A novel small molecule ameliorates ocular neovascularisation and synergises with anti-VEGF therapy

Ocular neovascularisation underlies blinding eye diseases such as retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. These diseases cause irreversible vision loss, and provide a significant health and economic burden. Biologics targeting vascular endothelial growth factor (VEGF) are the major approach for treatment. However, up to 30% of patients are non-responsive to these drugs and they are associated with ocular and systemic side effects. Therefore, there is a need for small molecule ocular angiogenesis inhibitors to complement existing therapies. We examined the safety and therapeutic potential of SH-11037, a synthetic derivative of the antiangiogenic homoisoflavonoid cremastranone, in models of ocular neovascularisation. SH-11037 dose-dependently suppressed angiogenesis in the choroidal sprouting assay ex vivo and inhibited ocular developmental angiogenesis in zebrafish larvae. Additionally, intravitreal SH-11037 (1 μM) significantly reduced choroidal neovascularisation (CNV) lesion volume in the laser-induced CNV mouse model, comparable to an anti-VEGF antibody. Moreover, SH-11037 synergised with anti-VEGF treatments in vitro and in vivo. Up to 100 μM SH-11037 was not associated with signs of ocular toxicity and did not interfere with retinal function or pre-existing retinal vasculature. SH-11037 is thus a safe and effective treatment for murine ocular neovascularisation, worthy of further mechanistic and pharmacokinetic evaluation

You Have the Right to Remain Powerless: Deprivation of Agency by Law Enforcement and the Legal and Carceral Systems

(Excerpt) The charges against Philadelphia Police Officer Phillip Nordo read like an episode of The Shield. The grand jury presentment, should you have the stomach for it, is closer to Law & Order: Special Victims Unit. For over twenty years, Officer Nordo groomed, sexually assaulted, and used crime reward funds to pay off vulnerable men in Philadelphia. Whether in his transport van, prison visiting rooms, or police interrogation rooms, he regularly exploited his unfettered access to and absolute control over vulnerable individuals. Though he was not convited until 2022, the communities he stalked and preyed upon knew exactly what Nordo was doing in the decades leading up to his arrest. Living in the streets where Nordo flexed his considerable power, these Philadelphians had nowhere to run, and no one to whom to report the bad detective. They could not call the other officers who took turns leaving Nordo alone with suspects for long stretches of time. Nor could they rely on the Internal Affairs Division, who corroborated rape allegations against Nordo and then kept him on payroll for another decade. And they certainly could not turn to Philadelphia prosecutors, who had quietly put Nordo on a “no call list.” This Article is not about Phillip Nordo. This Article is about the outright excision of agency that our legal system exacts on vulnerable communities. At every stage, our legal system strips already marginalized communities of power, particularly communities of color. Mass incarceration, a mechanism to uphold white supremacy, has further corroded individual and collective autonomy in these communities. This Article examines the ways in which law enforcement, the legal system, and the carceral state remove agency from individuals. In the final section, this Article suggests measures to immediately empower incarcerated individuals who have been stripped of their agency by our system

Start Up of a Nb-1%Zr Potassium Heat Pipe From the Frozen State

The start up of a liquid metal heat pipe from the frozen state was evaluated experimentally with a Nb-1%Zr heat pipe with potassium as the working fluid. The heat pipe was fabricated and tested at Los Alamos National Laboratory. RF induction heating was used to heat 13 cm of the 1-m-long heat pipe. The heat pipe and test conditions are well characterized so that the test data may be used for comparison with numerical analyses. An attempt was made during steady state tests to calibrate the heat input so that the heat input would be known during the transient cases. The heat pipe was heated to 675 C with a throughput of 600 W and an input heat flux of 6 W/cm(exp 2). Steady state tests, start up from the frozen state, and transient variations from steady state were performed

Internal Training Load Measures During a Competitive Season in Collegiate Women Lacrosse Athletes

International Journal of Exercise Science 13(4): 778-788, 2020. Monitoring internal load provides useful and non-invasive markers of training stress and adaptation. However, the relationship between internal load measures across a competitive window remains inconclusive and limited. The purpose of this study was to report various internal load measures, as well as their relationship, across a season in Division I women lacrosse athletes (n = 20). Ultra-short natural logarithm of the root mean square of successive differences (lnRMSSD), salivary testosterone, cortisol, the testosterone:cortisol ratio, and self-reported measures of fatigue and recovery were collected weekly for 13 weeks. Means ± SD were calculated to provide descriptive values and a repeated measure analysis of variance (ANOVA) was used to analyze changes in testosterone, cortisol, testosterone:cortisol ratio (n = 8), and lnRMSSD (n = 8) over the course of the season. Pearson correlations assessed relationships between all internal load measures. No significant time effect was observed in testosterone (p = 0.059), cortisol (p = 0.544), testosterone:cortisol ratio (p = 0.120), or lnRMSSD (p = 0.062). lnRMSSD was correlated with testosterone (r = 0.265), cortisol (r = -0.232), testosterone:cortisol ratio (r = 0.345), and fatigue (r = -0.256) (p \u3c 0.05). More research is needed to examine relationships among markers of internal stress across all phases of the training cycle. Routine monitoring may help practitioners optimize training programming to reduce injury, illness, and overtraining

Fabrication and Testing of Mo-Re Heat Pipes Embedded in Carbon/Carbon

Refractory-composite/heat-pipe-cooled wing an tail leading edges are being considered for use on hypersonic vehicles to limit maximum temperatures to values below material reuse limits and to eliminate the need to actively cool the leading edges. The development of a refractory-composite/heat-pipe-cooled leading edge has evolved from the design stage to the fabrication and testing of heat pipes embedded in carbon/carbon (C/C). A three-foot-long, molybdenum-rhenium heat pipe with a lithium working fluid was fabricated and tested at an operating temperature of 2460 F to verify the individual heat-pipe design. Following the fabrication of this heat pipe, three additional heat pipes were fabricated and embedded in C/C. The C/C heat-pipe test article was successfully tested using quartz lamps in a vacuum chamber in both a horizontal and vertical orientation. Start up and steady state data are presented for the C/C heat-pipe test article. Radiography and eddy current evaluations were performed on the test article

Genomic insights into the origin of farming in the ancient Near East

We report genome-wide ancient DNA from 44 ancient Near Easterners ranging in time between ~12,000 and 1,400 BC, from Natufian hunter–gatherers to Bronze Age farmers. We show that the earliest populations of the Near East derived around half their ancestry from a ‘Basal Eurasian’ lineage that had little if any Neanderthal admixture and that separated from other non-African lineages before their separation from each other. The first farmers of the southern Levant (Israel and Jordan) and Zagros Mountains (Iran) were strongly genetically differentiated, and each descended from local hunter–gatherers. By the time of the Bronze Age, these two populations and Anatolian-related farmers had mixed with each other and with the hunter–gatherers of Europe to greatly reduce genetic differentiation. The impact of the Near Eastern farmers extended beyond the Near East: farmers related to those of Anatolia spread westward into Europe; farmers related to those of the Levant spread southward into East Africa; farmers related to those of Iran spread northward into the Eurasian steppe; and people related to both the early farmers of Iran and to the pastoralists of the Eurasian steppe spread eastward into South Asia

Changes in Maximal Strength and Home Run Performance in Ncaa Division I Baseball Players Across 3 Competitive Seasons: A Descriptive Study

The purpose of this longitudinal, descriptive study was to observe changes in maximal strength measured via isometric clean grip mid-thigh pull and home runs (total and home runs per game) across three years of training and three competitive seasons for four National Collegiate Athletic Association (NCAA) Division 1 baseball players. A one-way repeated measures analysis of variance (ANOVA) was performed, revealing significant univariate effects of time for peak force (PF) (p = 0.003) and peak force allometrically scaled (PFa) (p = 0.002). Increases in PF were noted from season 1 to season 2 (p = 0.031) and season 3 (p = 0.004), but season 2 was not significantly different than season 3 (p = 0.232). Additionally, increases in PFa were noted from season 1 to season 2 (p = 0.010) and season 3 (p \u3c 0.001), but season 2 was not significantly different than season 3 (p = 0.052). Home runs per game rose from the 2009 (0.32) to 2010 season (1.35) and dropped during the 2011 season (1.07). A unique aspect of the study involves 2010 being the season in which ball-bat coefficient of restitution (BBCOR) bats were introduced to the NCAA competition

A genetic perspective on the recent demographic history of Ireland and Britain

While subtle yet discrete clusters of genetic identity across Ireland and Britain have been identified, their recent demographic history is unclear. Using genotype data from 6574 individuals with associated regional Irish or British ancestry, we identified genetic communities by applying Leiden community detection. Using haplotype segments segregated by length as proxy for time, we inferred regional Irish and British demographic histories. Using a subset of Irish participants, we provide genealogical context by estimating the enrichment/depletion of surnames within the Irish genetic communities. Through patterns of haplotype sharing, we find evidence of recent population bottlenecks in Orcadian, Manx and Welsh genetic communities. We observed temporal changes in genetic affinities within and between genetic communities in Ireland and Britain. Structure in Ireland is subtler compared to neighbouring British communities, with the Irish groups sharing relatively more short haplotype segments. In addition, we detected varying degrees of genetic isolation in peripheral Irish and British genetic communities across different time periods. Further, we observe a stable migration corridor between north-east Ireland and south-west Scotland while there is a recent migration barrier between south-east and west Ireland. Genealogical analysis of surnames in Ireland reflects history—Anglo-Norman surnames are enriched in the Wexford community while Scottish and Gallowglass surnames were enriched in the Ulster community. Using these new insights into the regional demographic history of Ireland and Britain across different time periods, we hope to understand the driving forces of rare allele frequencies and disease risk association within these populations