Adaptive protein divergence of BMP ligands takes place under developmental and evolutionary constraints

The bone morphogenetic protein (BMP) signaling network, comprising evolutionary conserved BMP2/4/Decapentaplegic (Dpp) and Chordin/Short gastrulation (Sog), is widely utilized for dorsal-ventral (DV) patterning during animal development. A similar network is required for posterior crossvein (PCV) formation in the Drosophila pupal wing. Although both transcriptional and post-transcriptional regulation of co-factors in the network gives rise to tissue-specific and species-specific properties, their mechanisms are incompletely understood. In Drosophila, BMP5/6/7/8-type ligands, Screw (Scw) and Glass bottom boat (Gbb), form heterodimers with Dpp for DV patterning and PCV development, respectively. Sequence analysis indicates that the Scw ligand contains two N-glycosylation motifs: one being highly conserved between BMP2/4- and BMP5/6/7/8-type ligands, and the other being Scw ligand specific. Our data reveal that N-glycosylation of the Scw ligand boosts BMP signaling both in cell culture and in the embryo. In contrast, N-glycosylation modifications of Gbb or Scw ligands reduce the consistency of PCV development. These results suggest that tolerance for structural changes of BMP5/6/7/8-type ligands is dependent on developmental constraints. Furthermore, gain and loss of N-glycosylation motifs in conserved signaling molecules under evolutionary constraints appear to constitute flexible modules to adapt to developmental processes.Peer reviewe

New resources for the Drosophila 4th chromosome : FRT101F enabled mitotic clones and Bloom syndrome helicase enabled meiotic recombination

Genes on the long arm of the Drosophila melanogaster 4th chromosome are difficult to study because the chromosome lacks mitotic and meiotic recombination. Without recombination numerous standard methods of genetic analysis are impossible. Here, we report new resources for the 4th. For mitotic recombination, we generated a chromosome with an FRT very near the centromere in 101F and a derivative that carries FRT101F with a distal ubiquitously expressed GAL80 transgene. This pair of chromosomes enables both unmarked and MARCM clones. For meiotic recombination, we demonstrate that a Bloom syndrome helicase and recombination defective double mutant genotype can create recombinant 4th chromosomes via female meiosis. All strains will be available to the community via the Bloomington Drosophila Stock Center. Additional resources for studies of the 4th are in preparation and will also be made available. The goal of the 4th Chromosome Resource Project is to accelerate the genetic analysis of protein-coding genes on the 4th, including the 44 genes with no demonstrated function. Studies of these previously inaccessible but largely conserved genes will close longstanding gaps in our knowledge of metazoan development and physiology.Peer reviewe

Феномен веры в мистическом опыте просветления

В статье исследуется феномен религиозной веры и делается вывод о существовании двух ее уровней. Первый из них - "вера просительная" (со многим количеством условий), характерна для человека, воспринимающего себя как смертное Тело-Эго и ориентированного на страх. Совершенной формой религиозной веры может считаться только "вера абсолютная" (безусловная), достижение которой является основной целью мистической практики просветления. Она характеризуется полным уничтожением Эго, формированием безусловного доверия и любви к Богу. Вера в имманентных мистических учениях приобретает форму доверия к своему истинному "Я"-Атману. Вера в трансцендентно-имманентной мистике приобретает форму доверия к трансцендентной силе, что подразумевает безусловную отдачу Ее воле.У статті проводиться дослідження феномену релігійної віри. Робиться висновок про існування двох її рівнів. Перший з них - "віра прохальна" (з багатьма умовами), характерна для людини, що сприймає себе як смертне Тіло-Его та зорієнтована на страх. Досконалою формою релігійної віри можна вважати тільки "віру абсолютну" (безумовну), досягнення якої постає основною метою містичної практики просвітлення. Цей рівень віри характеризується повним знищенням Его, формуванням безумовної довіри та любові до Бога. Віра у іманентних містичних ученнях має форму довіри до свого істинного "Я"-Атману. Віра в трансцендентно-іманентній містиці приймає форму довіри до трансцендентної сили, що вимагає безумовної віддачі Її волі.The phenomenon of religious faith is investigated in the article. The conclusion is that there are two levels of it. First of them is "faith-request" (with a number of conditions), it is typical for a person who perceives oneself as a mortal Body - Ego and who is orientated on fear. Just "absolute faith" (unconditional) can be considered to be a perfect form of religious faith, and the achievement of it is the main purpose of mystical practice of enlightening. It is characterized with complete destroying of Ego, with forming of unconditional trust and love to God. Faith in immanent mystical teachings acquires the form of trust to own true "I" - Atman. Faith in transcendental immanent mystics acquires the form of trust to transcendental power that means unconditional exposing to His will

Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy

BACKGROUND & AIMS: Spinal muscular atrophy (SMA) is an autosomal recessive, childhood-onset motor neuron disease. Onasemnogene abeparvovec (OA) is a gene therapy designed to address SMA\u27s root cause. In pivotal mouse toxicology studies, the liver was identified as a major site of OA toxicity. Clinical data reflect elevations in serum aminotransferase concentrations, with some reports of serious acute liver injury. Prophylactic prednisolone mitigates these effects. Herein, we aim to provide pragmatic, supportive guidance for identification, management, and risk mitigation of potential drug-induced liver injury. METHODS: Data from 325 patients with SMA who had received OA through 31 December 2019, in 5 clinical trials, a managed access program (MAP), and a long-term registry (RESTORE), and through commercial use, were analyzed. Liver-related adverse events, laboratory data, concomitant medications, and prednisolone use were analyzed. RESULTS: Based on adverse events and laboratory data, 90 of 100 patients had elevated liver function test results (alanine aminotransferase, and/or aspartate aminotransferase, and/or bilirubin concentrations). Of these, liver-associated adverse events were reported for 34 of 100 (34%) and 10 of 43 (23%) patients in clinical trials and MAP/RESTORE, respectively. Two patients in MAP had serious acute liver injury, which resolved completely. While all events in the overall population resolved, prednisolone treatment duration varied (range: 33-229 days), with a majority receiving prednisolone for 60-120 days. More than 60% had elevations in either alanine aminotransferase, aspartate aminotransferase, or bilirubin concentrations prior to dosing. Greater than 40% received potentially hepatotoxic concomitant medications. CONCLUSIONS: Hepatotoxicity is a known risk associated with OA use. Practitioners should identify contributing factors and mitigate risk through appropriate monitoring and intervention. LAY SUMMARY: Onasemnogene abeparvovec is a type of medicine called a gene therapy, which is used to treat babies and young children who have a rare, serious inherited condition called spinal muscular atrophy (SMA). It works by supplying a fully functioning copy of the survival motor neuron or SMN gene, which then helps the body produce enough SMN protein. However, it can cause an immune response that could lead to an increase in enzymes produced by the liver. This article provides information about the liver injury and how to prevent and recognize if it happens, so that it may be treated properly

Prescribing of long-acting beta-2-agonists/inhaled corticosteroids after the SMART trial

Background After the SMART trial evaluating the safety of salmeterol (long-acting beta-2-agonist (LABA)) in asthma patients, regulatory actions were taken to promote a guideline-adherent prescribing of LABA only to patients receiving inhaled corticosteroids (ICS). We aim to analyse LABA- and ICS-related prescription patterns after the SMART trial in Germany. Methods Patients documented in the Bavarian Association of Statutory Health Insurance Physicians database (approximately 10.5 million people) were included if they had a diagnosis of asthma and at least one prescription of LABA and/or ICS between 2004 and 2008. Annual period prevalence rates (PPRs) were estimated and Cochrane Armitage tests were used for time trend analyses. Results Highest annual PPRs were found for budesonide and the fixed combination of salmeterol/fluticasone. The proportion of “concomitant LABA and ICS users” increased from 52.0 to 57.6% within the study period, whereas for “LABA users without ICS” a slight decrease from 6.5 to 5.4% was found. In 2008, the proportion of patients with at least one quarter with a LABA prescription without concomitant ICS was highest in elderly, male patients (≈20%). In the majority of these patients, a concomitant diagnosis of COPD (i.e. asthma-COPD overlap syndrome [ACOS]) was present. Conclusions Between 2004 and 2008, we found a moderate increase in guideline-adherent LABA prescribing in a representative German population. Elderly men received a significant number of LABA prescriptions without concomitant ICS probably due to ACOS

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI

Search for stop and higgsino production using diphoton Higgs boson decays

Results are presented of a search for a "natural" supersymmetry scenario with gauge mediated symmetry breaking. It is assumed that only the supersymmetric partners of the top-quark (stop) and the Higgs boson (higgsino) are accessible. Events are examined in which there are two photons forming a Higgs boson candidate, and at least two b-quark jets. In 19.7 inverse femtobarns of proton-proton collision data at sqrt(s) = 8 TeV, recorded in the CMS experiment, no evidence of a signal is found and lower limits at the 95% confidence level are set, excluding the stop mass below 360 to 410 GeV, depending on the higgsino mass

Severe early onset preeclampsia: short and long term clinical, psychosocial and biochemical aspects

Preeclampsia is a pregnancy specific disorder commonly defined as de novo hypertension and proteinuria after 20 weeks gestational age. It occurs in approximately 3-5% of pregnancies and it is still a major cause of both foetal and maternal morbidity and mortality worldwide1. As extensive research has not yet elucidated the aetiology of preeclampsia, there are no rational preventive or therapeutic interventions available. The only rational treatment is delivery, which benefits the mother but is not in the interest of the foetus, if remote from term. Early onset preeclampsia (<32 weeks’ gestational age) occurs in less than 1% of pregnancies. It is, however often associated with maternal morbidity as the risk of progression to severe maternal disease is inversely related with gestational age at onset2. Resulting prematurity is therefore the main cause of neonatal mortality and morbidity in patients with severe preeclampsia3. Although the discussion is ongoing, perinatal survival is suggested to be increased in patients with preterm preeclampsia by expectant, non-interventional management. This temporising treatment option to lengthen pregnancy includes the use of antihypertensive medication to control hypertension, magnesium sulphate to prevent eclampsia and corticosteroids to enhance foetal lung maturity4. With optimal maternal haemodynamic status and reassuring foetal condition this results on average in an extension of 2 weeks. Prolongation of these pregnancies is a great challenge for clinicians to balance between potential maternal risks on one the eve hand and possible foetal benefits on the other. Clinical controversies regarding prolongation of preterm preeclamptic pregnancies still exist – also taking into account that preeclampsia is the leading cause of maternal mortality in the Netherlands5 - a debate which is even more pronounced in very preterm pregnancies with questionable foetal viability6-9. Do maternal risks of prolongation of these very early pregnancies outweigh the chances of neonatal survival? Counselling of women with very early onset preeclampsia not only comprises of knowledge of the outcome of those particular pregnancies, but also knowledge of outcomes of future pregnancies of these women is of major clinical importance. This thesis opens with a review of the literature on identifiable risk factors of preeclampsia

Measurement of associated W plus charm production in pp collisions at √s=7 TeV

Peer reviewe