Herpes simplex virus type 1 (HSV-1)-infected corneas can develop a blinding immunoinflammatory condition called herpes stromal keratitis (HSK), which involves the loss of corneal sensitivity due to ...retraction of sensory nerves and subsequent hyperinnervation with sympathetic nerves. Increased concentrations of the cytokine VEGF-A in the cornea are associated with HSK severity. Here, we examined the impact of VEGF-A on neurologic changes that underly HSK using a mouse model of HSV-1 corneal infection. Both CD4+ T cells and myeloid cells produced pathogenic levels of VEGF-A within HSV-1-infected corneas, and CD4+ cell depletion promoted reinnervation of HSK corneas with sensory nerves. In vitro, VEGF-A from infected corneas repressed sensory nerve growth and promoted sympathetic nerve growth. Neutralizing VEGF-A in vivo using bevacizumab inhibited sympathetic innervation, promoted sensory nerve regeneration, and alleviated disease. Thus, VEGF-A can shape the sensory and sympathetic nerve landscape within the cornea, with implications for the treatment of blinding corneal disease.
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•Sympathetic innervation of the cornea leads to ocular disease after HSV-1 infection•VEGF-A is produced by myeloid cells and CD4+ T cells after HSV-1 infection•VEGF-A impedes sensory innervation and promotes sympathetic innervation•Neutralizing VEGF-A alleviates HSV-1 disease by restoring corneal sensory nerves
Infection with herpes simplex virus can result in the replacement of sensory nerves with sympathetic nerves within the cornea, loss of blink reflex, and corneal pathology. Yun et al. reveal that VEGF-A produced by infiltrating myeloid and CD4+ T cells promotes nerve disruption within the cornea, with implications for the treatment of herpes stromal keratitis.
Children with relapsed central nervous system (CNS tumors), neuroblastoma, sarcomas, and other rare solid tumors face poor outcomes. This prospective clinical trial examined the feasibility of ...combining genomic and transcriptomic profiling of tumor samples with a molecular tumor board (MTB) approach to make real‑time treatment decisions for children with relapsed/refractory solid tumors.
Subjects were divided into three strata: stratum 1-relapsed/refractory neuroblastoma; stratum 2-relapsed/refractory CNS tumors; and stratum 3-relapsed/refractory rare solid tumors. Tumor samples were sent for tumor/normal whole-exome (WES) and tumor whole-transcriptome (WTS) sequencing, and the genomic data were used in a multi-institutional MTB to make real‑time treatment decisions. The MTB recommended plan allowed for a combination of up to 4 agents. Feasibility was measured by time to completion of genomic sequencing, MTB review and initiation of treatment. Response was assessed after every two cycles using Response Evaluation Criteria in Solid Tumors (RECIST). Patient clinical benefit was calculated by the sum of the CR, PR, SD, and NED subjects divided by the sum of complete response (CR), partial response (PR), stable disease (SD), no evidence of disease (NED), and progressive disease (PD) subjects. Grade 3 and higher related and unexpected adverse events (AEs) were tabulated for safety evaluation.
A total of 186 eligible patients were enrolled with 144 evaluable for safety and 124 evaluable for response. The average number of days from biopsy to initiation of the MTB-recommended combination therapy was 38 days. Patient benefit was exhibited in 65% of all subjects, 67% of neuroblastoma subjects, 73% of CNS tumor subjects, and 60% of rare tumor subjects. There was little associated toxicity above that expected for the MGT drugs used during this trial, suggestive of the safety of utilizing this method of selecting combination targeted therapy.
This trial demonstrated the feasibility, safety, and efficacy of a comprehensive sequencing model to guide personalized therapy for patients with any relapsed/refractory solid malignancy. Personalized therapy was well tolerated, and the clinical benefit rate of 65% in these heavily pretreated populations suggests that this treatment strategy could be an effective option for relapsed and refractory pediatric cancers.
ClinicalTrials.gov, NCT02162732. Prospectively registered on June 11, 2014.
We report .../Ar ratios (a constraint on net community production) and the triple isotopic composition of dissolved ... (a constraint on gross primary production) in samples collected from the ...surface mixed layer on 23 Southern Ocean transits. Samples were collected at 1-2... meridional resolution during the austral summer. Methodological limitations notwithstanding, the results constrain the net/gross production ratio, net ... production, and gross ... production at unprecedented resolution throughout the Southern Ocean mixed layer. Gross ... production rates inferred from the oxygen triple isotopes are greater than production rates calculated from a model based on remotely sensed chlorophyll. This result agrees with previous ... and ... incubations along 170...W. .../Ar ratios exceeding saturation are consistently observed within the Subantarctic and Polar Frontal Zones south of New Zealand and Australia, showing that a net autotrophic community predominates during austral summer. Lower .../Ar values are observed within the Drake Passage and Antarctic Zone, suggesting unresolved influences of low net community production, net heterotrophy, and upwelling of ...-undersaturated waters. In autotrophic waters of the austral summer mixed layer, ratios of net community production/gross ... production scatter about 0.13, corresponding to f ratios of ...0.25. Net community/gross ... production ratios show no meridional gradient across the Antarctic Circumpolar Current, suggesting that an approximately constant fraction of gross primary productivity is regenerated or exported. Our calculated net ... production rates are in satisfactory agreement with comparable published estimates. Net and gross ... production rates are highest in the Subantarctic and decline to the south, paralleling the well-known trend of chlorophyll a concentrations. In an analysis of variance of net ... production and gross ... production with other environmental variables, the strongest correlations are between net ... production and sea surface temperature (SST) (direct correlation), climatological ... (inverse correlation), and estimates of primary productivity derived from a remote sensing (direct correlation). These trends are as expected if aerosol iron input is the most important influence on production. They are unexpected if upwelling- derived ... and iron are the leading influence or if lower SSTs promote greater export in this region. (ProQuest-CSA LLC: ... denotes formulae/symbols omitted.)
The aim of this study was to determine whether iron deficiency anemia (IDA) in mothers alters their maternal cognitive and behavioral performance, the mother-infant interaction, and the infant's ...development. This article focuses on the relation between IDA and cognition as well as behavioral affect in the young mothers. This prospective, randomized, controlled, intervention trial was conducted in South Africa among 3 groups of mothers: nonanemic controls and anemic mothers receiving either placebo (10 microg folate and 25 mg vitamin C) or daily iron (125 mg FeS0₄, 10 microg folate, 25 mg vitamin C). Mothers of full-term normal birth weight babies were followed from 10 wk to 9 mo postpartum (n = 81). Maternal hematologic and iron status, socioeconomic, cognitive, and emotional status, mother-infant interaction, and the development of the infants were assessed at 10 wk and 9 mo postpartum. Behavioral and cognitive variables at baseline did not differ between iron-deficient anemic mothers and nonanemic mothers. However, iron treatment resulted in a 25% improvement (P < 0.05) in previously iron-deficient mothers' depression and stress scales as well as in the Raven's Progressive Matrices test. Anemic mothers administered placebo did not improve in behavioral measures. Multivariate analysis showed a strong association between iron status variables (hemoglobin, mean corpuscular volume, and transferrin saturation) and cognitive variables (Digit Symbol) as well as behavioral variables (anxiety, stress, depression). This study demonstrates that there is a strong relation between iron status and depression, stress, and cognitive functioning in poor African mothers during the postpartum period. There are likely ramifications of this poorer "functioning" on mother-child interactions and infant development, but the constraints around this relation will have to be defined in larger studies.
Therapeutic vaccines can be designed to enhance existing T cell memory populations for increased protection against re-infection. In the case of herpes simplex virus type 1, recurrent disease results ...from reactivation of latent virus in sensory ganglia, which is controlled in part by a ganglia-resident HSV-specific memory CD8+ T cell population. Thus, an important goal of a therapeutic HSV-1 vaccine would be to enhance this population.
HSV-1-infected mice were treated with TAK-779 to block CCR5- and CXCR3-mediated CD8+ T cell migration during both acute and latent infections. Additionally, HSV-1-specific CD8+ T cells were transferred into HSV-1 latently infected mice to mimic the effect of a therapeutic vaccine, and their migration into trigeminal ganglia (TG) was traced during steady-state latency, or during recovery of the TG-resident memory CD8+ T cell population following stress-, and corticosterone-induced depletion and HSV-1 reactivation from latency. Bromodeoxy uridine (BrdU) incorporation measured cell proliferation in vivo.
TAK-779 treatment during acute HSV-1 infection reduced the number of infiltrating CD8+ T cells but did not alter the number of viral genome copies. TAK-779 treatment during HSV latency did not affect the size of the TG-resident memory CD8+ T cell population. Transferred HSV-specific CD8+ T cells failed to access latently infected TG during steady-state latency, or during recovery of the TG resident HSV-specific CD8+ T cell population following exposure of latently infected mice to stress and corticosterone. Recovery of the HSV-specific CD8+ T cell population after stress and corticosterone treatment occurred with homeostatic levels of cell division and did not require CD4+ T cell help.
Our findings are consistent with the notion that the CD8+ T cells in latently infected TG are a tissue-resident memory (Trm) population that is maintained without replenishment from the periphery, and that when this population is disrupted, it recovers without proliferation or detectable recruitment of HSV-specific CD8+ T cells from the blood. The compartmentalization of the HSV-specific CD8+ memory T cell population in latently infected TG will complicate the design of therapeutic vaccines.
Extant research on stars has demonstrated stars’ immense direct and indirect contributions to value creation, yet it lags behind strategy scholarship, which has emphasized the dynamic nature of value ...creation associated with firms’ core resources. In particular, we lack knowledge regarding how stars’ knowledge creation varies across a star’s career. Drawing on insights from the stars and careers literatures, we develop theoretical arguments that suggest that over their careers, stars shift focus from emphasizing personal attainment and status to prioritizing legacy building—shifts that we predict will correspond to decreases in stars’ relative individual productivity and conveyance of explicit knowledge spillovers to collaborators (which reinforce stars’ status) and increases in stars’ relative conveyance of tacit knowledge spillovers (that aid in colleagues’ development) as stars advance in career tenure. We test our hypotheses through the analysis of patenting activities spanning the years 2000-2022, 291 firms, and 214,398 inventors, cumulating to more than 1,210,989 inventor-year observations. Through the integration of temporal and psychological perspectives in our consideration of stars’ multiple contributions to knowledge creation over their careers, we bring our understanding of stars into alignment with insights related to the dynamic value creation associated with firms’ resources and advance knowledge on stars’ roles in the micro-foundations of human capital-based competitive advantage.
The health care delivery system in the United States is challenged to meet the needs of a growing population of cancer survivors. A pressing need is to optimize overall function and reduce disability ...in these individuals. Functional impairments and disability affect most patients during and after disease treatment. Rehabilitation health care providers can diagnose and treat patients' physical, psychological, and cognitive impairments in an effort to maintain or restore function, reduce symptom burden, maximize independence and improve quality of life in this medically complex population. However, few care delivery models integrate comprehensive cancer rehabilitation services into the oncology care continuum. The Rehabilitation Medicine Department of the Clinical Center at the National Institutes of Health with support from the National Cancer Institute and the National Center for Medical Rehabilitation Research convened a subject matter expert group to review current literature and practice patterns, identify opportunities and gaps regarding cancer rehabilitation and its support of oncology care, and make recommendations for future efforts that promote quality cancer rehabilitation care. The recommendations suggest stronger efforts toward integrating cancer rehabilitation care models into oncology care from the point of diagnosis, incorporating evidence-based rehabilitation clinical assessment tools, and including rehabilitation professionals in shared decision-making in order to provide comprehensive cancer care and maximize the functional capabilities of cancer survivors. These recommendations aim to enable future collaborations among a variety of stakeholders to improve the delivery of high-quality cancer care.
A solution-based strategy for fabrication of high dielectric constant (κ) nanocomposites for flexible organic field effect transistors (OFETs) has been developed. The nanocomposite was composed of a ...high-κ polymer, cyanoethyl pullulan (CYELP), and a high-κ nanoparticle, zirconium dioxide (ZrO2). Organic field effect transistors (OFETs) based on neat CYELP exhibited anomalous behavior during device operation, such as large hysteresis and variable threshold voltages, which yielded inconsistent devices and poor electrical characteristics. To improve the stability of the OFET, we introduced ZrO2 nanoparticles that bind with residual functional groups on the high-κ polymer, which reduces the number of charge trapping sites. The nanoparticles, which serve as physical cross-links, reduce the hysteresis without decreasing the dielectric constant. The dielectric constant of the nanocomposites was tuned over the range of 15.6–21 by varying the ratio of the two components in the composite dielectrics, resulting in a high areal capacitance between 51 and 74 nF cm–2 at 100 kHz and good insulating properties of a low leakage current of 1.8 × 10–6 A cm–2 at an applied voltage of −3.5 V (0.25 MV cm–1). Bottom-gate, top-contact (BGTC) low operating voltage p-channel OFETs using these solution processable high-κ nanocomposites were fabricated by a contact film transfer (CFT) technique with poly(3-hexylthiophene) (P3HT) as the charge transport layer. Field effect mobilities as high as 0.08 cm2 V–1 s–1 and on/off current ratio of 1.2 × 103 for P3HT were measured for devices using the high-κ dielectric ZrO2 nanocomposite. These materials are promising for generating solution coatable dielectrics for low cost, large area, low operating voltage flexible transistors.
Handling potatoes can create opportunities to develop bruise resulting in quality defects that reduce the acceptability for purchase among retailers, processors, and consumers. Understanding cultivar ...specific bruise susceptibility can aid in developing appropriate bruise management programs. A two-year trial was conducted to examine bruise susceptibility in six commercially grown russet cultivars as affected by impact height. Russet Burbank, Ranger Russet, Clearwater Russet, Dakota Russet, Teton Russet, and Umatilla Russet were impacted using a device that dropped a 100 g steel weight from 8, 18, or 30 cm height to deliver a uniform impact on both the bud and stem end of a stationary tuber. Blackspot bruise incidence, severity and depth, and shatter bruise incidence were evaluated. Blackspot and shatter bruise were significantly influenced by impact height and tuber end in all cultivars. As impact height increased, blackspot bruise incidence, severity, depth, and shatter bruise incidence increased. There were no significant differences among cultivars or tuber ends in shatter bruise at the 8 cm impact height, but differences became evident at 18 and 30 cm impact heights. Overall, the bud end had lower blackspot bruise incidence, severity, and depth compared to the stem end for all cultivars, although the response difference between ends was dependent on cultivar. Clearwater Russet and Dakota Russet had the highest blackspot bruise incidence compared to other cultivars. Teton Russet had the lowest blackspot bruise incidence, severity rating, and depth among the six cultivars but had the highest shatter bruise incidence. This study provided insight on the importance of including more than one impact height to develop robust bruise susceptibility research protocols as well as develop cultivar-specific bruise management recommendations for the industry.
Monitoring soil moisture is still a challenge: it varies strongly in space and time and at various scales while conventional sensors typically suffer from small spatial support. With a sensor ...footprint up to several hectares, cosmic-ray neutron sensing (CRNS) is a modern technology to address that challenge.
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