ABSTRACT
Studies suggest that nonsyndromic cleft lip and palate (NSCLP) is polygenic with variable penetrance, presenting a challenge in identifying all causal genetic variants. Despite relatively ...high prevalence of NSCLP among Amerindian populations, no large whole exome sequencing (WES) studies have been completed in this population. Our goal was to identify candidate genes with rare genetic variants for NSCLP in a Honduran population using WES. WES was performed on two to four members of 27 multiplex Honduran families. Genetic variants with a minor allele frequency > 1% in reference databases were removed. Heterozygous variants consistent with dominant disease with incomplete penetrance were ascertained, and variants with predicted functional consequence were prioritized for analysis. Pedigree‐specific P‐values were calculated as the probability of all affected members in the pedigree being carriers, given that at least one is a carrier. Preliminary results identified 3,727 heterozygous rare variants; 1,282 were predicted to be functionally consequential. Twenty‐three genes had variants of interest in ≥3 families, where some genes had different variants in each family, giving a total of 50 variants. Variant validation via Sanger sequencing of the families and unrelated unaffected controls excluded variants that were sequencing errors or common variants not in databases, leaving four genes with candidate variants in ≥3 families. Of these, candidate variants in two genes consistently segregate with NSCLP as a dominant variant with incomplete penetrance: ACSS2 and PHYH. Rare variants found at the same gene in all affected individuals in several families are likely to be directly related to NSCLP.
The germinal center (GC) reaction is crucial for T cell-dependent immune responses and is targeted by B cell lymphomagenesis. Here we analyzed the transcriptional changes that occur in B cells during ...GC transit (naive B cells → centroblasts → centrocytes → memory B cells) by gene expression profiling. Naïve B cells, characterized by the expression of cell cycle-inhibitory and anti-apoptotic genes, become centroblasts by inducing an atypical proliferation program lacking c-Myc expression, switching to a proapoptotic program, and down-regulating cytokine, chemokine, and adhesion receptors. The transition from GC to memory cells is characterized by a return to a phenotype similar to that of naïve cells except for an apoptotic program primed for both death and survival and for changes in the expression of cell surface receptors including IL-2 receptor β. These results provide insights into the dynamics of the GC reaction and represent the basis for the analysis of B cell malignancies.
The full set of microRNAs (miRNAs) in the human genome is not known. Because presently known miRNAs have been identified by virtue of their abundant expression in a few cell types, many ...tissue-specific miRNAs remain unrevealed. To understand the role of miRNAs in B cell function and lymphomagenesis, we generated short-RNA libraries from normal human B cells at different stages of development (naive, germinal center, memory) and from a Burkitt lymphoma cell line. A combination of cloning and computational analysis identified 178 miRNAs (miRNome) expressed in normal and/or transformed B cell libraries. Most notably, the B cell miRNome included 75 miRNAs which to our knowledge have not been previously reported and of which 66 have been validated by RNA blot and/or RT-PCR analyses. Numerous miRNAs were expressed in a stage- or transformation-specific fashion in B cells, suggesting specific functional or pathologic roles. These results provide a resource for studying the role of miRNAs in B cell development, immune function, and lymphomagenesis.
The PubMed database offers an extensive set of publication data that can be useful, yet inherently complex to use without automated computational techniques. Data repositories such as the Genomic ...Data Commons (GDC) and the Gene Expression Omnibus (GEO) offer experimental data storage and retrieval as well as curated gene expression profiles. Genetic interaction databases, including Reactome and Ingenuity Pathway Analysis, offer pathway and experiment data analysis using data curated from these publications and data repositories. We have created a method to generate and analyze consensus networks, inferring potential gene interactions, using large numbers of Bayesian networks generated by data mining publications in the PubMed database. Through the concept of network resolution, these consensus networks can be tailored to represent possible genetic interactions. We designed a set of experiments to confirm that our method is stable across variation in both sample and topological input sizes. Using gene product interactions from the KEGG pathway database and data mining PubMed publication abstracts, we verify that regardless of the network resolution or the inferred consensus network, our method is capable of inferring meaningful gene interactions through consensus Bayesian network generation with multiple, randomized topological orderings. Our method can not only confirm the existence of currently accepted interactions, but has the potential to hypothesize new ones as well. We show our method confirms the existence of known gene interactions such as JAK-STAT-PI3K-AKT-mTOR, infers novel gene interactions such as RAS- Bcl-2 and RAS-AKT, and found significant pathway-pathway interactions between the JAK-STAT signaling and Cardiac Muscle Contraction KEGG pathways.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Allergy risk has become a significant public health issue with increasing prevalence. Exclusive breastfeeding is recommended for the first six months of life, but this recommendation is poorly ...adhered to in many parts of the world, including the Middle-East region, putting infants at risk of developing allergic sensitization and disorders. When breastfeeding is not possible or not adequate, a partially hydrolyzed whey formula (pHF-W) has shown proven benefits of preventing allergy, mainly atopic eczema, in children with a genetic risk. Therefore, besides stimulating breastfeeding, early identification of infants at risk for developing atopic disease and replacing commonly used formula based on intact cow milk protein (CMP) with a clinically proven pHF-W formula is of paramount importance for allergy prevention. If the child is affected by cow's milk protein allergy (CMPA), expert guidelines recommend extensively hydrolyzed formula (eHF), or an amino acid formula (AAF) in case of severe symptoms. The Middle-East region has a unique practice of utilizing pHF-W as a step-down between eHF or AAF and intact CMP, which could be of benefit. The region is very heterogeneous with different levels of clinical practice, and as allergic disorders may be seen by healthcare professionals of different specialties with different levels of expertise, there is a great variability in preventive and treatment approaches within the region itself. During a consensus meeting, a new approach was discussed and unanimously approved by all participants, introducing the use of pHF-W in the therapeutic management of CMPA. This novel approach could be of worldwide benefit.
Although mineral chelates are widely produced to be used as food fortifiers, the proof that these complexes are chelates is still missing. In our present work, iron II complexes using citric acid in ...different ratios are produced, and the occurrence of chelation is investigated along with its behavior according to a molar ratio between the ligand and the mineral. High performance liquid chromatography (HPLC), flame atomic absorption spectroscopy (FAAS), ultraviolet-visible spectroscopy (UV-Vis), Fourier-transform infrared (FTIR), and near infrared spectroscopy (NIR) were used for a non-structural characterization of these complexes. In contrast to published work, our findings show that the chelation of citric acid is achieved in the liquid form and at a low pH and that the molar ratio is very important in setting the direction of the reaction, either toward chelation or dimer formation. The ratio citric acid:iron 1:4 seems to be the most convenient ratio in which no free citric acid remains in the solution, while the 1:3 ratio behaves differently, requiring further investigations by such techniques as extended X-ray absorption fine structure spectroscopy (EXAFS), among others, in order to deeply identify the structural organization occurring in this ratio. NIR, extensively used in industries, proved to be very useful in the demonstration and characterization of chelates. These findings are particularly advantageous for pharmaceutical and food industries in offering an innovative competent fortifying agent to be used in combatting iron deficiency.
Abstract Background Nasal septal abscess (NSA) is a rare condition most commonly seen as a complication of nasal trauma. The diagnosis of NSA requires emergent treatment, because delayed management ...can result in significant morbidity. Typically, NSA presents as a purulent collection that can be managed with drainage, either surgically or at bedside. Case Report We report an unusual presentation of a spontaneous NSA in a 7-year-old boy as a solid nasal mass eroding the nasal septum. The solid, tumor-like nature of the mass necessitated intervention beyond drainage and was ultimately excised. Imaging initiated in the emergency department revealed a partially cystic mass and erosion of the septum, which was key to the diagnosis. Why Should an Emergency Physician be Aware of This? Given the ease with which a diagnosis of NSA may be missed and the need for urgent management upon diagnosis of a NSA, we aim to highlight the clinical, radiologic, and histopathologic aspects that aid in diagnosis of NSA. Imaging, obtaining culture results, and initiation of antibiotics are paramount in management. In addition, NSAs may also necessitate bedside drainage given their emergent nature.
Memory B cells provide rapid protection to previously encountered antigens; however, how these cells develop from germinal center B cells is not well understood. A previously described in vitro ...culture system using human tonsillar germinal center B cells was used to study the transcriptional changes that occur during differentiation of human memory B cells. Kinetic studies monitoring the expression levels of several known late B cell transcription factors revealed that BCL-6 is not expressed in memory B cells generated in vitro, and gene expression profiling studies confirmed that BCL-6 is not expressed in these memory B cells. Furthermore, ectopic expression of BCL-6 in human B cell cultures resulted in formation of fewer memory B cells. In addition, the expression profile of in vitro memory B cells showed a unique pattern that includes expression of genes encoding multiple costimulatory molecules and cytokine receptors, antiapoptotic proteins, T cell chemokines, and transcription factors. These studies establish new molecular criteria for defining the memory B cell stage in human B cells.
Pistachio and cashew contain allergenic proteins, which causes them to be removed from the diet of allergic people. Previous studies have demonstrated that food processing (thermal and non-thermal) ...can produce structural and/or conformational changes in proteins by altering their allergenic capacity. In this study, the influence of instant controlled pressure drop (DIC) on pistachio and cashew allergenic capacity has been studied. Western blot was carried out using IgG anti-11S and anti-2S and IgE antibodies from sera of patients sensitized to pistachio and cashew. DIC processing causes changes in the electrophoretic pattern, reducing the number and intensity of protein bands, as the pressure and temperature treatment increment, which results in a remarkable decrease in detection of potentially allergenic proteins. The harshest conditions of DIC (7 bar, 120 s) markedly reduce the immunodetection of allergenic proteins, not only by using IgG (anti 11S and anti 2S) but also when IgE sera from sensitized patients were used for Western blots. Such immunodetection is more affected in pistachio than in cashew nuts, but is not completely removed. Therefore, cashew proteins are possibly more resistant than pistachio proteins. According these findings, instant controlled pressure drop (DIC) can be considered a suitable technique in order to obtain hypoallergenic tree nut flour to be used in the food industry.
Traditional password authentication methods have raised many issues in the past, including insecure practices, so it comes as no surprise that the evolution of authentication should arrive in the ...form of password-less solutions. This research aims to explore the problems that password authentication and password policies present and aims to deploy Windows Hello for Business (WHFB) on-premises. This includes creating three virtual machines (VMs) and evaluating WHFB as a password-less solution and showing how an attacker with privileged access may retrieve the end user’s domain password from the computer’s memory using Mimikatz and describing the possible results. The conducted research tests are in the form of two attack methods. This was feasible by the creation of three VMs operating in the following way. The first VM will act as a domain controller (DC) and certificate authority server (CA server). The second VM will act as an Active Directory Federation Service (ADFS). The third VM will act as the end-user device. The test findings research summarized that password-less authentication is far more secure than the traditional authentication method; this is evidenced throughout the author’s tests. Within the first test, it was possible to retrieve the password from an enrolled device for WHFB while it was still in the second phase of the deployment. The second test was a brute-force attack on the PIN of WHFB; since WHFB has measures to prevent such attacks, the attack was unsuccessful. However, even though the retrieval of the password was successful, there are several obstacles to achieving this outcome. It was concluded that many organizations still use password authentication as their primary authentication method for accessing devices and applications. Larger organizations such as Microsoft and Google support the adoption of password-less authentication for end-users, and the current usage of password-less authentication shared by both organizations is encouraged. This usually leads organizations to adopt this new solution for their IT infrastructure. This is because it has been used and tested by millions of people and has proven to be safe. This supports the findings of increased usage and the need for password-less authentication by today’s users.
PDF
