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Presenilin 1 (PSEN1) encodes the catalytic subunit of γ-secretase, and PSEN1 mutations are the most common cause of early onset familial Alzheimer's disease (FAD). In order to elucidate pathways downstream of PSEN1, we characterized neural progenitor cells (NPCs) derived from FAD mutant PSEN1 subjects. Thus, we generated induced pluripotent stem cells (iPSCs) from affected and unaffected individuals from two families carrying PSEN1 mutations. PSEN1 mutant fibroblasts, and NPCs produced greater ratios of Aβ42 to Aβ40 relative to their control counterparts, with the elevated ratio even more apparent in PSEN1 NPCs than in fibroblasts. Molecular profiling identified 14 genes differentially-regulated in PSEN1 NPCs relative to control NPCs. Five of these targets showed differential expression in late onset AD/Intermediate AD pathology brains. Therefore, in our PSEN1 iPSC model, we have reconstituted an essential feature in the molecular pathogenesis of FAD, increased generation of Aβ42/40, and have characterized novel expression changes.

Abstract The automation of ab initio simulations is essential in view of performing high-throughput (HT) computational screenings oriented to the discovery of novel materials with desired physical properties. In this work, we propose algorithms and implementations that are relevant to extend this approach beyond density functional theory (DFT), in order to automate many-body perturbation theory (MBPT) calculations. Notably, an algorithm pursuing the goal of an efficient and robust convergence procedure for GW and BSE simulations is provided, together with its implementation in a fully automated framework. This is accompanied by an automatic GW band interpolation scheme based on maximally localized Wannier functions, aiming at a reduction of the computational burden of quasiparticle band structures while preserving high accuracy. The proposed developments are validated on a set of representative semiconductor and metallic systems.

El Cañón de las Hermosas está ubicado en el centro de Colombia, sobre una de las ramificaciones de la Cordillera de los Andes. Allí se concentraron varios de los síntomas más recurrentes en el diagnóstico del conflicto armado en Colombia: pobreza, desigualdad, precariedad y debilidad institucional, control social y territorial de los grupos armados, disputas por rentas ilegales derivadas del cultivo y tráfico de drogas ilícitas, e impactos sobre la territorialidad y el territorio. En un clima completamente adverso, la propia comunidad ha sido capaz de poner en marcha varios mecanismos de resistencia civil para la protección de la población que han sido reconocidos como plataformas eficaces orientadas al diálogo social y la construcción de paz.

La Unión Europea se relaciona con los países del Cercano Oriente y el Norte de África mediante la Política Europea de Vecindad y la Unión por el Mediterráneo. Estos instrumentos deberían ser una herramienta útil en la consecución de cierta estabilidad y en la promoción de la paz en la región. El análisis realizado en este trabajo pretende demostrar que el interés de la UE en cooperar a la estabilización del conflicto árabe israelí se ha mostrado de manera ambigua resultando en unas relaciones entre la UE e Israel muy limitadas. A su vez, se analiza el papel pasivo de la Unión en la resolución del conflicto, obviando su potencial como mediador diplomático y dejando en manos de EE. UU. la promoción de la paz entre Israel y sus vecinos. Recibido: 13 febrero 2023 Aceptado: 2 junio 2023

The conversion of semimetallic suspended graphene (Gr) to a large-gap semiconducting phase is here realized by controlled adsorption of atomic hydrogen (deuterium) on free-standing nanoporous Gr veils. This approach allows to achieve a very clean and neat adsorption, overcoming any spurious influence associated to the presence of substrates. The effects of local rehybridization from sp2 to sp3 chemical bonding are investigated by combining X-ray photoelectron spectroscopy and high-resolution electron energy-loss spectroscopy (HREELS) with ab-initio based modelling. We find that the hydrogen adatoms on the C sites induce a stretching frequency, clearly identified in the vibrational spectra thanks to the use of the D isotope. Overall, the results are compatible with the predicted fingerprints of adsorption on both sides of Gr corresponding to the graphane configuration. Moreover, HREELS of the deuterated samples shows a sizeable opening of the optical band gap, i.e. 3.25 eV, consistent with the modified spectral density observed in the valence band photoemission. The results are in agreement with ab-initio calculations by GW and Bethe–Salpeter equation approaches, predicting a large quasiparticle gap opening and huge exciton binding energy.

We present the case of an infant referred to our NICU born at 39 weeks’ gestation with persistent hypoglycemia with elevated insulin levels (HI) requiring diazoxide to maintain normoglycemia. Additionally, polycystic kidney disease (PKD) was detected by ultrasound. Molecular genetic testing revealed pathogenic variants in the PMM2gene, i.e., a variant in the promoter region and a missense variant in the coding region. The precoding variant was recently described in 11 European families with similar phenotypes, either in a homozygous state or as compound heterozygous with a pathogenic coding variant. In neonates with HI associated with PKD, this rare recessive disorder should be considered.

The gluten-free diet has become popular among the public. People who are using this diet have reported symptom relief once gluten has been removed from their diet. Nonceliac gluten sensitivity (NCGS) has emerged as a new diagnosis for those patients who have tested negative for celiac disease. Although there are no diagnostic markers established for NCGS, its symptomatology ranges from gastrointestinal symptoms to neuropsychiatric symptoms. Indeed, some of these symptoms are also seen in patients with irritable bowel syndrome (IBS), such as abdominal pain, bloating, altered bowel movement, diarrhea, and constipation. It is important to add that unlike celiac disease, NGCS has never been associated with any long-term malignancy. We aim to review the recent clinical data available on this topic and address the overlap symptoms between NCGS and IBS. We concluded that despite the overlap symptoms between both diseases, NCGS is a real clinical phenomenon that awaits its own diagnostic clinical criteria and specific laboratory markers. We suggest that patients with gluten sensitivity who are negative for celiac disease should be considered for NCGS.

Individuals naturally carry bacteria and other microbes as part of their natural flora, with some being opportunistic pathogens. Approximately 30% of the population is known to carry Staphylococcus aureus in their nasal cavity, an organism that causes infections ranging from soft tissue abscesses to toxic shock syndrome. This problem is compounded by the presence of antibiotic-resistant strains such as Methicillin-Resistant Staphylococcus aureus (MRSA). Commensal bacteria present on cadavers pose a risk to those who handle the body. As a Medical School Anatomy laboratory that performs hands-on cadaveric dissection, we wanted to know whether the embalming process is sufficient to kill all commensal bacteria that pose a risk to staff and students. Even if these strains do not cause disease in these individuals, secondary transmission could occur to friends and family, who may be at higher risk of acquiring an infection. Embalming is assumed to eliminate all microbial contamination on the body. However, there are limited studies to confirm this. This study characterises the incidence of antibiotic sensitive and resistant bacteria in cadavers donated for medical teaching and research. We have screened for Methicillin-Resistant Organisms (MRO) and Extended-Spectrum Beta-Lactamase (ESBL) producing bacteria. In this study group of cadavers, approximately 46% (16/35) carry an MRO, while 51% (18/35) carry an ESBL positive organism prior to embalming. By determining the organisms’ presence pre- and post-embalming, we can evaluate the embalming procedure’s effectiveness. Our results show embalming eliminates detectable microbes in about 51% (18/35) of the cadavers. MRO dropped by 75% (16 to 4 positive cadavers), while ESBL organisms went down by almost 95% (from 18 to 1 positive cadaver). There was a further decrease in the number of positive cadavers after storage at 4 °C to 6% (2/32). Thus, although the embalming process does not immediately sterilise all the cadavers, prolonged storage at 4 °C can further reduce the number of viable bacteria.

Despite advancements in the development of cell-based in-vitro neuronal network models, the lack of appropriate computational tools limits their analyses. Methods aimed at deciphering the effective connections between neurons from extracellular spike recordings would increase utility of in vitro local neural circuits, especially for studies of human neural development and disease based on induced pluripotent stem cells (hiPSC). Current techniques allow statistical inference of functional couplings in the network but are fundamentally unable to correctly identify indirect and apparent connections between neurons, generating redundant maps with limited ability to model the causal dynamics of the network. In this paper, we describe a novel mathematically rigorous, model-free method to map effective—direct and causal—connectivity of neuronal networks from multi-electrode array data. The inference algorithm uses a combination of statistical and deterministic indicators which, first, enables identification of all existing functional links in the network and then reconstructs the directed and causal connection diagram via a super-selective rule enabling highly accurate classification of direct, indirect, and apparent links. Our method can be generally applied to the functional characterization of any in vitro neuronal networks. Here, we show that, given its accuracy, it can offer important insights into the functional development of in vitro hiPSC-derived neuronal cultures.

The COVID-19 pandemic has changed individuals' lifestyles to a great extent, particularly in Italy. Although many concerns about it have been highlighted, its impact on children and adolescents has scarcely been examined. The purpose of this study was to explore behavioral consequences and coping strategies related to the pandemic among families in Italy, by focusing on developmental ages from the caregivers' perspective, 3 weeks into quarantine. An exploratory cross-sectional online survey was conducted over 14 days. Google Forms was employed to conduct the survey. Demographic variables and pre-existing Psychological Weaknesses (PsW) were asked. Adults' sleep difficulties (SleepScore) and coping strategies during quarantine were assessed. Behavioral changes related to quarantine of both subjects completing the form (COVIDStress) and their children (when present) were questioned. Of the 6,871 respondents, we selected 6,800 valid questionnaires; 3,245 declared children aged under 18 years of age (caregivers). PsWs were recognizable in 64.9% among non-caregivers and in 61.5% of caregivers, with a mean PsW score of 1.42 ± 1.26 and 1.30 ± 1.25 over 3 points, respectively. The 95.5% of the non-caregivers and the 96.5% of caregivers presented behavioral changes with a mean COVIDStress of 3.85 ± 1.82 and 4.09 ± 1.79 over 8, respectively (p

Abstract Purpose One of the major contributors to the progression of knee osteoarthritis (OA) is the condition of loading in the knee joint. Innovatively designed load‐sharing implants may be effective in terms of reducing joint load. The effects of these implants on contact joint mechanics can be evaluated through cadaver experiments. In this work, a case study is carried out with cadaver knee specimens to carry out a preliminary investigation into a novel load‐sharing knee implant, in particular to study the surgical procedures required for attachment, and to determine the contact pressures in the joint with and without the implant. Methods Contact pressure in the tibiofemoral joint was measured using pressure mapping sensors, with and without the implant, and radiographs were conducted to investigate the influence of the implant on joint space. The implant was designed from a 3D model of the specimen reconstructed by segmenting MR images of the knee, and it was manufactured by CNC machining. Results It was observed that attachment of the implant does not affect the geometry of the hard/soft tissues. Radiographs showed that the implant led to an increase in the joint space on the medial side. Contact pressure measurements showed that the implant reduced the load on the medial side by approximately 18% under all tested loading conditions. By increasing the load from 800 to 1600 N, the percentage of load reduction in the lateral side was decreased by 8%. After applying 800, 1200, and 1600 N load it was observed that the peak contact pressures were 3.7, 4.6, and 5.5 MPa, respectively. Conclusions This new knee implant shows some promise as a treatment for OA, through its creation of a conducive loading environment in the knee joint, without sacrificing or damaging any of the hard or soft tissues. This device could be as effective as, for example, the Atlas® system, but without some complications seen with other devices; this would need to be validated through similar results being observed in an appropriate in vivo study.

Graphene nanoribbons confine electrons to just one dimension and this gives rise to strong electron–hole interactions. Here, the authors investigate the creation and recombination of biexcitons in these structures by ultrafast optical pulses using femtosecond transient absorption spectroscopy.

Background and study aims Colon preparation rates are the limiting factor for a successful diagnostic colonoscopy in children. Different colon cleansing protocols have been published for use in children. Unfortunately, the applicability of those published research protocols has not been formally evaluated in routine clinical practice. We investigated the success rate of our previously published colon cleansing protocol as utilized in our clinical practice. Patients and methods This was a retrospective study. In the clinical practice, the colon cleansing protocol included PEG-3350 at a dose of 2 g/kg/day plus Dulcolax (Bisacodyl, Boehringer Ingelheim, TX USA) 5 mg/day for 2 days. Adequate colon preparation was graded between 1 – 5, as previously described, and grade ≥ 4.0 was considered an adequate preparation. Patients were instructed to complete a questionnaire that included PEG-3350 dose, number of stools per day, consistency of each stool, and side effects (vomiting, abdominal pain). Clinical and endoscopic results were compared between the protocol under research conditions and routine practice. Results The success rate of the colon preparation in our clinical practice was similar to the results observed under our research protocol (75 % vs. 73.6 %). Moreover, the total number of stools, stool consistency, and the intubation rate of the terminal ileum were also similar. We concluded, that in our experience, the colon cleansing protocol used under research conditions was effective and appropriate for use in routine clinical practice. Conclusion We recommend testing each new protocol under the routine conditions of clinical practice to confirm its applicability for general practitioners.

Many protocols have been designed to differentiate human embryonic stem cells (ESCs) and human induced pluripotent stem cells (iPSCs) into neurons. Despite the relevance of electrophysiological properties for proper neuronal function, little is known about the evolution over time of important neuronal electrophysiological parameters in iPSC-derived neurons. Yet, understanding the development of basic electrophysiological characteristics of iPSC-derived neurons is critical for evaluating their usefulness in basic and translational research. Therefore, we analyzed the basic electrophysiological parameters of forebrain neurons differentiated from human iPSCs, from day 31 to day 55 after the initiation of neuronal differentiation. We assayed the developmental progression of various properties, including resting membrane potential, action potential, sodium and potassium channel currents, somatic calcium transients and synaptic activity. During the maturation of iPSC-derived neurons, the resting membrane potential became more negative, the expression of voltage-gated sodium channels increased, the membrane became capable of generating action potentials following adequate depolarization and, at day 48-55, 50% of the cells were capable of firing action potentials in response to a prolonged depolarizing current step, of which 30% produced multiple action potentials. The percentage of cells exhibiting miniature excitatory post-synaptic currents increased over time with a significant increase in their frequency and amplitude. These changes were associated with an increase of Ca2+ transient frequency. Co-culturing iPSC-derived neurons with mouse glial cells enhanced the development of electrophysiological parameters as compared to pure iPSC-derived neuronal cultures. This study demonstrates the importance of properly evaluating the electrophysiological status of the newly generated neurons when using stem cell technology, as electrophysiological properties of iPSC-derived neurons mature over time.