A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease

Purpose: The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families. Methods: To investigate the genetic cause of the disease, exome or genome sequencing were performed in 5 unrelated families identified via different research networks and Matchmaker Exchange. Deep clinical and brain imaging evaluations were performed by clinical pediatric neurologists and neuroradiologists. The functional effect of the candidate variant on both MED11 RNA and protein was assessed using reverse transcriptase polymerase chain reaction and western blotting using fibroblast cell lines derived from 1 affected individual and controls and through computational approaches. Knockouts in zebrafish were generated using clustered regularly interspaced short palindromic repeats/Cas9. Results: The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death. Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits. A zebrafish knockout model recapitulates key clinical phenotypes. Conclusion: Loss of the C-terminal of MED subunit 11 may affect its binding efficiency to other MED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration

Design and Integration of Automation Systems with Manual Operation: Small and Medium Enterprises Issues

Today it is more and more mandatory for all commercial companies to comply with the principles and methodologies of Industry 4.0 and to achieve the related capabilities protecting their competitiveness and taking a leading-edge position on market as regards technologies. Specifically, the whole production and sale system must achieve the fundamental characteristics of Industry 4.0 approach, but specially the manufacturing companies must also change and update their management procedures, internal organization, resource training, assets and all production process to keep safe their current business capacities. This evolution process is even more critical for Small and Medium Enterprises (SME), that traditionally tend to be conservative and to protect their way of operation, usually characterized by a low level of automation. The work presented focuses on the design and integration of a semi-automatic welding cell of train bolster in a SME which is currently realizing a project aimed to the acquisition of Industry 4.0 capabilities, with special focus on manufacturing processes. Among them, one of the most important is the production of welded-steel critical structures, that the Company supplies to prime manufacturer of railway rolling stock systems. The experience gained during the activity, the criticalities due to the integration processes and the adopted design methodologies are here described. The work has been carried out consistently with the Systems Engineering principles, starting from the requirements elicitation and analysis to the systematic approach for the design and integration activities

POST PARTUM RECURRENCY RATE FOR CLINICAL MANIFESTATION OF HUMAN PAPILLOMA VIRUS IN THE ANOGENITAL TRACT AFTER SECOND TRIMESTER LASER CO2 TREATMENT A RANDOMIZED TRIAL

AMERICAN JOURNAL OF OBST-GY

Channelling and induced defects at ion-bombarded aligned multiwall carbon nanotubes

A detailed investigation of ion channelling and defect production for a highly-ordered array of multi-wall carbon nanotubes is presented. The effects of argon ion bombardment (0.25–5 keV) carried out either parallel (top) or perpendicular (side) to their axis, have been studied by Raman, X-Ray Photoelectron Spectroscopy and Scanning Electron Microscopy. Raman spectra provided evidence of channelling of the Ar+ ions observed for top bombardment along the whole 180 μm carbon nanotube length, while the penetration length is limited to the first 10 μm when the ions impinge from the side. The nature of defects, determined through the spectral fingerprints of the C 1s core level as a function of energy and flux, unveils a distorted sp3-like bonding increase and the π-excitation decrease till quenching. Dangling bond states due to displaced carbon atoms become significant only at beam energies higher than 0.25 keV and high flux. These results on anisotropic channelling and selective defects creation open new perspectives in the application of highly-ordered arrays of multi-wall carbon nanotubes as anisotropic detectors

Cervical intraepithelial neoplasia: Risk factors for persistence and recurrence in adolescents

One of the most common sexually transmitted infections in adolescents is human papillomavirus. These infections can occur in one or multiple areas of the female genitalia but the vulva is usually the initial site of implantation for HPV. We carried out a long-term follow-up study of adolescents to evaluate the incidence of single or multiple lesions in the lower genital tract, the correlation between sexual behaviour and their localisation and behavioural risk factors for persistence and recurrence of HPV lesions and cervical intraepithelial lesion (CIN). We interviewed 268 women aged 12-21 years who had previously had cytology and/or physical examination suspicious for HPV infection. We asked them information about their lifestyle, sexual behaviour, work, personal or family history of genital warts and school attendance. Those who smoked more than five cigarettes a day were considered "smokers". We have no specific data about oral contraception although we know that none of the patients had used oral contraceptives for more than two years. Two hundred and thirty-four young women between the ages of 12 and 21 years were included in the study. The diagnostic schedule for a complete evaluation included exo- and endocervical cytology, colposcopy and directed biopsy. We found that in 126 out of 234 (53.8%) adolescents using contraceptives, only 85 (36.3%) had used a condom. The sites most frequently affected by lesions were the vulva, perianus and perineum (194/234; 82.9%), and the cervix (125/234; 53.4%). Vaginal lesions were detected in only 29/234 patients (12.3%). In 161 patients, sexual habits, age at first intercourse (p = 0.68), frequency of intercourse (p = 0.49) and number of lifetime partners (p = 0.27) as well as age (p = 0.26) played a role in transmission and incidence of HPV infection but not in the location of the lesions. This could be due to coexistent clinical and subclinical multiple infections as well as transmission via intercourse or from other sources, including tampons. HPV infection is detected by abnormal pap test, but the low correlation with colposcopic and histological findings in this study justify the support of other examinations such as colposcopy and punch biopsy for diagnosis. Moreover more attention should be paid to the psychological aspect of diagnoses and treatment of adolescents compared to older women as there was a high rate of patients lost in our study: 75/234 (32.05%) before LASER surgery and 55/159 (34.59%) during follow-up. Only 12-45% of sexually active adolescent girls had obtained Pap smear screening. In our study we found no correlation between treatment failure and cigarette smoking or between the use of oral contraceptives and persistence/recurrence after LASER surgery

Conservative approach to preneoplastic cervical lesions in postmenopause

Aim: To evaluate the recurrence rate of high-grade squamous intraepithelial lesions in postmenopausal women previously submitted to laser CO2 conization and the role of persistent oncogenic HPV types. Patients and Methods: Fifty-five patients with a cytological diagnosis of high-grade squamous intraepithelial lesions were triaged with a standard colposcopy. Hormonal replacement therapy was considered as significative in influencing cervical trophism. Vaginal smears for microbiological examination were obtained. H-R HPV test was performed by PCR. The follow-up checks including cytology, colposcopy and HVP test were performed for a minimum of 5 years. Results: Histological analysis revealed 19 CIN2 (cervical intraepithelial lesions) and 36 CIN3 lesions. The cumulative failure rate at first treatment was 14%. HPV test was positive for HPV 16 type in all patients. Forty-two patients during the follow up checks resulted negative to cytology, colposcopy and HR HPV test. At the one-year follow-up check, 7 patients revealed normal cytological and abnormal colposcopical findings and persistent positive HR HPV test. At the five-year follow-up check, 14 patients with a normal cytological smear had a recurrence of CIN2/3 and positive HR HPV test. Conclusion: In postmenopause, the correct management of H-R squamous intraepithelial lesions is still debated. However, a satisfactory follow-up is the main requirement for the conservative management. HPV typing in the follow-up is important to detect persistent types to identify women at risk of developing cervical abnormalities. The incidence of cervical neoplasia does not decrease with increasing age. Since HPV positivity predicted subsequent infection, testing postmenopausal patients for the virus may be a cost-effective method of disease prevention

Nitrogen segregation in nanocarbons

International audienc