cox proportional hazard ratio was calculated to evaluate prosthetic joint infection (PJI) and revision surgery through follow-up. Mean follow-up was 3.9 years. Results: In the acute postoperative period, morbidly obese patients trended towards increased hospital length of stay, facility discharge and 90-day hospital returns. At final follow-up, a higher percentage of morbidly obese patients had clinically significant (>5%) BMI loss; however, this was not significant. Cox hazard ratio with BMI <30 kg/m 2 as a reference demonstrated no significant difference in survival to PJI and all-cause revision in the morbidly obese cohort. Conclusion Morbidly obese patients (BMI >40 kg/m2 ) require increased resource expenditure in the acute postoperative period. However, they are not inferior to the control cohorts (BMI <30 kg/m2 , BMI 30-40 kg/m2 ) in terms of PJI or all-cause revisions at mid-term follow-up.

Asthma ; complications ; therapy ; Humans ; Invasive Pulmonary Aspergillosis ; complications ; drug therapy ; Male ; Middle Aged ; Pulmonary Disease, Chronic Obstructive ; complications ; therapy

The human Gadd45 protein family plays critical roles in DNA repair, negative growth control, genomic stability, cell cycle checkpoints and apoptosis. Here we report the crystal structure of human Gadd45γ [corrected], revealing a unique dimer formed via a bundle of four parallel helices, involving the most conserved residues among the Gadd45 isoforms. Mutational analysis of human Gadd45γ [corrected] identified a conserved, highly acidic patch in the central region of the dimer for interaction with the proliferating cell nuclear antigen (PCNA), p21 and cdc2, suggesting that the parallel dimer is the active form for the interaction. Cellular assays indicate that: (1) dimerization of Gadd45γ [corrected] is necessary for apoptosis as well as growth inhibition, and that cell growth inhibition is caused by both cell cycle arrest and apoptosis; (2) a conserved and highly acidic patch on the dimer surface, including the important residues Glu87 and Asp89, is a putative interface for binding proteins related to the cell cycle, DNA repair and apoptosis. These results reveal the mechanism of self-association by Gadd45 proteins and the importance of this self-association for their biological function.
Amino Acid Motifs ; Animals ; Apoptosis ; radiation effects ; CDC2 Protein Kinase ; Cell Cycle ; Cell Survival ; Crystallography, X-Ray ; Cyclin B ; metabolism ; Cyclin-Dependent Kinase Inhibitor p21 ; metabolism ; Cyclin-Dependent Kinases ; HeLa Cells ; Humans ; Intracellular Signaling Peptides and Proteins ; chemistry ; genetics ; metabolism ; Mice ; Mutagenesis, Site-Directed ; Mutation, Missense ; Proliferating Cell Nuclear Antigen ; metabolism ; Protein Binding ; Protein Interaction Domains and Motifs ; Protein Multimerization ; Protein Structure, Quaternary ; Ultraviolet Rays

BACKGROUND/AIMS: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) remains the most common EUS-guided tissue acquisition technique. This study aimed to evaluate the performance of a new Franseen tip fine needle biopsy (FNB) device for EUSguided sampling of solid lesions and compare it with the historical FNA technique. METHODS: Acquire® 22 G FNB needle (Boston Scientific Co., Natick, MA, USA) was used for solid tumor sampling (Study group). Tissue was collected for rapid on-site evaluation, and touch and crush preparations were made. Historical EUS-FNA samples obtained using Expect® 22 G FNA needle (Boston Scientific Co.) were used as controls (Control group). All specimens were independently evaluated by two cytopathologists blinded to the formal cytopathological diagnosis. RESULTS: Mean cell block histology scores were significantly higher (p=0.046) in the FNB group (51 samples) despite a significantly lower (p < 0.001) mean number of passes compared to the FNA group (50 specimens). The overall diagnostic yields for the FNB vs. FNA groups were 96% vs. 88%. The degree of tumor differentiation was adequately assessed in all cell block qualifying lesions in the FNB group. Two patients developed post-FNB abdominal pain. CONCLUSIONS: The new Franseen tip FNB device provides histologically superior and cytologically comparable specimens to those obtained by FNA, but with fewer passes.
Abdominal Pain ; Biopsy, Fine-Needle* ; Diagnosis ; Endoscopic Ultrasound-Guided Fine Needle Aspiration ; Humans ; Needles ; Prospective Studies*

The prevalence of non-communicable diseases (NCDs) across the globe has reached epidemic proportions, with more than three quarters of NCD deaths now occurring in low- and middle-income countries (LMIC).1 NCDs encompass a broad range of chronic conditions, which include cardiovascular diseases, cancers, chronic respiratory diseases, diabetes, and mental disorders.2 To mitigate the growing global NCD burden and its associated challenges, upscaling high-impact essential interventions for the prevention and control of NCDs has remained a priority, especially in low-resource settings. One such intervention is strengthening self-care strategies or self-management of individuals living with NCDs.3 In the past few decades, the self-management approach to NCD has proven to be a cost-effective strategy to improve a patient’s quality of life by reducing symptom severity and decreasing pain. This approach has also encouraged patients to become key decision makers in the treatment process.4 Self-management includes both technological (e.g. smartphone applications, telemonitoring systems, or wearable devices) and non-technological interventions (social support, educational materials, or in-person training seminars).5 Telemedicine has played several important roles in the whole spectrum of care for patients with NCD. These include promotion of healthy behaviors, prevention of risk factors, prompt recognition and initiation of treatment, disease monitoring and follow-up, rehabilitation, and palliation. Telemedicine not only increases access to health care but also improves the quality of health care especially in rural areas.6 7 The unique challenges resulting from the COVID-19 pandemic has limited patient access to health care, especially in geographically isolated and disadvantaged areas. This literature review aims to determine the effectiveness of telemedicine on clinical and psychosocial outcomes of adult patients diagnosed with NCDs. We conducted a literature search on PubMed, EBSCOhost, ProQuest, Google Scholar, and Gale using the search words “telemedicine,” “adult,” “non-communicable disease,” “self-management,” and “teleconsultation.” We filtered the results to only include randomized controlled trials (RCT). To narrow down the scope of this literature review, only previous studies that compared telemedicine and usual care (non-telemedicine) among adults with non-communicable diseases, and those that report clinical and psychosocial outcomes—i.e., symptom outcomes, laboratory outcomes, knowledge on disease, or behavior outcomes that pertain to self-management of disease—were assessed. We excluded studies if they were done among patients <18 years old, if they included telemedicine that supplemented rather than replaced the usual (face-to-face) care, if they were not able to report outcomes between groups, or if they did not meet the criteria of a RCT. Two reviewers independently reviewed the abstracts yielded from the search strategy and assessed them based on the set criteria. If neither reviewer was able to rule out an article based on the abstract, the full text was retrieved and assessed to determine inclusion into the study. After the final assessment, a total of 9 RCT reports were included in this review. The general characteristics and key findings of the 9 studies included in this literature review are summarized in Table 1. The included studies, published in various journals between 2014 and 2021, were carried out in eight countries—two studies were done in Australia, and one each in Bangladesh, India, Italy, USA, Germany, China, and the Netherlands. The studies enrolled patients who were diagnosed with type 2 diabetes mellitus (DM) (n=3), chronic obstructive pulmonary disease (n=1), type 1 DM (n=1), congestive heart failure (n=1), stroke (n=1), osteoarthritis (n=1), and various non-specific chronic conditions, including type 2 DM, hypertension, coronary artery diseases, heart failure, chronic depression, and schizophrenia (n=1). The sample sizes of the studies included ranged from 29 to 10,815 participants. Follow-up periods ranged from 3 to 36 months. The telemedicine techniques that were used in the studies included mobile phone-based health interventions, telemedicine-based visits, and telephone-based health coaching. In general, most of the studies included in this review reported that telemedicine is as good as, if not better than, usual care approaches in achieving clinical and psychosocial outcomes.
Noncommunicable Diseases ; Chronic Disease