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Amputation as a result of impaired wound healing is a serious complication of diabetes. Inadequate angiogenesis contributes to poor wound healing in diabetic patients. Endothelial progenitor cells (EPCs) normally augment angiogenesis and wound repair but are functionally impaired in diabetics. Here we report that decreased expression of manganese superoxide dismutase (MnSOD) in EPCs contributes to impaired would healing in a mouse model of type 2 diabetes. A decreased frequency of circulating EPCs was detected in type 2 diabetic (db/db) mice, and when isolated, these cells exhibited decreased expression and activity of MnSOD. Wound healing and angiogenesis were markedly delayed in diabetic mice compared with normal controls. For cell therapy, topical transplantation of EPCs onto excisional wounds in diabetic mice demonstrated that diabetic EPCs were less effective than normal EPCs at accelerating wound closure. Transplantation of diabetic EPCs after MnSOD gene therapy restored their ability to mediate angiogenesis and wound repair. Conversely, siRNA-mediated knockdown of MnSOD in normal EPCs reduced their activity in diabetic wound healing assays. Increasing the number of transplanted diabetic EPCs also improved the rate of wound closure. Our findings demonstrate that cell therapy using diabetic EPCs after ex vivo MnSOD gene transfer accelerates their ability to heal wounds in a mouse model of type 2 diabetes.

Positively charged oligo[poly(ethylene glycol) fumarate] (OPF+) scaffolds loaded with Schwann cells bridge spinal cord injury (SCI) lesions and support axonal regeneration in rat. The regeneration achieved is not sufficient for inducing functional recovery. Attempts to increase regeneration would benefit from understanding the effects of the scaffold and transplanted cells on lesion environment. We conducted morphometric and stereological analysis of lesions in rats implanted with OPF+ scaffolds with or without loaded Schwann cells 1, 2, 3, 4, and 8 weeks after thoracic spinal cord transection. No differences were found in collagen scarring, cyst formation, astrocyte reactivity, myelin debris, or chondroitin sulfate proteoglycan (CSPG) accumulation. However, when scaffold-implanted animals were compared with animals with transection injuries only, these barriers to regeneration were significantly reduced, accompanied by increased activated macrophages/microglia. This distinctive and regeneration permissive tissue reaction to scaffold implantation was independent of Schwann cell transplantation. Although the tissue reaction was beneficial in the short term, we observed a chronic fibrotic host response, resulting in scaffolds surrounded by collagen at 8 weeks. This study demonstrates that an appropriate biomaterial scaffold improves the environment for regeneration. Future targeting of the host fibrotic response may allow increased axonal regeneration and functional recovery.

•A total of 23,583 patients in a national surgical registry were analyzed.•The use of the microscope was associated with longer operative times.•The use of microscope did not influence rates of postoperative complications. A single level discectomy is one of the most common procedures performed by spine surgeons. While some practitioners utilize the microscope, others do not. We postulate improved visualization with an intraoperative microscope decreases complications and inferior outcomes. A multicenter surgical registry was utilized for this retrospective cohort analysis. Patients with degenerative spinal diagnoses undergoing elective single level discectomies from 2010 to 2014 were included. Univariate analysis was performed comparing demographics, patient characteristics, operative data, and outcomes for discectomies performed with and without a microscope. Multivariable logistic regression analysis was then applied to compare outcomes of micro- and macrodiscectomies. Query of the registry yielded 23,583 patients meeting inclusion criteria. On univariate analysis the microscope was used in a greater proportion of the oldest age group as well as Hispanic white patients. Patients with any functional dependency, history of congestive heart failure, chronic corticosteroid use, or anemia (hematocrit<35%) also had greater proportions of microdiscectomies. Thoracic region discectomies more frequently involved use of the microscope than cervical or lumbar discectomies (25.0% vs. 16.4% and 13.0%, respectively, p<0.001). Median operative time (IQR) was increased in microscope cases [80min (60, 108) vs. 74min (54, 102), p<0.001]. Of the patients that required reoperation within 30days, 2.5% of them had undergone a microdiscectomy compared to 1.9% who had undergone a macrodiscectomy, p=0.044. On multivariable analysis, microdiscectomies were more likely to have an operative time in the top quartile of discectomy operative times, ≥103min (OR 1.256, 95% CI 1.151-1.371, p<0.001). In regards to other multivariable outcome models for any complication, surgical site infection, dural tears, reoperation, and readmission, no significant association with microdiscectomy was found. The use of the microscope was found to significantly increase the odds of longer operative time, but not influence rates of postoperative complications. Thus, without evidence from this study that the microscope decreases complications, the use of the microscope should be at the surgeon’s discretion, validating the use of both macro and micro approaches to discectomy as acceptable standards of care.

Positively charged oligo[poly(ethylene glycol) fumarate] (OPF+) scaffolds loaded with Schwann cells bridge spinal cord injury (SCI) lesions and support axonal regeneration in rat. The regeneration achieved is not sufficient for inducing functional recovery. Attempts to increase regeneration would benefit from understanding the effects of the scaffold and transplanted cells on lesion environment. We conducted morphometric and stereological analysis of lesions in rats implanted with OPF+ scaffolds with or without loaded Schwann cells 1, 2, 3, 4, and 8 weeks after thoracic spinal cord transection. No differences were found in collagen scarring, cyst formation, astrocyte reactivity, myelin debris, or chondroitin sulfate proteoglycan (CSPG) accumulation. However, when scaffold-implanted animals were compared with animals with transection injuries only, these barriers to regeneration were significantly reduced, accompanied by increased activated macrophages/microglia. This distinctive and regeneration permissive tissue reaction to scaffold implantation was independent of Schwann cell transplantation. Although the tissue reaction was beneficial in the short term, we observed a chronic fibrotic host response, resulting in scaffolds surrounded by collagen at 8 weeks. This study demonstrates that an appropriate biomaterial scaffold improves the environment for regeneration. Future targeting of the host fibrotic response may allow increased axonal regeneration and functional recovery.

Hydrogel scaffolds provide a beneficial microenvironment in transected rat spinal cord. A combinatorial biomaterials based strategy provided a microenvironment that facilitated regeneration while reducing foreign body reaction to the 3-dimensional spinal cord construct. We used poly lactic-co-glycolic acid microspheres to provide sustained release of rapamycin from Schwann cell (SC)-loaded, positively charged oligo-polyethylene glycol fumarate scaffolds. Three dose formulations of rapamycin were compared to controls in 53 rats. We observed a dose-dependent reduction in the fibrotic reaction to the scaffold and improved functional recovery over 6 weeks. Recovery was replicated in a second cohort of 28 animals that included retransection injury. Immunohistochemical and stereological analysis demonstrated that blood vessel number, surface area, vessel diameter, basement membrane collagen, and microvessel phenotype within the regenerated tissue was dependent on the presence of SCs and rapamycin. TRITC-dextran injection demonstrated enhanced perfusion into scaffold channels. Rapamycin also increased the number of descending regenerated axons, as assessed by Fast Blue retrograde axonal tracing. These results demonstrate that normalization of the neovasculature was associated with enhanced axonal regeneration and improved function after spinal cord transection.

Given the limited availability of serological testing to date, the seroprevalence of SARS-CoV-2-specific antibodies in different populations has remained unclear. Here, we report very low SARS-CoV-2 seroprevalence in two San Francisco Bay Area populations. Seroreactivity was 0.26% in 387 hospitalized patients admitted for non-respiratory indications and 0.1% in 1,000 blood donors in early April 2020. We additionally describe the longitudinal dynamics of immunoglobulin-G (IgG), immunoglobulin-M (IgM), and in vitro neutralizing antibody titers in COVID-19 patients. The median time to seroconversion ranged from 10.3–11.0 days for these 3 assays. Neutralizing antibodies rose in tandem with immunoglobulin titers following symptom onset, and positive percent agreement between detection of IgG and neutralizing titers was >93%. These findings emphasize the importance of using highly accurate tests for surveillance studies in low-prevalence populations, and provide evidence that seroreactivity using SARS-CoV-2 anti-nucleocapsid protein IgG and anti-spike IgM assays are generally predictive of in vitro neutralizing capacity. Highly accurate antibody tests for SARS-CoV-2 are needed for surveillance in low-prevalence populations. Here, the authors find seroprevalence of less than 1% in two San Francisco Bay Area populations at the beginning of April, and that seroreactivity is generally predictive of in vitro neutralising activity.

Despite increased Atlantic hurricane risk, projected trends in hurricane frequency in the warming climate are still highly uncertain, mainly due to short instrumental record that limits our understanding of hurricane activity and its relationship to climate. Here we extend the record to the last millennium using two independent estimates: a reconstruction from sedimentary paleohurricane records and a statistical model of hurricane activity using sea surface temperatures (SSTs). We find statistically significant agreement between the two estimates and the late 20th century hurricane frequency is within the range seen over the past millennium. Numerical simulations using a hurricane-permitting climate model suggest that hurricane activity was likely driven by endogenous climate variability and linked to anomalous SSTs of warm Atlantic and cold Pacific. Volcanic eruptions can induce peaks in hurricane activity, but such peaks would likely be too weak to be detected in the proxy record due to large endogenous variability. The authors present two independent reconstructions and a model simulations of Atlantic hurricane activity over the last millennium and show that it is mainly driven by internal climate variability instead of external forcings.

Oxygen vacancies in proximity to surfaces and heterointerfaces in oxide thin film heterostructures have major effects on properties, resulting, for example, in emergent conduction behaviour, large changes in metal-insulator transition temperatures or enhanced catalytic activity. Here we report the discovery of a means of reversibly controlling the oxygen vacancy concentration and distribution in oxide heterostructures consisting of electronically conducting In 2 O 3 films grown on ionically conducting Y 2 O 3 -stabilized ZrO 2 substrates. Oxygen ion redistribution across the heterointerface is induced using an applied electric field oriented in the plane of the interface, resulting in controlled oxygen vacancy (and hence electron) doping of the film and possible orders-of-magnitude enhancement of the film's electrical conduction. The reversible modified behaviour is dependent on interface properties and is attained without cation doping or changes in the gas environment. Oxygen vacancies near the interface in oxide heterostructures can lead to large changes in properties, including metal–insulator transition temperatures or catalytic activity. Here, the authors demonstrate a way to reversibly control the oxygen-vacancy concentration and distribution in oxide heterostructures.

Medium-range forecasts of Hurricane Sandy’s track were characterized by widely diverging solutions, with some suggesting that Sandy would make landfall over the mid-Atlantic region of the United States, while others forecast the storm to move due east to the north of Bermuda. Here, dynamical processes responsible for the eastward-tracking forecasts are diagnosed using an 80-member ensemble of experimental Global Forecast System (GFS) forecasts initialized five days prior to landfall. Comparing the ensemble members with tracks to the east against those with tracks to the west indicates that the eastern members were characterized by a lower-amplitude upper-tropospheric anticyclone on the poleward side of Sandy during the first 24 h of the forecast, which in turn was associated with a westerly perturbation steering wind. The amplification of this ridge in each set of members was modulated by differences in the advection of potential vorticity (PV) by the irrotational wind associated with Sandy’s secondary circulation and isentropic lift along a warm front that formed on the poleward side of Sandy. The amplitude of the irrotational wind in this region was proportional to the 0-h water vapor mixing ratio, and to a lesser extent the 0-h upper-tropospheric horizontal divergence. These two quantities modulated the vertical profile of grid-scale condensation within the model and subsequent upper-tropospheric divergence. The results from this study suggest that additional observations within regions of large-scale precipitation outside the tropical cyclone (TC) core could benefit TC track forecasts, particularly when the TC is located near an upper-tropospheric PV gradient.

Epithelial ovarian cancer (EOC) is hallmarked by a high degree of heterogeneity. To address this heterogeneity, a classification scheme was developed based on gene expression patterns of 1538 tumours. Five, biologically distinct subgroups — Epi‐A, Epi‐B, Mes, Stem‐A and Stem‐B — exhibited significantly distinct clinicopathological characteristics, deregulated pathways and patient prognoses, and were validated using independent datasets. To identify subtype‐specific molecular targets, ovarian cancer cell lines representing these molecular subtypes were screened against a genome‐wide shRNA library. Focusing on the poor‐prognosis Stem‐A subtype, we found that two genes involved in tubulin processing, TUBGCP4 and NAT10 , were essential for cell growth, an observation supported by a pathway analysis that also predicted involvement of microtubule‐related processes. Furthermore, we observed that Stem‐A cell lines were indeed more sensitive to inhibitors of tubulin polymerization, vincristine and vinorelbine, than the other subtypes. This subtyping offers new insights into the development of novel diagnostic and personalized treatment for EOC patients. Graphical Abstract Ovarian carcinomas remain a leading cause of cancer death among woman worldwide. Here, a novel rational patient stratification is proposed to unravel the heterogeneity of these cancers and provide means to guide novel intervention strategies.