TRAF4-mediated nonproteolytic ubiquitination of androgen receptor promotes castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) poses a major clinical challenge with the androgen receptor (AR) remaining to be a critical oncogenic player. Several lines of evidence indicate that AR induces a distinct transcriptional program after androgen deprivation in CRPCs. However, the mechanism triggering AR binding to a distinct set of genomic loci in CRPC and how it promotes CRPC development remain unclear. We demonstrate here that atypical ubiquitination of AR mediated by an E3 ubiquitin ligase TRAF4 plays an important role in this process. TRAF4 is highly expressed in CRPCs and promotes CRPC development. It mediates K27-linked ubiquitination at the C-terminal tail of AR and increases its association with the pioneer factor FOXA1. Consequently, AR binds to a distinct set of genomic loci enriched with FOXA1- and HOXB13-binding motifs to drive different transcriptional programs including an olfactory transduction pathway. Through the surprising upregulation of olfactory receptor gene transcription, TRAF4 increases intracellular cAMP levels and boosts E2F transcription factor activity to promote cell proliferation under androgen deprivation conditions. Altogether, these findings reveal a posttranslational mechanism driving AR-regulated transcriptional reprogramming to provide survival advantages for prostate cancer cells under castration conditions.

Trends in the Use of Recombinant Activated Factor VII and Prothrombin Complex Concentrate in Heart Transplant Patients in Virginia.

OBJECTIVES: To explore trends in intraoperative procoagulant factor concentrate use in patients undergoing heart transplantation (HTx) in Virginia. Secondarily, to evaluate their association with postoperative thrombosis. DESIGN: Patients who underwent HTx were identified using a statewide database. Trends in off-label recombinant activated factor VII (rFVIIa) use and on-label and off-label prothrombin complex concentrate (PCC) use were tested using the Mantel-Haenszel test. Multivariate logistic regression was used to test for an association between procoagulant factor concentrate administration and thrombosis. SETTING: Virginia hospitals performing HTx. PARTICIPANTS: Adults undergoing HTx between 2012 and 2022. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 899 patients who required HTx, 100 (11.1%) received off-label rFVIIa, 69 (7.7%) received on-label PCC, and 80 (8.9%) received off-label PCC. There was a downward trend in the use of rFVIIa over the 10-year period (p = 0.04). There was no trend in on-label PCC use (p = 0.12); however, there was an increase in off-label PCC use (p < 0.001). Patients who received rFVIIa were transfused more and had longer cardiopulmonary bypass time (p < 0.001). Receipt of rFVIIa was associated with increased thrombotic risk (odds ratio [OR] 1.92; 95% CI 1.12-3.29; p = 0.02), whereas on-label and off-label PCC use had no association with thrombosis (OR 0.98, 95% CI 0.49-1.96, p = 0.96 for on-label use; and OR 0.61, 95% CI 0.29-1.30, p = 0.20 for off-label use). CONCLUSIONS: Use of rFVIIa in HTx decreased over the past decade, whereas off-label PCC use increased. Receipt of rFVIIa was associated with thrombosis; however, patients who received rFVIIa were more severely ill, and risk adjustment may have been incomplete.

Hydrogenated TiO2 Carbon Support for PtRu Anode Catalyst in High-Performance Anion-Exchange Membrane Fuel Cells.

The availability of durable, high-performance electrocatalysts for the hydrogen oxidation reaction (HOR) is currently a constraint for anion-exchange membrane fuel cells (AEMFCs). Herein, a rapid microwave-assisted synthesis method is used to develop a core-shell catalyst support based on a hydrogenated TiO2 /carbon for PtRu nanoparticles (NPs). The hydrogenated TiO2 provides a strong metal-support interaction with the PtRu NPs, which improves the catalyst's oxophilicity and HOR activity compared to commercial PtRu/C and enables greater size control of the catalyst NPs. The as-synthesized PtRu/TiO2 /C-400 electrocatalyst exhibits respectable performance in an AEMFC operated at 80 °C, yielding the highest current density (up to 3× higher) within the catalytic region (compared at 0.80-0.90 V) and voltage efficiency (68%@ 0.5 A cm-2 ) values in the compared literature. In addition, the cell demonstrates promising short-term voltage stability with a minor voltage decay of 1.5 mV h-1 . This "first-of-its-kind in alkaline" work may open further research avenues to develop rapid synthesis methods to prepare advanced core-shell metal-oxide/carbon supports for electrocatalysts for use in the next-generation of AEMFCs with potential applicability to the broader electrochemical systems research community.

Self-Assembled DNA Nanocages Promote Cell Migration and Differentiation of Human Umbilical Vein Endothelial Cells.

DNA nanocages have been explored for abilities to influence cellular behavior and functions. Recent times have seen the development of new emergent functionalities of DNA nanodevices as a class of biomaterials with an immense capacity to interface with biological systems and with vast potential in disease diagnosis and therapeutics. Being chemically robust and biocompatible in nature, DNA nanocages have been surface modified and structurally fine-tuned to find emerging applications in the field of stem-cell therapy and tissue regeneration. DNA nanocages can be used for therapeutic angiogenesis that involves the induction of blood vessel formation and can be used to treat ischemic diseases like stroke or heart failure. This work addresses the effect of DNA nanocages' structural topology on their capacity to stimulate endothelial cell angiogenesis. We tested a panel of four DNA nanocage geometries and checked their potential on the differentiation of human umbilical vein endothelial cells (HUVECs). While different DNA nanocage geometries showed successful induction of angiogenesis and cell migration in HUVECs, tetrahedral DNA cages showed the maximum uptake and angiogenesis potential, thus indicating that not only the composition of materials, but also the 3D arrangement of ligands might play role in stimulating angiogenesis.

Designer, Programmable DNA-peptide hybrid materials with emergent properties to probe and modulate biological systems.

The chemistry of DNA endows it with certain functional properties that facilitate the generation of self-assembled nanostructures, offering precise control over their geometry and morphology, that can be exploited for advanced biological applications. Despite the structural promise of these materials, their applications are limited owing to lack of functional capability to interact favourably with biological systems, which has been achieved by functional proteins or peptides. Herein, we outline a strategy for functionalizing DNA structures with short-peptides, leading to the formation of DNA-peptide hybrid materials. This proposition offers the opportunity to leverage the unique advantages of each of these bio-molecules, that have far reaching emergent properties in terms of better cellular interactions and uptake, better stability in biological media, an acceptable and programmable immune response and high bioactive molecule loading capacities. We discuss the synthetic strategies for the formation of these materials, namely, solid-phase functionalization and solution-coupling functionalization. We then proceed to highlight selected biological applications of these materials in the domains of cell instruction & molecular recognition, gene delivery, drug delivery and bone & tissue regeneration. We conclude with discussions shedding light on the challenges that these materials pose and offer our insights on future directions of peptide-DNA research for targeted biomedical applications.

The E3 ligase TRAF4 promotes IGF signaling by mediating atypical ubiquitination of IRS-1.

Insulin-like growth factor (IGF) is a potent mitogen that activates the IGF receptor (IGFR)/insulin receptor substrate (IRS) axis, thus stimulating growth in normal cells and uncontrolled cell proliferation in cancer. Posttranslational modifications of IRS such as ubiquitination tightly control IGF signaling, and we previously identified IRS-1 as a potential substrate for the E3 ubiquitin ligase TRAF4 using an unbiased screen. Here we provide evidence that TRAF4-mediated ubiquitination of IRS-1 is physiologically relevant and crucial for IGF signal transduction. Through site-directed mutagenesis we found that TRAF4 promotes an atypical K29-linked ubiquitination at the C-terminal end of IRS-1. Its depletion abolishes AKT and ERK phosphorylation downstream of IGF-1 and inhibits breast cancer cell proliferation. Overexpression of TRAF4 enhances IGF1-induced IGFR-IRS-1 interaction, IRS-1 tyrosine phosphorylation, and downstream effector protein activation, whereas mutation of IRS-1 ubiquitination sites completely abolishes these effects. Altogether, our studies demonstrate that nonproteolytic ubiquitination of IRS-1 is a key step in conveying IGF-1 stimulation from IGFR to IRS-1.

A new aggregation induced emission enhancement (AIEE) dye which self-assembles to panchromatic fluorescent flowers and has application in sensing dichromate ions.

We report for the very first time the crystal structure and self-assembly of a new aggregation-induced emission enhancement (AIEE) dye 4-(5-methoxythiazolo[4,5-b]pyridin-2-yl)-N,N-dimethylaniline (TPA) and its application in sensing dichromate ions. TPA reveals cyan blue emission under UV and visible light. The self-assembly properties of TPA were studied extensively by scanning electron microscopy (SEM) which revealed the formation of beautiful flower-like morphologies. These structures revealed both green and red fluorescence under FITC and rhodamine filters respectively when observed through fluorescence microscopy connoting the panchromatic emission properties of TPA from blue to red. The interactions which cause self-assembled structure formation in TPA were also validated theoretically using density functional theory (DFT) calculations. Crystal and molecular structure analysis of TPA was carried out via single-crystal X-ray diffraction to visualize the intermolecular interactions occurring in the solid-state and to study the structure-photophysical property relationship in the aggregated state. The photophysical properties of TPA were also studied extensively by UV-visible and fluorescence spectroscopy and its quantum yield and fluorescence lifetime were calculated by time-correlated single-photon counting (TCSPC). Interestingly, TPA could efficiently sense dichromate (Cr2O72-) ions in an acidic medium and an interesting morphological transition from a fluorescent flower to non-fluorescent disassembled structures could also be observed. The limit of detection of TPA for Cr2O72- ions was found to be as low as 5.5 nM, suggesting its exceptional sensitivity. More importantly, TPA could selectively sense Cr2O72- ions in real water samples even in the presence of other metal ions routinely present in polluted water, hence making it practically useful for water quality monitoring.

Extracorporeal life support for cardiogenic shock during pregnancy and postpartum: a single center experience.

BACKGROUND: The use of veno-arterial extracorporeal membrane oxygenation (VA ECMO) for cardiogenic shock in pregnant and postpartum patients remains limited by concerns of bleeding, hemolysis, and fetal risks. This case series examines the underlying characteristics and management strategies for this high-risk population. METHODS: All pregnant and post-partum patients who underwent VA ECMO in the cardiovascular intensive care unit between January 1, 2016 and November 1, 2019, were included in this retrospective study. Management of maternal and fetal O2 delivery, left ventricular (LV) unloading, anticoagulation, and ECMO circuit characteristics were evaluated. RESULTS: Five patients required veno-arterial ECMO for restoration of systemic perfusion. Three patients developed peripartum cardiomyopathy, one septic cardiomyopathy, and one acute right ventricular (RV) failure. The median age was 30.6 years, with median gestational age in pregnant patients of 31 weeks. Maternal and fetal survival to discharge was 80%. Bleeding was the primary complication, with two patients requiring blood transfusions; one requiring interventional radiology (IR) embolization and the other requiring surgical intervention to control bleeding. One patient was successfully delivered on VA ECMO. No fetal complications were directly attributed to VA ECMO. CONCLUSIONS: VA ECMO can be employed successfully in obstetric patients with cardiogenic shock with appropriate patient selection. Further research is needed to determine if VA ECMO provides a survival advantage over traditional management strategies in this vulnerable population.

Airflow-Assisted Impact of Drops of Various Viscosities: The Role of Viscous Dissipation, Normal Imposed Pressure, and Shear Flow of Air.

The role of liquid viscosity on the spreading for an airflow-assisted impact of drops on a surface is investigated. The spreading diameter is found to increase with the Reynolds number of the airflow (Reair) for a given viscosity and impact Weber number (We) compared to the still air. The increment is higher at a low We for viscous drops, whereas the effect of Reair dominates at the intermediate We as the viscosity decreases. Two extra forces, the normal imposed pressure and shear force of air, act on the drop and influence the spreading along with the viscous dissipation. The drop's curvature decreases depending on the viscosity and impact velocity while spreading. Large-scale eddies near the drop-surface region are observed due to the separation of the incident airflow. The formation of eddies signifies low-pressure zones, which extract the trapped air, causing the spreading diameter of the viscous drop to increase at a low We. With the increase in the We, the lamella thickness of low-viscosity drops decreases and is pushed out by the air shear causing the spreading factor to increase. The boundary layer thickness is estimated using the energy balance method to predict the maximum spreading factor. The prediction compares well with the experimental one for higher viscosities. The accuracy improves when the effect of low pressure is incorporated. To confirm, the experimental spreading is compared with that obtained from three existing models, and one, which considers the influence, is observed to provide a better prediction.

Nuclear plasticity increases susceptibility to damage during confined migration.

Large nuclear deformations during migration through confined spaces have been associated with nuclear membrane rupture and DNA damage. However, the stresses associated with nuclear damage remain unclear. Here, using a quasi-static plane strain finite element model, we map evolution of nuclear shape and stresses during confined migration of a cell through a deformable matrix. Plastic deformation of the nucleus observed for a cell with stiff nucleus transiting through a stiffer matrix lowered nuclear stresses, but also led to kinking of the nuclear membrane. In line with model predictions, transwell migration experiments with fibrosarcoma cells showed that while nuclear softening increased invasiveness, nuclear stiffening led to plastic deformation and higher levels of DNA damage. In addition to highlighting the advantage of nuclear softening during confined migration, our results suggest that plastic deformations of the nucleus during transit through stiff tissues may lead to bending-induced nuclear membrane disruption and subsequent DNA damage.

Decline in PM2.5 concentrations over major cities around the world associated with COVID-19.

The COVID-19 started from Wuhan city in China, slowly spread across the globe after December 2019. Due to movement of people from one city to other cities, one country to other countries, infection spreads and COVID-19 became a pandemic. Efforts were made at local, regional and national levels to lockdown the movement of people and to keep infected one in quarantine or isolation to stop the spread of COVID-19. The traffic, market and small industries were closed, as a result pronounced decline in the concentrations of particulate matters (PM) were observed. Normally these sources contribute to the high concentrations of particulate matters (PM2.5) which represents air quality of a location. In this short communication, we present analysis of PM2.5 of major cities (New York, Los Angeles, Zaragoza, Rome, Dubai, Delhi, Mumbai, Beijing and Shanghai) around the world suffered severely with the COVID-19. Our analysis shows decline in PM2.5 concentration due to lockdown, mainly due to less movement of people to keep "social distancing" to control the spread of CORONA-19. The low concentrations of PM2.5 reflect the efforts made in the cities to curb the spread of infection, that improve air quality.

Fixed and dilated pupils, not a contraindication for extracorporeal support: a case series.

Extracorporeal membrane oxygenation is considered a relative contraindication for patients with severe neurological injury manifested by fixed and dilated pupils. The inability to provide adequate cardiopulmonary support while attempting to treat the underlying neurologic disease results in a fatal outcome. The impairment of cerebral perfusion, compounded by the underlying neurologic condition, results in signs of brainstem dysfunction often equated with a fatal prognosis. As a result, these patients are not considered to be candidates for initiation of extracorporeal membrane oxygenation. We present a case series of three patients with complex neurologic conditions with fixed and dilated pupils, who received extracorporeal membrane oxygenation. All three patients achieved a significant neurologic recovery. Two survived with a cerebral performance category scale of 1, and the third succumbed to multi-organ failure after achieving a Glasgow Coma Scale of 11T. The decision to initiate extracorporeal membrane oxygenation should be based upon the pathophysiology of the underlying neurologic condition and not solely upon isolated clinical findings. Extracorporeal membrane oxygenation use is normally reserved for patients with reversible underlying processes, and a neurologic exam with fixed and dilated pupils is often interpreted as an irreversible neurologic injury. The implementation and success of extracorporeal membrane oxygenation in this patient population require understanding of complex neurologic diseases, rapid recognition of neurocardiogenic shock, and expeditious initiation of cardiopulmonary support in carefully selected patients. The patients described demonstrate that fixed and dilated pupils are not a contraindication for extracorporeal support in select patients.

Evolving trends in infective endocarditis in a developing country: a consequence of medical progress?

BACKGROUND: Staphylococcus has replaced streptococcus as the most common cause of infective endocarditis (IE) in developed health care systems. The trend in developing countries is less clear. AIM: To examine the epidemiological trends of infective endocarditis in a developing nation. METHODS: Single-centre, retrospective study of patients admitted with IE to a tertiary hospital in Malaysia over a 12-year period. RESULTS: The analysis included 182 patients (n = 153 Duke's definite IE, n = 29 possible IE). The mean age was 51 years. Rheumatic heart disease was present in 42%, while 7.6% were immunocompromised. IE affected native valves in 171 (94%) cases. Health-care associated IE (HCAIE) was recorded in 68 (37.4%). IE admission rates increased from 25/100,000 admissions (2012) to 59/100,000 admissions (2017). At least one major complication on admission was detected in 59 (32.4%) patients. Left-sided IE was more common than right-sided IE [n = 159 (87.4%) vs. n = 18 (9.9%)]. Pathogens identified by blood culture were staphylococcus group [n = 58 (40.8%)], streptococcus group [n = 51 (35.9%)] and Enterococcus species [n = 13 (9.2%)]. staphylococcus infection was highest in the HCAIE group. In-hospital death occurred in 65 (35.7%) patients. In-hospital surgery was performed for 36 (19.8%) patients. At least one complication was documented in 163 (85.7%). CONCLUSION: Staphylococcus is the new etiologic champion, reflecting the transition of the healthcare system. Streptococcus is still an important culprit organism. The incidence rate of IE appears to be increasing. The rate of patients with underlying rheumatic heart disease is still high.

Finite element study of functionally graded porous femoral stems incorporating body-centered cubic structure.

The mismatch between stiffness of the femoral dense stem and host bone causes complications to patients, such as aseptic loosening and bone resorption. Three-dimensional finite-element models of homogeneous porous (HGP) and functionally graded porous (FGP) stems incorporating body-centered cubic (BCC) structures are proposed in this article as an alternative to the dense stems. The relationship between the porosity and strut thickness of the BCC structure was developed to construct the finite-element models. Three levels of porosities (20%, 50%, and 80%) were modeled in HGP and FGP stems. The porosity of the stems was decreased distally according to the sigmoid function (n = 0.1, n = 1 and n = 10) with 3 grading exponents. The results showed that FGP stems transferred 120%-170% higher stresses to the femur (Gruen zone 7) as compared to the solid stem. Conversely, the stresses in HGP and FGP stems were 12%-34% lower than the dense stem. The highest micromotions (105-147 µm) were observed for stems of 80% overall porosity, and the lowest (42-46 µm) was for stems of 20% overall porosity. Finally, FGP stems with a grading exponent of n = 10 resulted in an 11%-28% reduction in micromotions.

Transition Metal Ion-Mediated Tyrosine-Based Short-Peptide Amphiphile Nanostructures Inhibit Bacterial Growth.

We report the design and synthesis of a biocompatible small-peptide-based compound for the controlled and targeted delivery of encapsulated bioactive metal ions through transformation of the internal nanostructures of its complexes. A tyrosine-based short-peptide amphiphile (sPA) was synthesized and observed to self-assemble into ß-sheet-like secondary structures. The self-assembly of the designed sPA was modulated by application of different bioactive transition-metal ions, as was confirmed by spectroscopic and microscopic techniques. These bioactive metal-ion-conjugated sPA hybrid structures were further used to develop antibacterial materials. As a result of the excellent antibacterial activity of zinc ions the growth of clinically relevant bacteria such as Escherichia coli was inhibited in the presence of zinc⋅sPA conjugate. Bacterial testing demonstrated that, due to high biocompatibility with bacterial cells, the designed sPA acted as a metal ion delivery agent and might therefore show great potential in locally addressing bacterial infections.

Temporal Differences in Outcomes During Long-Term Mechanical Circulatory Support.

BACKGROUND: Device indications have changed for placement of continuous-flow left ventricular assist devices (CF-LVADs). We performed a multicenter analysis evaluating temporal variations in outcomes after CF-LVAD implantation. METHODS & RESULTS: We retrospectively defined 3 time intervals to reflect changes in CF-LVAD technology (period 1, 2004-2009; period 2, 2010-2012; and period 3, 2012-2014). A total of 1,064 patients (Heartmate II [HMII] = 835; Heartware [HVAD] = 229) underwent CF-LVAD implantation from May 2004 to October 2014. Device utilization was different between periods: period 1: HMII = 134 (100%); period 2: HMII = 480 (88%) and HW = 63 (12%); and period 3: HMII = 221 (57%) and HW = 166 (43%); P < .001. Despite few baseline group differences, adjusted survivals were similar among the time periods (P = .96). Adjusted multivariable analysis revealed age (per 10-year increase) and Interagency Registry for Mechanically Assisted Circulatory Support category (1 vs all others) as the only independent predictors of mortality: P < .001 and P = .008, respectively. Furthermore, it also showed the later periods to be at an increased risk of adverse events: 1) pump thrombosis (periods 2 and 3); and 2) gastrointestinal bleeding (period 3). CONCLUSIONS: Despite significant differences in device types, indications, and patient characteristics, post-implantation survivals were similar across time intervals. The most recent cohort seems to be at an increased risk of gastrointestinal bleeding and pump thrombosis.

Early postoperative management after lung transplantation: Results of an international survey.

INTRODUCTION: Little data exist regarding optimal therapeutic strategies postoperatively after lung transplant (LTx). Current practice patterns rely on expert opinion and institutional experience resulting in nonuniform postoperative care. To better define current practice patterns, an international survey of LTx clinicians was conducted. METHODS: A 30-question survey was sent to transplant clinicians via email to the International Society of Heart and Lung Transplantation open forum mailing list and directly to the chief transplant surgeon and pulmonologist of all LTx centers in the United States. RESULTS: Fifty-two clinicians representing 10 countries responded to the survey. Sedatives use patterns included: opiates + propofol (57.2%), opiates + dexmedetomidine (18.4%), opiates + intermittent benzodiazepines (14.3%), opiates + continuous benzodiazepines (8.2%), and opiates alone (2%). About 40.4% reported no formal sedation scale was followed and 13.5% of programs had no formal policy on sedation and analgesia. A lung protective strategy was commonly employed, with 13.8%, 51.3%, and 35.9% of respondents using tidal volumes of <6 mL/kg ideal body weight (IBW), 6 mL/kg IBW, and 8 mL/kg IBW, respectively. CONCLUSION: Practice patterns in the early postoperative care of lung transplant recipients differ considerably among centers. Many of the reported practices do not conform to consensus guidelines on management of critically ill patients.

Ventricular Assist Device Therapy in Older Patients With Heart Failure: Characteristics and Outcomes.

BACKGROUND: Limited data exist on outcomes in patients ≥70 years of age supported with the use of continuous-flow left ventricular assist devices (LVADs). METHODS: Data on 1149 continuous-flow LVAD recipients was queried from the Mechanical Circulatory Support Research Network. Groups were assigned based on age: ≥70 years ("older patients") and <70 years. The primary outcome was survival at one-year based on age grouping. RESULTS: Compared with younger patients (54.3 ± 11.2 y; n = 986), older patients (73.4 ± 3.0 y) constituted only 14% of LVAD implants. Older patients had similar rates of device thrombosis (P = .47) and stroke (P = .44), but survival-free of gastrointestinal bleeding (GIB) at 1 year was lower compared with younger patients (58% vs 69%; P < .01). Unadjusted survival at 1 year in older patients was 75% compared with 84% in younger patients, and at 2 years 65% versus 73% (P = .18). Age ≥70 years was not associated with increased mortality (adjusted hazard ratio [aHR] 0.94, 95% confidence interval [CI] 0.70-1.26; P = .67). Preoperative creatinine (aHR 1.57, 95% CI: 1.30-1.89, P < .0001), bilirubin (aHR 1.22, 95% CI 1.05-1.42; P = .010), and ischemic cardiomyopathy (aHR 1.43, 95% CI 1.11-1.84; P = .005) portended increased risk of death. In older patients, the only predictor of mortality was creatinine (HR 2.1, 95% CI 1.2-3.4; P = .007). Creatinine ≥1.4 mg/dL was associated with a 1-year survival of 65%, compared with 84% when the creatinine was <1.4 mg/dL (P = .009). CONCLUSION: Age >70 years is an important consideration when assessing LVAD risk, but other correlates may be more predictive of LVAD survival. Older patients without renal dysfunction have survival similar to younger patients. Older patients should be counseled about age-correlated risks, including higher rates of GIB.