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We present a new open-source tool for magnetospheric computations, that is modelling of cosmic ray propagation in the geomagnetosphere, named "Oulu - Open-source geomagneToSphere prOpagation tool" (OTSO). A tool of this nature is required to interpret experiments and study phenomena within the cosmic ray research field. Here, we demonstrate several applications of OTSO, namely the computation of asymptotic directions of selected cosmic ray stations, effective rigidity cut-off across the globe at various conditions within the design, and general properties, including the magnetospheric models employed. OTSO was applied to the investigation of several ground-level enhancement events after which comparison and validation of OTSO with older widely used tools such as MAGNETOCOSMICS was performed, and good agreement was achieved. The necessary background for the analysis of two notable ground-level enhancements was produced using OTSO and their spectral and angular characteristics show good agreement with prior studies and spacecraft data. This validation of OTSO's current abilities reveals its usefulness to the cosmic ray research field and its open-source nature further allows for the tool to be developed beyond its current capabilities by users to meet the needs of the research community.

H3B-5942 in combination with palbocyclib shows synergy in vitro and in vivo

Additional methods provided.

Supplementary Figure from Covalent ERα Antagonist H3B-6545 Demonstrates Encouraging Preclinical Activity in Therapy-Resistant Breast Cancer

Supplementary Data from Covalent ERα Antagonist H3B-6545 Demonstrates Encouraging Preclinical Activity in Therapy-Resistant Breast Cancer

Enriched GSEA pathways

Nearly 30% of patients with relapsed breast cancer present activating mutations in estrogen receptor alpha (ERα) that confer partial resistance to existing endocrine-based therapies. We previously reported the development of H3B-5942, a covalent ERα antagonist that engages cysteine-530 (C530) to achieve potency against both wild-type (ERαWT) and mutant ERα (ERαMUT). Anticipating that the emergence of C530 mutations could promote resistance to H3B-5942, we applied structure-based drug design to improve the potency of the core scaffold to further enhance the antagonistic activity in addition to covalent engagement. This effort led to the development of the clinical candidate H3B-6545, a covalent antagonist that is potent against both ERαWT/MUT, and maintains potency even in the context of ERα C530 mutations. H3B-6545 demonstrates significant activity and superiority over standard-of-care fulvestrant across a panel of ERαWT and ERαMUT palbociclib sensitive and resistant models. In summary, the compelling preclinical activity of H3B-6545 supports its further development for the potential treatment of endocrine therapy–resistant ERα+ breast cancer harboring wild-type or mutant ESR1, as demonstrated by the ongoing clinical trials (NCT03250676, NCT04568902, NCT04288089). Summary: H3B-6545 is an ERα covalent antagonist that exhibits encouraging preclinical activity against CDK4/6i naïve and resistant ERαWT and ERαMUT tumors.

H3B-6527 response in 40 HCC cell lines and 625 cell lines.

Legends describing each of the supplementary figures and tables

RNA-seq analysis of 24 CCLE HCC cell lines.

Activation of the fibroblast growth factor receptor FGFR4 by FGF19 drives hepatocellular carcinoma (HCC), a disease with few, if any, effective treatment options. While a number of pan-FGFR inhibitors are being clinically evaluated, their application to FGF19-driven HCC may be limited by dose-limiting toxicities mediated by FGFR1–3 receptors. To evade the potential limitations of pan-FGFR inhibitors, we generated H3B-6527, a highly selective covalent FGFR4 inhibitor, through structure-guided drug design. Studies in a panel of 40 HCC cell lines and 30 HCC PDX models showed that FGF19 expression is a predictive biomarker for H3B-6527 response. Moreover, coadministration of the CDK4/6 inhibitor palbociclib in combination with H3B-6527 could effectively trigger tumor regression in a xenograft model of HCC. Overall, our results offer preclinical proof of concept for H3B-6527 as a candidate therapeutic agent for HCC cases that exhibit increased expression of FGF19. Cancer Res; 77(24); 6999–7013. ©2017 AACR.

The first ground-level enhancement of the current Solar Cycle 25 occurred on 28 October 2021. It was observed by several space-borne and ground-based instruments, specifically neutron monitors. A moderate count-rate increase over the background was observed by high-altitude polar stations on the South Pole and Dome C stations at the Antarctic plateau. Most of the neutron monitors registered only marginal count-rate increases. Using detrended records and employing a method verified by direct space-borne measurements, we derive the rigidity spectra and angular distributions of the incoming solar protons in the vicinity of Earth. For the analysis, we employed a newly computed and parameterized neutron-monitor yield function. The rigidity spectra and anisotropy of solar protons were obtained in their time evolution throughout the event. A comparison with the Solar and Heliospheric Observatory/Energetic and Relativistic Nuclei and Electron (SOHO/ENRE) experiment data is also performed. We briefly discuss the results derived from our analysis.

The first solar proton event of solar cycle 25 was detected on 28 October 2021 by several neutron monitors (NMs) in the polar regions, the strongest signal was registered by the DOMC/DOMB monitors located at the Antarctic plateau at Concordia French-Italian research station. It is identified as the GLE (ground-level enhancement) #73 in the International GLE database. Here, we report the observations of the GLE by the global NM network and present the derived angular and spectral features of solar energetic protons with their dynamical evolution throughout the event employing a state-of-the-art model based on analysis of the neutron monitor data. Using the derived spectra we computed the related terrestrial effects, namely the cosmic rate induced ionization at several altitudes on a global map and discuss possible implications.

Inappropriate sinus tachycardia (IST) is a common observation in patients with post-COVID-19 syndrome (PCS) but has not yet been fully described to date. To investigate the prevalence and the mechanisms underlying IST in a prospective population of PCS patients. Consecutive patients admitted to the PCS Unit between June and December 2020 with a resting sinus rhythm rate ≥ 100 bpm were prospectively enrolled in this study and further examined by an orthostatic test, 2D echocardiography, 24-h ECG monitoring (heart rate variability was a surrogate for cardiac autonomic activity), quality-of-life and exercise capacity testing, and blood sampling. To assess cardiac autonomic function, a 2:1:1 comparative sub-analysis was conducted against both fully recovered patients with previous SARS-CoV-2 infection and individuals without prior SARS-CoV-2 infection. Among 200 PCS patients, 40 (20%) fulfilled the diagnostic criteria for IST (average age of 40.1 ± 10 years, 85% women, 83% mild COVID-19). No underlying structural heart disease, pro-inflammatory state, myocyte injury, or hypoxia were identified. IST was accompanied by a decrease in most heart rate variability parameters, especially those related to cardiovagal tone: pNN50 (cases 3.2 ± 3 vs. recovered 10.5 ± 8 vs. non-infected 17.3 ± 10; p

Measurements of the natural radiation background with different devices and at various conditions are important from a methodological point of view in order to compare and eventually inter-calibrate different experimental sets, also to provide a reliable basis for improving the existing models for assessment of the environmental radiation in the Earth’s atmosphere. Here, we report results from methodological measurements with a small portable device, namely mobile dosimetry unit (MDU)-1 Liulin, performed in different conditions in the Arctic region, including the altitude profile of the atmospheric radiation obtained during the flight of the HEMERA-2 zero-pressure balloon. A comparison with a calibrated device is also performed. It was demonstrated that the MDU-1 Liulin can provide reliable measurements of the radiation background in the Arctic atmosphere during a zero-pressure balloon flight.

Purpose The purpose of this paper is to explore how potential exposure to missionary activity impacts both English language proficiency and labor market earnings of male and female immigrants to the USA. Design/methodology/approach This study uses the pooled files of the American Community Survey (2005–2009). To estimate the relationship between the missionary activity of both Protestants and Catholics on an immigrant’s English language proficiency using a linear probability model and their labor market earnings using the human capital earnings function that is estimated with an ordinary least squares model. Among other relevant variables, the analysis controls for the colonial heritage of the immigrant’s country of origin. Findings Overall, and within colonial heritages, the results indicate that male and female immigrants from countries with a higher concentration of Protestant missionaries tend to exhibit higher levels of English language proficiency and earnings, and those from countries with a greater concentration of Catholic missionaries exhibit lower levels of both, compared to countries with lower concentrations of missionaries. Furthermore, a greater proficiency in English enhances earnings. One of the important implications of the findings in this paper is that a “missionary variable” often used in other studies is too aggregate and may mask important findings because of strikingly different effects of Protestant and Catholic activities and characteristics of the missionaries. Originality/value This study explores for the first time how, through a missionary concentration variable, potential exposure to missionary activity impacts the English language proficiency and earnings of immigrants.

The body naturally and continuously secretes sweat for thermoregulation during sedentary and routine activities at rates that can reflect underlying health conditions, including nerve damage, autonomic and metabolic disorders, and chronic stress. However, low secretion rates and evaporation pose challenges for collecting resting thermoregulatory sweat for non-invasive analysis of body physiology. Here we present wearable patches for continuous sweat monitoring at rest, using microfluidics to combat evaporation and enable selective monitoring of secretion rate. We integrate hydrophilic fillers for rapid sweat uptake into the sensing channel, reducing required sweat accumulation time towards real-time measurement. Along with sweat rate sensors, we integrate electrochemical sensors for pH, Cl−, and levodopa monitoring. We demonstrate patch functionality for dynamic sweat analysis related to routine activities, stress events, hypoglycemia-induced sweating, and Parkinson’s disease. By enabling sweat analysis compatible with sedentary, routine, and daily activities, these patches enable continuous, autonomous monitoring of body physiology at rest., Low secretion rates and evaporation pose challenges for collecting resting thermoregulatory sweat for non-invasive analysis of body physiology. Here the authors present wearable microfluidics-based patches for continuous sweat monitoring at rest that enable detection of pH, Cl−, and levodopa for dynamic sweat analysis related to routine activities, stress events, hypoglycemia-induced sweating, and Parkinson’s disease.

As global numbers of COVID-19 grow, chronic neurological symptoms, including those of autonomic dysfunction, are being reported with increasing frequency. Mounting evidence suggests that many patients experience chronic and sometimes debilitating symptoms long after their acute infectious period, leading to the new diagnostic category of post-acute COVID syndrome. Many symptoms of post-acute COVID syndrome appear autonomic in nature, suggesting that autonomic impairment may play a central role in the underlying pathophysiology. In this review, we discuss the autonomic symptoms and manifestations of post-acute COVID syndrome, potential mechanisms involved, and future directions for a better understanding of this novel condition.

Research on the efficacy of foreign aid has been extensively conducted over the last three decades, but empirically the results remain inconclusive. Previous literature has relied upon linear growth model to estimate their models, methods inconsistent with the existence of poverty traps. These approaches have found that the effect of foreign is either negative, to positive, or even conditional on the policy environment in the country. More recent theoretical literature has started to point towards a nonlinear effect of foreign aid on the level of income. This nonlinear effect is consistent with a poverty trap model. To provide empirical support for this theory this paper relaxes the assumption of linearity in the model to determine if the efficacy of foreign aid is nonlinear. To accomplish this the relationship between foreign aid and the level of income is examined using a cross sectional data set of 72 countries that received Official Development Aid between 1985 and 2014 using a multivariate adaptive regressive splines (MARS) estimation. The MARS model is a nonlinear approach that systematically identifies both threshold levels and interaction terms between independent variables. Most importantly, the MARS model will detect if foreign aid has a statistically significant threshold effect. This finding would be consistent with the poverty trap hypothesis and also explain why there has been a lack of consensus so far. The results suggest that by using a nonlinear estimation we significantly improve, 18 to 44 percent reduction in the residual sum of squares, the fit of our growth model compared to an ordinary least squares estimation, as well as also detect a threshold in the effect of foreign aid that is consistent with a poverty trap hypothesis. These results are consistent when we analyze foreign aid as either a percent of gross national income—threshold at 4.6 percent—or per capita—threshold at $24.97. Below these thresholds the effect of foreign aid is either negative, or statistically zero, but when foreign aid is sufficiently large the effect is large and positive. We also detect significant interactions between foreign aid and both human capital and population growth. The policy implication being that if a country is going to experience a positive impact on their level of income the amount of foreign aid needs to be sufficiently large enough. Furthermore, the interactions suggest that some degree of selectivity should take place on which countries are best equipped to use aid.

This article is concerned with the awarding of PhDs in the USA and Canada in the post-WW II period, overall, by gender and major academic discipline. The effects of the explanatory variables lagged by 6 years, to allow for time-to-degree completion, are consistent with the model. Military conscription with educational exemptions and the Vietnam War increased male PhDs in the USA, but, as expected, had no effect for US females or in Canada. This suggests that the war and draft effect for US males were not reflecting other unmeasured North American effects. Government expenditures on research and development enhanced the PhD production, especially for males and in the physical sciences. The cyclical indicator, the adult male unemployment rate, has a weak positive effect for males in both the USA and Canada, suggesting that during the post-WW II period, the positive effect on graduate-level education of the reduced opportunity cost of time due to a recession was stronger than the negative wealth effect of th...

Background The medial ulnar collateral ligament (MUCL) is the primary stabilizer against valgus stress on the elbow. The anatomy of the 3 bundles of the MUCL has been well studied in adults, but our review of the English literature found no study evaluating the origin of the MUCL in a large group of asymptomatic, skeletally immature elbows as it relates to the medial epicondylar physis. Methods Magnetic resonance T1-coronal images of 44 skeletally immature elbows (ages 5 to 17 y) with no history of fracture were evaluated by 2 independent musculoskeletal radiologists, a board-certified orthopaedic surgeon with fellowship training in pediatric orthopaedics, and an orthopaedic surgery resident. The location of the origin of the anterior bundle of the MUCL (aMUCL) was identified and its distance from the medial epicondylar physis was measured. Results All 44 images showed that the aMUCL attached either on or medial to the medial epicondylar physis. The average distance from the origin of the aMUCL to the medial epicondylar physis was 3.1 mm. There was no statistically significant relationship between age and location of the aMUCL insertion relative to the physis (P=0.183). Conclusions In the skeletally immature elbow, the aMUCL originates medial to the medial epicondylar physis. Clinical relevance Although treatment of medial epicondylar humeral fractures remains controversial, understanding the relationship between the aMUCL and the medial epicondylar physis may be helpful in making decisions regarding fracture management.

Compared to other immigrants to the United States, recent Jewish immigrants from the former Soviet Union have achieved high levels of English language proficiency and earnings. They experience disadvantages in both dimensions at arrival, but because of steeper improvements with duration in the United States, they reach parity or surpass the English proficiency and earnings of other immigrants. This pattern is seen in the most recent data, the American Community Survey, 2005 to 2009, which is studied here, but also in earlier censuses (1980-2000). The Russian Jews, whether male or female, have higher levels of schooling and English proficiency. Moreover, they appear to secure greater earnings payoffs in the US labor market from their schooling, their labor market experience in the US, and their proficiency in English. What is perhaps remarkable is that the Russian Jewish immigrants from the late 19th and early 20th centuries (1881 to 1920's) also experienced high levels of human capital accumulation and economic success (measured by earnings or occupational attainment). And their US-born children achieved even greater successes compared to other native-born children. This is not emerging from a highly selective immigrant population. The Russian Jewish migration is a mass migration influenced, in part, by refugee motivations. This leads to the obvious but still unanswered question: What is it about the Jews of the Former Russian Empire/Soviet Union that has resulted in their high levels of success in the United States over the past 25 years?