Evolutionarily Conserved Sequence Features Regulate the Formation of the FG Network at the Center of the Nuclear Pore Complex.

The nuclear pore complex (NPC) is the portal for bidirectional transportation of cargos between the nucleus and the cytoplasm. While most of the structural elements of the NPC, i.e. nucleoporins (Nups), are well characterized, the exact transport mechanism is still under much debate. Many of the functional Nups are rich in phenylalanine-glycine (FG) repeats and are believed to play the key role in nucleocytoplasmic transport. We present a bioinformatics study conducted on more than a thousand FG Nups across 252 species. Our results reveal the regulatory role of polar residues and specific sequences of charged residues, named 'like charge regions' (LCRs), in the formation of the FG network at the center of the NPC. Positively charged LCRs prepare the environment for negatively charged cargo complexes and regulate the size of the FG network. The low number density of charged residues in these regions prevents FG domains from forming a relaxed coil structure. Our results highlight the significant role of polar interactions in FG network formation at the center of the NPC and demonstrate that the specific localization of LCRs, FG motifs, charged, and polar residues regulate the formation of the FG network at the center of the NPC

The Weighted Independent Domination Problem: ILP Model and Algorithmic Approaches

This work deals with the so-called weighted independent domination problem, which is an $NP$-hard combinatorial optimization problem in graphs. In contrast to previous work, this paper considers the problem from a non-theoretical perspective. The first contribution consists in the development of three integer linear programming models. Second, two greedy heuristics are proposed. Finally, the last contribution is a population-based iterated greedy metaheuristic which is applied in two different ways: (1) the metaheuristic is applied directly to each problem instance, and (2) the metaheuristic is applied at each iteration of a higher-level framework---known as construct, merge, solve \& adapt---to sub-instances of the tackled problem instances. The results of the considered algorithmic approaches show that integer linear programming approaches can only compete with the developed metaheuristics in the context of graphs with up to 100 nodes. When larger graphs are concerned, the application of the populated-based iterated greedy algorithm within the higher-level framework works generally best. The experimental evaluation considers graphs of different types, sizes, densities, and ways of generating the node and edge weights

The weighted independent domination problem: ILP model and algorithmic approaches

This work deals with the so-called weighted independent domination problem, which is an N P -hard combinatorial optimization problem in graphs. In contrast to previous theoretical work from the liter- ature, this paper considers the problem from an algorithmic perspective. The first contribution consists in the development of an integer linear programming model and a heuristic that makes use of this model. Sec- ond, two greedy heuristics are proposed. Finally, the last contribution is a population-based iterated greedy algorithm that takes profit from the better one of the two developed greedy heuristics. The results of the compared algorithmic approaches show that small problem instances based on random graphs are best solved by an efficient integer linear programming solver such as CPLEX. Larger problem instances are best tackled by the population-based iterated greedy algorithm. The experimental evaluation considers random graphs of different sizes, densities, and ways of generating the node and edge weights

Respective Prognostic Value of Genomic Grade and Histological Proliferation Markers in Early Stage (pN0) Breast Carcinoma

Genomic grade (GG) is a 97-gene signature which improves the accuracy and prognostic value of histological grade (HG) in invasive breast carcinoma. Since most of the genes included in the GG are involved in cell proliferation, we performed a retrospective study to compare the prognostic value of GG, Mitotic Index and Ki67 score.A series of 163 consecutive breast cancers was retained (pT1-2, pN0, pM0, 10-yr follow-up). GG was computed using MapQuant Dx(R).GG was low (GG-1) in 48%, high (GG-3) in 31% and equivocal in 21% of cases. For HG-2 tumors, 50% were classified as GG-1, 18% as GG-3 whereas 31% remained equivocal. In a subgroup of 132 ER+/HER2- tumors GG was the most significant prognostic factor in multivariate Cox regression analysis adjusted for age and tumor size (HR = 5.23, p = 0.02).In a reference comprehensive cancer center setting, compared to histological grade, GG added significant information on cell proliferation in breast cancers. In patients with HG-2 carcinoma, applying the GG to guide the treatment scheme could lead to a reduction in adjuvant therapy prescription. However, based on the results observed and considering (i) the relatively close prognostic values of GG and Ki67, (ii) the reclassification of about 30% of HG-2 tumors as Equivocal GG and (iii) the economical and technical requirements of the MapQuant micro-array GG test, the availability in the near future of a PCR-based Genomic Grade test with improved performances may lead to an introduction in clinical routine of this test for histological grade 2, ER positive, HER2 negative breast carcinoma

Dedicated mobile application for drug adverse reaction reporting by patients with relapsing remitting multiple sclerosis (Vigip-SEP study): study protocol for a randomized controlled trial

BackgroundThe reporting of adverse drug reactions (ADR) by patients represents an interesting challenge in the field of pharmacovigilance, but the reporting system is not adequately implemented in France. In 2015, only 20 MS patients in France reported ADR due to first-line disease-modifying drugs (DMD), while more than 3000 patients were initiated on DMD.The aim of this study is to validate a proof-of-concept as to whether the use of a mobile application (App) increases ADR reporting among patients with relapsing-remitting multiple sclerosis (RR-MS) receiving DMD.Methods/designWe designed a multi-centric, open cluster-randomized controlled trial, called the Vigip-SEP study (NCT03029897), using the App My eReport France® to report ADR to the appropriate authorities in E2B language, in accordance with European regulations. RR-MS patients who were initiated on, or switched, first-line DMD will be included. In the experimental arm, a neurologist will introduce the patient to the App to report ADR to the appropriate French authorities. In the control arm, the patient will be informed of the existence of the App but will not be introduced to its use and will then report ADR according to the usual reporting procedures. Primary assessment criteria are defined as the average number of ADR per patient and per center. We assume that the App will increase patient reporting by 10-fold. Therefore, we will require 24 centers (12 per arm: 6 MS academic expert centers, 3 general hospitals, 3 private practice neurologists), allowing for an expected enrollment of 180 patients (alpha risk 5%, power 90% and standard deviation 4%).DiscussionIncreasing patient reporting of ADR in a real-life setting is extremely important for therapeutic management of RR-MS, particularly for monitoring newly approved DMD to gain better knowledge of their safety profiles. To increase patient involvement, teaching patients to use tools, such as mobile applications, should be encouraged, and these tools should be tested rigorously

Reporte de atención clínica integral

El Proyecto de Aplicación Profesional en Atención Clínica Interdisciplinaria tuvo como objetivo general ofrecer servicios de atención y orientación profesional a los consultantes que la solicitaron para encontrar respuesta a los diferentes motivos de consulta psicológica y nutricional. Se les brindó el acompañamiento psicológico y nutricional a niños, adolescentes, adultos y familias en los siguientes escenarios: el Centro de Atención Psicológica, Centros de Desarrollo Comunitario del DIF Zapopan como DIF Arenales Tapatíos, DIF Santa María del Pueblito, DIF Santa Ana Tepetitlán Centro Polanco, Bufete Jurídico Clínica Ignacio Ellacuría y Clínica Nutricia. El proyecto ofreció principalmente espacios de atención en modalidad presencial y algunos en línea, donde se atendieron problemáticas tales como: consecuencias tras vivir la Pandemia de Covid-19, diferentes tipos de violencia, TCAS, problemas relacionales, depresión, ideación suicida, situaciones postraumáticas, y complicaciones en el desarrollo de una vida saludable tanto en los aspectos nutricionales como en el acceso a la justicia. Asimismo, se describen los múltiples aprendizajes tanto personales como profesionales, a través de las experiencias e intervenciones a lo largo del Proyecto de Aplicación Profesional.ITESO, A.C

On the Nuclear Pore Complex and Its Roles in Nucleo-Cytoskeletal Coupling and Mechanobiology

The nuclear pore complex (NPC) is primarily recognized for its function as the gateway for nucleocytoplasmic traffic, regulating biochemical exchange between the cytoplasm and the nucleoplasm. On the other hand, the LINC complex, comprised of SUN-domain and KASH-domain proteins, is typically credited as the main physical bridge across the nuclear envelope. However, recent evidence suggests that the NPC is also directly engaged with the cytoskeletal elements and the nucleoskeleton, and as such provides a direct physical association between the nucleus and the cytoskeleton. Moreover, by controlling the transport of inner nuclear membrane proteins, including components of the LINC complex, the NPC plays additional roles in physically connecting the cytoskeleton and the nucleus. This review examines the NPC’s direct and indirect contributions to nucleo-cytoskeletal coupling and mechanobiology

Nucleoporins' exclusive amino acid sequence features regulate their transient interaction with and selectivity of cargo complexes in the nuclear pore.

Nucleocytoplasmic traffic of nucleic acids and proteins across the nuclear envelop via the nuclear pore complexes (NPCs) is vital for eukaryotic cells. NPCs screen transported macromolecules based on their morphology and surface chemistry. This selective nature of the NPC-mediated traffic is essential for regulating the fundamental functions of the nucleus, such as gene regulation, protein synthesis, and mechanotransduction. Despite the fundamental role of the NPC in cell and nuclear biology, the detailed mechanisms underlying how the NPC works have remained largely unknown. The critical components of NPCs enabling their selective barrier function are the natively unfolded phenylalanine- and glycine-rich proteins called "FG-nucleoporins" (FG Nups). These intrinsically disordered proteins are tethered to the inner wall of the NPC, and together form a highly dynamic polymeric meshwork whose physicochemical conformation has been the subject of intense debate. We observed that specific sequence features (called largest positive like-charge regions, or lpLCRs), characterized by extended subsequences that only possess positively charged amino acids, significantly affect the conformation of FG Nups inside the NPC. Here we investigate how the presence of lpLCRs affects the interactions between FG Nups and their interactions with the cargo complex. We combine coarse-grained molecular dynamics simulations with time-resolved force distribution analysis to disordered proteins to explore the behavior of the system. Our results suggest that the number of charged residues in the lpLCR domain directly governs the average distance between Phe residues and the intensity of interaction between them. As a result, the number of charged residues within lpLCR determines the balance between the hydrophobic interaction and the electrostatic repulsion and governs how dense and disordered the hydrophobic network formed by FG Nups is. Moreover, changing the number of charged residues in an lpLCR domain can interfere with ultrafast and transient interactions between FG Nups and the cargo complex

A Comparison of Abdominal Aortic Calcification Index (Aci) between Hemodialysis Patients and Control Group (Non-Diabetic, Non-Hypertensive Traumatic Patients)

BACKGROUND AND OBJECTIVE: Calcification of media layer of peripheral arteries (Monkeburg sclerosis) often occurs with age and in diabetic patients with chronic renal failure. The appearance of this mark in hemodialysis patients can help predict cardiovascular events. Therefore, this study was conducted to compare the Abdominal Aortic Calcification Index (ACI) in hemodialysis and non-renal patients. METHODS: In this cross sectional study, 84 hemodialysis patients who had the inclusion criteria were enrolled.  157 traumatic patients who had no chronic diseases like diabetes or hypertension were enrolled as the control group. The evaluation of CT scan sections, put the patients in three ACI groups (0-40), (41-80) and (81-120). FINDINGS: A sum of 241 patients were enrolled in the study [ 84 (34.9%) in the case and 157 (65.1%) in the control group]. There was a significant difference in ACI between the two groups (P< 0.001). Comparing the chance of ACI in two groups, dialysis patients have a 22.67 times more chance to have severe ACI than mild ACI {CI  95% (4.987-103.062) (p=0.001)}, and also dialysis patients have a 7.32 times more chance to have severe ACI than moderate one {CI 95%(1.486-34.891) (p=0.001)}. CONCLUSION: According to more severe ACI in dialysis patients in comparison to healthy people, renal disease and dialysis may have an essential role in vascular calcification and its complications