Gamma-D crystallin gene (CRYGD) mutation causes autosomal dominant congenital cerulean cataracts

Congenital cataracts are a major cause of bilateral visual impairment in childhood. We mapped the gene responsible for autosomal congenital cerulean cataracts to chromosome 2q33-35 in a four generation family of Moroccan descent. The maximum lod score (7.19 at recombination fraction theta=0) was obtained for marker D2S2208 near the g-crystallin gene (CRYG) cluster. Sequencing of the coding regions of the CRYGA, B, C, and D genes showed the presence of a heterozygous C>A transversion in exon 2 of CRYGD that is associated with cataracts in this family. This mutation resulted in a proline to threonine substitution at amino acid 23 of the protein in the first of the four Greek key motifs that characterise this protein. We show that although the x ray crystallography modelling does not indicate any change of the backbone conformation, the mutation affects a region of the Greek key motif that is important for determining the topology of this protein fold. Our data suggest strongly that the proline to threonine substitution may alter the protein folding or decrease the thermodynamic stability or solubility of the protein. Furthermore, this is the first report of a mutation in this gene resulting in autosomal dominant congenital cerulean cataracts

Full Scale Proton Beam Impact Testing of new CERN Collimators and Validation of a Numerical Approach for Future Operation

New collimators are being produced at CERN in the framework of a large particle accelerator upgrade project to protect beam lines against stray particles. Their movable jaws hold low density absorbers with tight geometric requirements, while being able to withstand direct proton beam impacts. Such events induce considerable thermo-mechanical loads, leading to complex structural responses, which make the numerical analysis challenging. Hence, an experiment has been developed to validate the jaw design under representative conditions and to acquire online results to enhance the numerical models. Two jaws have been impacted by high-intensity proton beams in a dedicated facility at CERN and have recreated the worst possible scenario in future operation. The analysis of online results coupled to post-irradiation examinations have demonstrated that the jaw response remains in the elastic domain. However, they have also highlighted how sensitive the jaw geometry is to its mounting support inside the collimator. Proton beam impacts, as well as handling activities, may alter the jaw flatness tolerance value by $\pm$ 70 ${\mu}$m, whereas the flatness tolerance requirement is 200 ${\mu}$m. In spite of having validated the jaw design for this application, the study points out numerical limitations caused by the difficulties in describing complex geometries and boundary conditions with such unprecedented requirements.Comment: 22 pages, 17 figures, Prepared for submission to JINS

In-hospital worsening heart failure: a clinically relevant endpoint?

Outcome measures used for the clinical evaluation of patients with acute heart failure differ between studies and may neither adequately address the characteristic presenting symptoms and signs nor reflect the pathophysiological processes involved. In‐hospital worsening of heart failure (WHF) is associated with poor outcomes and thus a potential endpoint conveying clinically meaningful prognostic information.Current definitions of WHF are based on the combination of worsening symptoms and signs and the intensification of treatment during admission. Definitions vary across studies and do not fully account for baseline therapy or circumstances in which there is failure to respond to treatment. Further, there are limited data to inform healthcare professionals as to which patients are most at risk of developing in‐hospital WHF.In this opinion piece, we review the definitions for WHF used in recent and ongoing clinical trials and propose a novel definition, which captures failure to respond to treatment as well as clinical worsening (deterioration of symptoms and signs) of the patient's condition. Such a definition, applied consistently across studies, would help clarify the characteristics of patients likely to develop in‐hospital WHF, allow comparative assessments of the effectiveness of interventions, and help guide appropriate patient management in order to improve outcomes

The influence of environmental and core temperature on cyclooxygenase and PGE2 in healthy humans.

Whether cyclooxygenase (COX)/prostaglandin E2 (PGE2) thermoregulatory pathways, observed in rodents, present in humans? Participants (n = 9) were exposed to three environments; cold (20 °C), thermoneutral (30 °C) and hot (40 °C) for 120 min. Core (Tc)/skin temperature and thermal perception were recorded every 15 min, with COX/PGE2 concentrations determined at baseline, 60 and 120 min. Linear mixed models identified differences between and within subjects/conditions. Random coefficient models determined relationships between Tc and COX/PGE2. Tc [mean (range)] increased in hot [+ 0.8 (0.4-1.2) °C; p < 0.0001; effect size (ES): 2.9], decreased in cold [- 0.5 (- 0.8 to - 0.2) °C; p < 0.0001; ES 2.6] and was unchanged in thermoneutral [+ 0.1 (- 0.2 to 0.4) °C; p = 0.3502]. A relationship between COX2/PGE2 in cold (p = 0.0012) and cold/thermoneutral [collapsed, condition and time (p = 0.0243)] was seen, with higher PGE2 associated with higher Tc. A within condition relationship between Tc/PGE2 was observed in thermoneutral (p = 0.0202) and cold/thermoneutral [collapsed, condition and time (p = 0.0079)] but not cold (p = 0.0631). The data suggests a thermogenic response of the COX/PGE2 pathway insufficient to defend Tc in cold. Further human in vivo research which manipulates COX/PGE2 bioavailability and participant acclimation/acclimatization are warranted to elucidate the influence of COX/PGE2 on Tc

Influence of the drought on antioxidant and enzymatic activities of two Pinus species in humid and sub-humid climate

Pinus genus is widespread in the Mediterranean region and the most common in Tunisia. The impact of high temperatures in the mid-summer period (July 2015 and July 2016) on phenols and biological properties were examined in vitro. The study was carried out in two arboreta, in humid and sub-humid climates, dry needles of Pinus pinea and Pinus pinaster were used for secondary metabolites, antioxidant activities, and enzymatic inhibitory activities. The amount of all measured parameters increased from 2015 to 2016 in the two pine species in the two arboreta. Pinus pinea produced more phenols and showed higher antioxidant activity and a-amylase and lipoxygenase inhibitory activities than Pinus pinaster. Besides, both species generally presented better biological activities and higher phenol amounts in 2016 than in 2015, being 2016 warmer and drier than 2015 in both harvest zones. It was evident that both species in every bioclimatic zones adapted to the new climate conditions producing more secondary metabolites that rendered better antioxidant and inhibitory enzymatic activities. These findings confirmed the impact of mid-summer water deficits on pine species in the context of climate change and help to select the most resistant species for future reforestation.info:eu-repo/semantics/publishedVersio

Profile of patients with HPV infection at the regional hospital of Saint-Louis, Senegal

Background: Objectives of current study was to define the sociodemographic characteristics of patients, to determine the frequency of HPV infection at the CHRSL and to describe factors associated with HPV infection. Methods: This was a prospective cross-sectional study conducted in the gynecology-obstetrics department of the Saint Louis Regional Hospital Center from November 11, 2019 to November 11, 2021, a period of 24 months. We studied sociodemographic, clinical and test results characteristics. Samples were taken from patients in the gynaecological position using a dedicated kit (cytobrush and tube). Viral research was carried out using the Atila Biosystems device for amplification and detection of viral DNA. This test genotypes HPV 16, 18 and 45, and detects 12 other HR HPVs (31, 33, 35, 39, 51, 52, 56, 58, 59, 66 and 68) simultaneously using three probes labelled with different fluorophores. Analysis was performed using Epi-Info software and Excel 2010. Results: The study population comprised 128 patients. The mean age of the patients was 41.95 years, with extremes of 23 and 70 years. They were married (92.97%) and housewives (46.88%). Almost all patients (77.34%) were genitally active. The average age at marriage was 21.78 years, and polygamous households predominated (53.91%). The average age at first intercourse was 20.05 years. The average age at first pregnancy was 21.78. Over (57.81%) of patients had at least two partners. Incense was used in 97.66% of cases. The viral HPV test was positive in (38.28%) of patients. High-risk papillomaviruses were the most common, at 63.27%. Colposcopy was performed in 17.19%; normal and satisfactory in (63.64%) of patients, with 22.27% of cervical biopsies, and histology showed one CIN2 and two CIN3. Therapeutically, one thermoablation and two hysterectomies were performed. Conclusions: HPV viral typing in primary screening for cervical cancer offers opportunities and remains realistic and feasible in less developed countries such as Senegal, despite modest resources

Correspondence for the Trust Fund for the Commission of Experts

Pubblico ministero cercasihttps://scholarlycommons.law.case.edu/documents_780/1102/thumbnail.jp

321. Deletion of Mutated GAA Repeats from the Intron 1 of the Frataxin Gene Using the CRISPR System Restores the Protein Expression in a Friedreich Ataxia Model

The CRISPR system is now widely used as a molecular tool to edit the genome. We used this technique in Friedreich Ataxia (FRDA), an inherited autosomal disease known to cause a decrease of the mitochondrial frataxin protein. Genetic analysis revealed a GAA repeat expansion within the intron 1 of the frataxin (FXN) gene. We used cells derived from the YG8sR mouse model where the mouse frataxin gene is knockout but contain a human FXN mutated transgene on one allele. We then deleted the GAA trinucleotide repeat using 2 specific guide RNAs (gRNAs) co-expressed with either S. pyogenes (Sp) or S. aureus (Sa) Cas9. We were able to monitored an increase up to 2-fold of frataxin mRNA and protein levels in clone cells. We also confirmed these results in vivo using DNA electroporation in the Tibialis anterior muscle of the YG8R mice. Ongoing in vivo investigation of a systemically injected AAV-DJ vector expressing the SaCas9 and 2 successful selected gRNAs in the mouse model YG8sR will hopefully provide more details answers on the efficacy of the approach and give us preliminary data to go forward for clinical trial. The deletion of the GAA repeats expansion then might be a highly valuable gene therapy approach for FRDA patients

Second T = 3/2 state in 9^9B and the isobaric multiplet mass equation

Recent high-precision mass measurements and shell model calculations~[Phys. Rev. Lett. {\bf 108}, 212501 (2012)] have challenged a longstanding explanation for the requirement of a cubic isobaric multiplet mass equation for the lowest $A = 9$ isospin quartet. The conclusions relied upon the choice of the excitation energy for the second $T = 3/2$ state in $^9$B, which had two conflicting measurements prior to this work. We remeasured the energy of the state using the $^9{\rm Be}(^3{\rm He},t)$ reaction and significantly disagree with the most recent measurement. Our result supports the contention that continuum coupling in the most proton-rich member of the quartet is not the predominant reason for the large cubic term required for $A = 9$ nuclei