Context:
Prior studies showed that Axl /Tyro3 null mice have delayed first estrus and abnormal cyclicity due to developmental defects in GnRH neuron migration and survival.
Objective:
The objective ...of the study was to test whether the absence of Axl would alter reproductive function in mice and that mutations in AXL are present in patients with Kallmann syndrome (KS) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH).
Design and Setting:
The sexual maturation of Axl null mice was examined. The coding region of AXL was sequenced in 104 unrelated, carefully phenotyped KS or nIHH subjects. Frequency of mutations was compared with other causes of GnRH deficiency. Functional assays were performed on the detected mutations.
Results:
Axl null mice demonstrated delay in first estrus and the interval between vaginal opening and first estrus. Three missense AXL mutations (p.L50F, p.S202C, and p.Q361P) and one intronic variant 6 bp upstream from the start of exon 5 (c.586-6 C>T) were identified in two KS and 2 two nIHH subjects. Comparison of the frequencies of AXL mutations with other putative causes of idiopathic hypogonadotropic hypogonadism confirmed they are rare variants. Testing of the c.586-6 C>T mutation revealed no abnormal splicing. Surface plasmon resonance analysis of the p.L50F, p.S202C, and p.Q361P mutations showed no altered Gas6 ligand binding. In contrast, GT1-7 GnRH neuronal cells expressing p.S202C or p.Q361P demonstrated defective ligand dependent receptor processing and importantly aberrant neuronal migration. In addition, the p.Q361P showed defective ligand independent chemotaxis.
Conclusions:
Functional consequences of AXL sequence variants in patients with idiopathic hypogonadotropic hypogonadism support the importance of AXL and the Tyro3, Axl, Mer (TAM) family in reproductive development.
This article provides an analysis of case with the possible delay of the deadline within which the President of the Republic is obliged to appoint a mandate for formation of a Government as to art. ...99. There is no explicit deadline in the Constitution, by which the latter must appoint the mandate, as e.g. he is obliged by art. 75 to convene the newly elected Parliament within 1-month-term. The case is especially important as there is no practice of the Constitutional Court on this matter, while there are quite a few rulings on the other aspects of art. 99 and the applicable terms after the first mandate has been appointed. While there are also some gaps in the constitutional framework, the Constitutional Court has adopted the term “reasonable term”, beyond which any delay shall be in contradiction with the Constitution. Precisely this “reasonability” in the context of appointing the first mandate will be analysed, in the context of the entire constitutional regulation of art. 99 for forming a regular Government but also in the spirit of a parliamentary Republic.
This comprehensive review focuses on the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and its impact as the cause of the COVID‐19 pandemic. Its objective is to provide a cohesive ...overview of the epidemic history and evolutionary aspects of the virus, with a particular emphasis on its emergence, global spread, and implications for public health. The review delves into the timelines and key milestones of SARS‐CoV‐2's epidemiological progression, shedding light on the challenges encountered during early containment efforts and subsequent waves of transmission. Understanding the evolutionary dynamics of the virus is crucial in monitoring its potential for adaptation and future outbreaks. Genetic characterization of SARS‐CoV‐2 is discussed, with a focus on the emergence of new variants and their implications for transmissibility, severity, and immune evasion. The review highlights the important role of genomic surveillance in tracking viral mutations linked to establishing public health interventions. By analyzing the origins, global spread, and genetic evolution of SARS‐CoV‐2, valuable insights can be gained for the development of effective control measures, improvement of pandemic preparedness, and addressing future emerging infectious diseases of international concern.
Pestalone (1) is a prominent marine natural product first isolated by M. Cueto et al. in 2001 from a co-fermentation of a marine fungus with a marine bacterium. For more than 10 years, 1 had been ...considered as a promising new antibiotic compound, the reported MIC against methicillin-resistant Staphylococcus aureus (MRSA) being 37 ng/mL. After overcoming the limited availability of 1 by total synthesis (N. Slavov et al., 2010) we performed new biological tests, which did not confirm the expected degree of antibiotic activity. The observed activity of pestalone against different MRSA strains was 3–10 μg/mL, as determined independently in two laboratories. A number of synthetic derivatives of 1 including pestalachloride A and other isoindolinones (formed from 1 by reaction with amines) did not exhibit higher activities as compared to 1 against MRSA and a series of plant pathogens.
The aim of this study was to determine the effect of the sweet flag (A. calamus L) extract addition of growth performance, haematological (white blood cells, red blood cells, hemoglobin, hematocrit) ...and biochemical (glucose, urea, creatinine, total protein, albumin, ASAT, ALAT, Ca, P, Mg, triglycerides, cholesterol) blood parameters of common carp Cyprinus carpio L) cultivated in recirculation system. Carps were randomly selected and distributed into four concrete tanks for the growth trial (8 fish/tank). Fish were divided into experimental (E) and control groups (C), each of them with two replicates and mean initial weight 908.5+ or -171.2 g and 913.8+ or -147.4 g, respectively. They were fed with pelleted carp feed with 25% crude protein, produced by the "Top mix" company, having a granule size of 6 mm. To the fish feed on the experimental group (E) was added 1% aqueous extract of A. calamus root, as well as oiling the pellets with 5 mL of sunflower oil for every 100 g of feed. Carps from control group (C) were fed with feed only greased with the same amount of sunflower oil. The daily ration that the studied fish received was 1.8% of their live weight. The duration of the trial period was 45 days. At the end of the experiment with 5.2% was measured a higher average live weight in the fish receiving the sweet flag supplement compare to the value of this parameter of carps from control group, and the differences were statistically significant (P<0.05). The survival rate was 100% in control and experimental variants. At the end of the experiment, the average individual weight gain of the experimental fish fed with the supplement was higher with 53.2% compared to this one of carps from control. The feed conversion ratio in experimental carps, supplemented with 1% sweet flag extract was with 16.1% lower than that of control fish, although the differences were not relevant (P>0.05).Better blood biochemical and haematological parameters were measured in carp fed with sweet flag supplement.
Simple presentations of the life cycle model often suggest a constant level of real consumption in retirement. Similarly, financial planners commonly suggest that people save for retirement in such a ...way as to enable them to maintain a level retirement standard of living equal to their standard of living while working. However, constant consumption with age is only optimal under the precise and unlikely condition that the subjective rate of time preference is equal to the real interest rate. Most people exhibit a positive rate of pure time preference, and additionally discount the future by both mortality and morbidity risks. In comparison, the real interest rate is roughly 0%—and the term structure of interest rates suggests this condition is likely to persist. These considerations suggest that optimal consumption in the life cycle model declines with age. This finding has major implications for optimal retirement saving. For instance, we find that for many, perhaps most, people in the bottom half of the lifetime earnings distribution, it is optimal to spend out their retirement wealth well before death and to live on Social Security alone after that. Very low earners may find it optimal to not engage in retirement saving at all. TOPICS: Long-term/retirement investing, portfolio theory Key Findings ▪ Under plausible assumptions, optimal consumption in the life cycle model declines with age. ▪ For many people in the bottom half of the lifetime earnings distribution, it is optimal to spend out retirement wealth well before death and live on Social Security alone after that. ▪ These results stand in contrast to standard financial planning advice that people save for retirement in such a way as to enable them to maintain a level retirement standard of living equal to their standard of living while working.
Viral hemorrhagic fever poses a significant public health challenge due to its severe clinical presentation and high mortality rate. The diagnostic process is hindered by similarity of symptoms ...across different diseases and the broad spectrum of pathogens that can cause hemorrhagic fever. In this study, we applied viral metagenomic analysis to 43 serum samples collected by the Public Health Laboratory (
, FUNED) in Minas Gerais State, Brazil, from patients diagnosed with hemorrhagic fever who had tested negative for the standard local hemorrhagic disease testing panel. This panel includes tests for Dengue virus (DENV) IgM, Zika virus IgM, Chikungunya virus IgM, yellow fever IgM, Hantavirus IgM,
IgM/IgG, and
IgM, in addition to respective molecular tests for these infectious agents. The samples were grouped into 18 pools according to geographic origin and analyzed through next-generation sequencing on the NextSeq 2000 platform. Bioinformatic analysis revealed a prevalent occurrence of commensal viruses across all pools, but, notably, a significant number of reads corresponding to the DENV serotype 2 were identified in one specific pool. Further verification via real-time PCR confirmed the presence of DENV-2 RNA in an index case involving an oncology patient with hemorrhagic fever who had initially tested negative for anti-DENV IgM antibodies, thereby excluding this sample from initial molecular testing. The complete DENV-2 genome isolated from this patient was taxonomically classified within the cosmopolitan genotype that was recently introduced into Brazil. These findings highlight the critical role of considering the patient's clinical condition when deciding upon the most appropriate testing procedures. Additionally, this study showcases the potential of viral metagenomics in pinpointing the viral agents behind hemorrhagic diseases. Future research is needed to assess the practicality of incorporating metagenomics into standard viral diagnostic protocols.
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