Sex difference in OA : Should we blame estrogen?

Funding: The authors declared that this study has received no financial support.Peer reviewedPublisher PD

Attitudes, Perceptions and Intimate Partner Violence: A Study of the Nigerian Context

Intimate partner violence (IPV) is a major public health issue affecting many women around the world. It is a topic that has attracted a great deal of research over the years, but the dynamics of the issue in some parts of the world, especially in Sub-Saharan Africa, is still very vague, necessitating more research in the region. This study uses a cross-sectional population-based survey to explore attitudes of women towards gender roles in a Sub-Saharan African country – Nigeria, as this is one of the factors that is likely to influence IPV occurrence. The results show that attitudes towards gender roles in Nigeria are more supportive of male dominance and women being subservient to their husband/partner, and also suggest that addressing such attitudes may be an important strand of action in tackling IPV issues in the country

Die genetische Variabilität des Gamma-Glutamyl-Carboxylase-Gens (GGCX) bei Patienten mit angeborener Verminderung der Vitamin-K-abhängigen Gerinnungsfaktoren und in der Allgemeinbevölkerung

Die Gamma-Glutamyl-Carboxylase spielt eine Schlüsselrolle im menschlichen Organismus, da sie für die posttranslationale Modifikation sämtlicher Vitamin-K-abhängiger Proteine verantwortlich ist. Ein hereditärer Mangel aller Vitamin-K-abhängigen Faktoren aufgrund eines Defekts in der Gamma-Glutamyl-Carboxylase (VKCFD1) ist sehr selten und geht mit einer gesteigerten Blutungsneigung einher. Aktuelle Arbeiten zeigen eine weitere Manifestation von Mutationen im Gamma-Glutamyl-Carboxylase-Gen, die ein dermatologisches Krankheitsbild, ähnlich der Pseudoxanthoma elasticum, darstellt. In diesen Fällen zeigen die Patienten sowohl dermatologische Effloreszenzen im Sinne der PXE als auch eine Verminderung der Vitamin-K-abhängigen Faktoren. Es wird vermutet, dass die PXE-ähnlichen Hautveränderungen auf eine Funktionsstörung des Matrix-Gla-Proteins zurückzuführen sein könnten. In der vorliegenden Arbeit wurde eine Mutationsdiagnostik bei vier Patienten mit kongenitalem Mangel aller Vitamin-K-abhängigen Gerinnungsfaktoren durchgeführt. Insgesamt wurden dabei fünf Mutationen nachgewiesen, davon vier Missense-Mutationen und eine Stopp-Mutation. Zwei der Patienten wiesen eine „compound Heterozygotie“ auf. Bei den gefunden Mutationen wurden drei im Rahmen dieser Arbeit erstmals aufgezeigt, die anderen zwei waren in der Literatur bereits beschrieben. Bei einer der Mutationen konnte ein „Founder“-Effekt in Bezug auf einen anderen Patienten aus der Literatur nachgewiesen werden. Sollte zukünftig diese Mutation in Deutschland vorkommen und sich auch auf die „Founder“-Mutation zurückführen lassen, böte sich dieser Mechanismus als eine Erklärung für das gehäufte Vorkommen der VKCFD Typ 1 in Deutschland an. Ein Hinweis auf eine PXE-like Disorder konnte bei keinem der Patienten nachgewiesen werden. Zusätzlich wurde die genetische Variabilität des Gamma-Glutamyl-Carboxylase-Gens in der Normalbevölkerung untersucht. Für die Untersuchungen wurde zunächst die DNA einer phänotypisch unauffälligen Kontrollgruppe, bestehend aus 200 gesunden Blutspendern, auf Genvariationen im GGCX-Gen analysiert. Nach der Isolierung und der Amplifikation der DNA wurde mit sämtlichen Proben zunächst ein Mutations-Screening mittels dHPLC durchgeführt. Auffällige Abschnitte und solche, bei denen häufige und/oder mehrere Polymorphismen bereits bekannt waren, wurden sequenziert. Auf diese Weise wurden acht Polymorphismen in den codierenden bzw. die Exone flankierenden Genabschnitten nachgewiesen. Davon wurden zwei erstmals beschrieben (c.43+33T>A; c.1288-38T>C). Schließlich sollte mit dieser Arbeit versucht werden zu klären, wie eine möglichst effiziente Diagnostik von Mutationen bzw. Polymorphismen des GGCX-Gens möglich ist. In unseren Untersuchungen wurde sowohl mit der dHPLC (Wave-System) als Screening-Methode gearbeitet als auch Genabschnitte sequenziert. Mittels der dHPLC kann ein hohes Probenaufkommen in kurzer Zeit mit vergleichsweise geringem Aufwand und vergleichsweise geringeren Kosten (ca. 30 € pro Genuntersuchung vs. Komplettsequenzierung ca. 300 €) bewältigt werden. Bei Genabschnitten mit vielen oder häufigen Polymorphismen ist dies ineffektiv, weil es nur das Vorhandensein einer Veränderung, nicht jedoch die Veränderung selbst beschreiben kann. Daher empfiehlt es sich, beide Methoden zu kombinieren, welches sich als die effizienteste und rationalste Methode für die Mutationsdiagnostik darstellt. Die Ergebnisse der vorliegenden Arbeit sind von grundsätzlichem Interesse für die biomedizinische Forschung. Eventuell wird es damit dann möglich sein, Krankheitsentstehungen und ihre Verläufe bei Mutationen der Gamma-Glutamyl-Carboxylase besser zu verstehen und damit eine noch effektivere und nebenwirkungsärmere Therapie einzusetzen.The Gamma-glutamyl-carboxylase plays a key role in the human organism, as it is responsible for posttranslational modification of all vitamin-K-dependant proteins. A hereditary deficiency of all vitamin-K-dependant factors based on a defect of the Gamma-glutamyl-carboxylase (VKCFD 1) is rare and corresponds with an increased tendency to bleeding complications. Recent studies show an additional clinical manifestation of the GGCX gene, which seems to be a dermatological disease pattern similar to Pseudoxanthoma Elasticum. In these cases patients show dermatological efflorescences as well as a decrease of all vitamin-K-dependant factors. It is assumed, that the cutaneous changes could be attributed to a disfunction of matrix-gla-protein. In this thesis a mutation diagnosis on four patients with congential deficiency of all vitamin-K-dependent clotting factors have been undertaken. In total, five mutations have been detected – four missense mutations and one stop_mutation. Two of the patients exhibited „compound heterozygosity“. In this study, two of the detected mutations have been documented for the first time; the other three have already been described in literature before. At one of the mutations a „founder effect“ in connection with another patients could be found. If this mutation should occur in Germany again and be traced back to this „founder mutation“, this mechanism would be an explanation for an accumulation of VKCFD Typ 1 in Germany. A sign for PXE-like disorder could not be detected in any of the patients. In addition the genetic variability of the Gamma-glutamyl-carboxylase-gene in the overall population has been researched. For the examinations, DNA of a control group (200 healthy blood donors) without pathological phenotypical findings have been analysed for gene variations on the GGCX-gene. After the isolation and amplification all DNA samples have been analysed with mutations screening by dHPLC. Noticiable parts and those, for which frequent and/or prevalent polymorphisms have been stated before, were sequenced. Eight polymorphisms in the coding and exon-flanking regions have been detected by applying this method, two of them for the first time (c.43+33T>A; c.1288-38T>C). Additionaly, the thesis tried to clarify how efficient diagnostic of mutations and polymorphisms of the GGCX-gene could be undertaken. In our research we applied dHPLC (WAVE-system) as well as gene sequencing. By applying the dHPLC-method a larger batch of samples can be analysed in a short-time span with comparable less effort and, even more important, comparably at lower costs (approximately €30 per gene analysis vs. complete sequencing at € 300). When applied at gene parts with numerous or frequent polymorphisms, the method is ineffective, as only the existence of alteration per se is marked, but not the alteration type. Looking at the quality of the results, it is recommendable to combine the two methods, which results in the most efficient and most rational method for mutation diagnosis. The results of this thesis bear fundamental interest for the biomedical sciences & research. There might be options, for better understanding pathogeneses and their characteristics in Gamma-glutamyl-carboxylase-gene defects and therefore develop a therapy which will be more effective and with few side effects

Synthesis and evaluation of designed PKC modulators for enhanced cancer immunotherapy.

Bryostatin 1 is a marine natural product under investigation for HIV/AIDS eradication, the treatment of neurological disorders, and enhanced CAR T/NK cell immunotherapy. Despite its promising activity, bryostatin 1 is neither evolved nor optimized for the treatment of human disease. Here we report the design, synthesis, and biological evaluation of several close-in analogs of bryostatin 1. Using a function-oriented synthesis approach, we synthesize a series of bryostatin analogs designed to maintain affinity for bryostatin's target protein kinase C (PKC) while enabling exploration of their divergent biological functions. Our late-stage diversification strategy provides efficient access to a library of bryostatin analogs, which per our design retain affinity for PKC but exhibit variable PKC translocation kinetics. We further demonstrate that select analogs potently increase cell surface expression of CD22, a promising CAR T cell target for the treatment of leukemias, highlighting the clinical potential of bryostatin analogs for enhancing targeted immunotherapies

Room to Glo: A systematic comparison of semantic change detection approaches with word embeddings

Word embeddings are increasingly used for the automatic detection of semantic change; yet, a robust evaluation and systematic comparison of the choices involved has been lacking. We propose a new evaluation framework for semantic change detection and find that (i) using the whole time series is preferable over only comparing between the first and last time points; (ii) independently trained and aligned embeddings perform better than continuously trained embeddings for long time periods; and (iii) that the reference point for comparison matters. We also present an analysis of the changes detected on a large Twitter dataset spanning 5.5 years.This work was supported by The Alan Turing Institute under the EPSRC grant EP/N510129/1

Abietane diterpenoids and neolignans from the roots of Pinus kesiya

The phytochemical investigation of the ethyl acetate extract of Pinus kesiya Royle ex Gordon roots led to the isolation of two abietane diterpenes, 7-oxo-15-hydroxy-dehydroabietic acid (1) and dehydroabietic acid (2) as well as two neolignans, cedrusin (3) and cedrusin-4-O-β-D-glucopyranoside (4). Their structures were determined by combination of spectral analysis and comparison with reported data. Among them, compound 1 was isolated from the genus Pinus for the first time. Keywords. Pinus kesiya, abietane diterpenes, neolignans, dehydroabietic acid, cedrusin

Skin resident memory CD8 T cells with a potential of producing IL-17A are accumulated in disease-naïve non -lesional sites of psoriasis

筑波大学 (University of Tsukuba)201

Skin resident memory CD8 T cells with a potential of producing IL-17A are accumulated in disease-naïve non -lesional sites of psoriasis

筑波大学 (University of Tsukuba)201

6-Month Change in Pain and Function by Pre-Operative Pain and Function among Patients Selected for Total Knee Replacement in the United States

Background/Purpose: The increase in total knee replacements (TKRs) between 1979 and 2006 is staggering. Debate is growing regarding the appropriate utilization of TKRs. We examined pain, function, quality of life (QOL), and satisfaction at 6-month post-surgery by pain and function at time of surgery. Methods: Data came from the nationally representative FORCE-TJR cohort of patients from 150 surgeons. Participants had primary, unilateral TKRs due to osteoarthritis between 2011 and 2014. Their knee pain (KOOS), physical functions (SF36), and QOL were measured at pre- and 6 months post-surgery. We classified patients as having high or low pre-operative pain (KOOS Pain \u3c 70 vs. ≥70), low or high pre-operative physical function (SF-36 PCS \u3c 40 vs. ≥40), and grouped as: 1) Low pain-High function (LP-HF), 2) Low pain-Low function (LP-LF), 3) High pain-High function (HP-HF), and 4) High pain-Low function (HP-LF). We compared pre- and post-operative changes in pain and function scores among the four groups. Results: Of 4,563 participants, 5% had pre-operative LP-HF and 75% HP-LF. By 6-month post-surgery, 85% of LP-HF patients reported no change and 4% reported worse symptoms; the HP-LF group had 18% no change and 52% with large improvement. For function in the LP-HF group, mean 6-month change (SD) was 2.6 (7.8), with post-operative mean of 50.0 (7.4). Mean change for the HP-LF group was 11.9 (9.0), with post-operative mean of 42.0 (9.5). For pain score in the LP-HF group, mean 6-month change was 8.3 (14.6), with post-operative mean (SD) of 88.9 (13.0). The HP-LF group had average improvement of 37.2 (19.7), and post-operative mean of 79.9 (17.3). QOL was better among the LP-HF than HP-LF groups; satisfaction was similar. Conclusion: The majority of patients had appropriate TKR utilization and achieved large improvement in pain and function. Patients with pre-operative LP-HF achieved the smaller mean change, but better absolute outcomes