Genetic events associated with venetoclax resistance in CLL identified by whole-exome sequencing of patient samples.

Although BCL2 mutations are reported as later occurring events leading to venetoclax resistance, many other mechanisms of progression have been reported though remain poorly understood. Here, we analyze longitudinal tumor samples from 11 patients with disease progression while receiving venetoclax to characterize the clonal evolution of resistance. All patients tested showed increased in vitro resistance to venetoclax at the posttreatment time point. We found the previously described acquired BCL2-G101V mutation in only 4 of 11 patients, with 2 patients showing a very low variant allele fraction (0.03%-4.68%). Whole-exome sequencing revealed acquired loss(8p) in 4 of 11 patients, of which 2 patients also had gain (1q21.2-21.3) in the same cells affecting the MCL1 gene. In vitro experiments showed that CLL cells from the 4 patients with loss(8p) were more resistant to venetoclax than cells from those without it, with the cells from 2 patients also carrying gain (1q21.2-21.3) showing increased sensitivity to MCL1 inhibition. Progression samples with gain (1q21.2-21.3) were more susceptible to the combination of MCL1 inhibitor and venetoclax. Differential gene expression analysis comparing bulk RNA sequencing data from pretreatment and progression time points of all patients showed upregulation of proliferation, B-cell receptor (BCR), and NF-κB gene sets including MAPK genes. Cells from progression time points demonstrated upregulation of surface immunoglobulin M and higher pERK levels compared with those from the preprogression time point, suggesting an upregulation of BCR signaling that activates the MAPK pathway. Overall, our data suggest several mechanisms of acquired resistance to venetoclax in CLL that could pave the way for rationally designed combination treatments for patients with venetoclax-resistant CLL.

Influenza virus-membrane fusion triggered by proton uncaging for single particle studies of fusion kinetics.

We report a method for studying membrane fusion, focusing on influenza virus fusion to lipid bilayers, which provides high temporal resolution through the rapid and coordinated initiation of individual virus fusion events. Each fusion event proceeds through a series of steps, much like multistep chemical reaction. Fusion is initiated by a rapid decrease in pH that accompanies the "uncaging" of an effector molecule from o-nitrobenzaldehyde, a photoisomerizable compound that releases a proton to the surrounding solution within microseconds of long-wave ultraviolet irradiation. In order to quantify pH values upon UV irradiation and uncaging, we introduce a simple silica nanoparticle pH sensor, useful for reporting the pH in homogeneous nanoliter volumes under conditions where traditional organic dye-type pH probes fail. Subsequent single-virion fusion events are monitored using total internal reflection fluorescence microscopy. Statistical analysis of these stochastic events uncovers kinetic information about the fusion reaction. This approach reveals that the kinetic parameters obtained from the data are sensitive to the rate at which protons are delivered to the bound viruses. Higher resolution measurements can enhance fundamental fusion studies and aid antiviral antifusogenic drug development.

A Rare Case of HHV-6 Encephalitis in an Immunocompetent Host: Case Report and Literature Review.

Human herpesvirus-6 (HHV-6) is a virus known for causing the highly contagious infection, roseola infantum, and has been associated with causing encephalitis in pediatric patients and less commonly in adult patients as well. Regardless of the patient's age, the primary HHV-6 infection could be complicated by neurological sequelae including encephalitis, acute encephalopathy with biphasic seizures syndrome, or demyelinating disease. HHV-6 encephalitis does occur in an adult as a primary infection or reactivation. However, immunocompromised, hematopoietic stem cell transplantation patients, and solid organ transplant recipients are the most affected population. Here we present a rare case of HHV-6 encephalitis in a 26-year-old healthy immunocompetent male. HHV-6 viral DNA was detected in the cerebrospinal fluid during the acute stage of the disease, and the diagnosis was confirmed by quantitative polymerase chain reaction (PCR). The patient was treated with ganciclovir and had a complete response to treatment without any further complication. The pathophysiology, clinical course, and treatment in otherwise immunocompetent adult patients are also discussed.

Codon Selection Affects Recruitment of Ribosome-Associating Factors during Translation.

An intriguing aspect of protein synthesis is how cotranslational events are managed inside the cell. In this study, we developed an in vivo bimolecular fluorescence complementation assay coupled to SecM stalling (BiFC-SecM) to study how codon usage influences the interactions of ribosome-associating factors that occur cotranslationally. We profiled ribosomal associations of a number of proteins, and observed differential association of chaperone proteins TF, DnaK, GroEL, and translocation factor Ffh as a result of introducing synonymous codon substitutions that change the affinity of the translating sequence to the ribosomal anti-Shine-Dalgarno (aSD) sequence. The use of pausing sequences within proteins regulates their transit within the translating ribosome. Our results indicate that the dynamics between cellular factors and the new polypeptide chain are affected by how codon composition is designed. Furthermore, associating factors may play a role in processes including protein quality control (folding and degradation) and cellular respiration.

Probióticos y prebióticos en pacientes con enfermedad celíaca y sensibilidad al gluten no celíaca / Probiotics and prebiotics for patients with celiac disease and non-celiac gluten sensitivity

La enfermedad celíaca y la sensibilidad al gluten no celíaca han tenido un aumento en su incidencia, esto las ha convertido en tema de interés en la búsqueda de enfoques terapéuticos innovadores que ayuden a mejorar los síntomas intestinales y extraintestinales. Esta revisión pretende determinar los efectos del uso de probióticos y prebióticos en la enfermedad celíaca y sensibilidad al gluten no celíaca. Se realizó una búsqueda en bases de datos HINARI, PubMed y Scopus en idioma español e inglés, se incluyeron artículos originales y de revisión con un máximo de cinco años desde su publicación. El uso de probióticos y prebióticos para la enfermedad celíaca ha mostrado beneficios restaurando la composición del microbiota intestinal, en especial con el uso de Lactobacilli y Bifidobacterium spp.; en la sensibilidad al gluten no celíaca, el uso se ve limitado al no conocer con exactitud su fisiopatología; no obstante, se propone como mejor pauta terapéutica una dieta libre de gluten. El uso de probióticos y prebióticos podría aliviar los síntomas gastrointestinales y mejorar la disbiosis en pacientes con enfermedad celíaca y sensibilidad al gluten no celíaca. Sin embargo, se necesitan más estudios que evidencien los beneficios de su uso como alternativa terapéutica

Celiac disease and non-celiac gluten sensitivity are entities that have shown an increase in incidence, making them a topic of interest to provide innovative therapeutic approaches and improve intestinal and extraintestinal symptoms. This review intends to determine the effects of the use of probiotics and prebiotics in celiac disease and non-celiac gluten sensitivity. A narrative review was undertaken by searching for original and review articles no older than five years since publication through data bases consulted: HINARI, PubMed and Scopus in Spanish and English. The use of probiotics and prebiotics in celiac disease has shown benefits by restoring the composition of the intestinal microbiota, especially with the use of Lactobacilli and Bifidobacterium spp.; in non-celiac gluten sensitivity, its use is limited as its pathophysiology is not exactly known, therefore, a gluten-free diet is currently considered to be the best therapeutic guideline. The use of probiotics and prebiotics could alleviate gastrointestinal symptoms and improve dysbiosis in patients with celiac disease and non-celiac gluten sensitivity. However, more studies are needed to demonstrate the benefits of its use as a therapeutic alternative

Slowing Translation between Protein Domains by Increasing Affinity between mRNAs and the Ribosomal Anti-Shine-Dalgarno Sequence Improves Solubility.

Recent studies have demonstrated that effective protein production requires coordination of multiple cotranslational cellular processes, which are heavily affected by translation timing. Until recently, protein engineering has focused on codon optimization to maximize protein production rates, mostly considering the effect of tRNA abundance. However, as it relates to complex multidomain proteins, it has been hypothesized that strategic translational pauses between domains and between distinct individual structural motifs can prevent interactions between nascent chain fragments that generate kinetically trapped misfolded peptides and thereby enhance protein yields. In this study, we introduce synthetic transient pauses between structural domains in a heterologous model protein based on designed patterns of affinity between the mRNA and the anti-Shine-Dalgarno (aSD) sequence on the ribosome. We demonstrate that optimizing translation attenuation at domain boundaries can predictably affect solubility patterns in bacteria. Exploration of the affinity space showed that modifying less than 1% of the nucleotides (on a small 12 amino acid linker) can vary soluble protein yields up to ∼7-fold without altering the primary sequence of the protein. In the context of longer linkers, where a larger number of distinct structural motifs can fold outside the ribosome, optimal synonymous codon variations resulted in an additional 2.1-fold increase in solubility, relative to that of nonoptimized linkers of the same length. While rational construction of 54 linkers of various affinities showed a significant correlation between protein solubility and predicted affinity, only weaker correlations were observed between tRNA abundance and protein solubility. We also demonstrate that naturally occurring high-affinity clusters are present between structural domains of ß-galactosidase, one of Escherichia coli's largest native proteins. Interdomain ribosomal affinity is an important factor that has not previously been explored in the context of protein engineering.

Uso indiscriminado de sucedaneos de la leche materna en Bolivia y su impacto en la economía familiar / Indiscriminate use of breast milk substitutes and its impact on the Bolivian family economy

OBJETIVO: Estimar el presupuesto mensual que las familias destinan a la lactancia artificial de infantes en Bolivia analizando algunos factores sociales y epidemiológicos relacionados a la lactancia materna. MATERIAL Y MÉTODOS: Se realizaron encuestas a madres asistentes a consulta pediátrica del Hospital del Niño Dr. Ovidio Aliaga Uria, hospital universitario de tercer nivel de la ciudad de La Paz, que incluyeron sólo a madres que daban de lactar a bebés menores de un año (infantes), investigando el tipo de lactancia, el uso de fórmulas; estimando el costo de cada una de las diversas fórmulas utilizadas, calculando el volumen requerido, y el presupuesto mensual estimado, necesario para invertirlo exclusivamente para leche artificial. RESULTADOS: En el grupo estudio de infantes entre 0 a 6 meses de edad se comprobó que solo18% de infantes recibe lactancia exclusiva, 58% recibe lactancia mixta y 24% usa fórmulas de manera exclusiva. En el grupo de 6 a 12 meses de edad reciben lactancia exclusiva 8%, lactancia mixta 63% y lactancia en base a formula 29%. Los primeros 6 meses se utiliza un promedio de 30 latas de leche de formula implicando un gasto de entre Bs.5.530 bs (USD 801.-) si se compra en farmacias o supermercados y Bs. 5,202 (USD 754.) si se compra en mercado libre informal. En cuanto al uso de números de empaque o latas en los siguientes meses el número total es de 36 latas, implicando un costo de Bs. 6,936 (USD 1.005.-), si se compra exclusivamente en farmacias y 6,660 bs en mercado libre.

OBJECTIVE: To estimate proportion of the monthly family budget allocated for artificial feeding of infants and discuss the social and some epidemiological factors related to breastfeeding. METHODS: An operative survey has been conducted interviewing mothers attending out patients pediatric Unit of Dr. Ovidio Aliaga Uria Children's Hospital, which included only interviews to mothers breastfeeding just infants under one year, searching data about type of feeding, preferences of formula; cost of each of the different formulas , volume of formula recommended to use monthly budget. RESULTS: in the group of 0-6 months of age 18% of mothers offer exclusive breastfeeding, while mixed feeding is preferred by 58% and 24% use exclusively just formula. In the group of babies of 6 to 12 months 8% receive breast milk, while , 63% offer mixed breastfeeding and formulas, and just formulas in offer to 29%. The first 6 months an average of 30 cans are consumed, involving an estimate expenditure of Bs. 5.530.- (USD 801.-) and Bs. 5.202 (USD 754.-) in the next 6 months, depending on the formula brand, infant age, type of feeding bottle used

Aplicación de la terapia de aceptación y compromiso (ACT) a la conducta inapetente: un estudio de caso / Application of acceptance and commitment therapy (ACT) in inapetente conduct: a case study

En este artículo se presenta un estudio de caso acerca de la conducta inapetente abordado desde la Terapia de Aceptación y Compromiso. En primer lugar, se concibió a la evitación experiencial como una dimensión transdiagnóstica común a diversas problemáticas humanas. Seguidamente, se revisó la historia del participante y se prosiguió con la evaluación del caso mediante el Cuestionario Parental de Aceptación y Acción (PAAQ) y un registro de duración de conducta, en base a todo ello se realizó un análisis funcional del caso. Posteriormente, se aplicó la Terapia de Aceptación y Compromiso (ACT) con la finalidad de romper el repertorio de evitación y encaminar la vida de los principales involucrados hacia las acciones que se consideren valiosas; tras ello, se realizaron tres seguimientos. Finalmente, se analizaron y discutieron los resultados obtenidos a partir de los exitosos beneficios topográficos y funcionales reflejados de forma contingente a la aplicación de la ACT en el campo de los problemas de conducta alimentaria.

In this article a case study on the loss of appetite approached from the Acceptance and Commitment Therapy is presented. First, experiential avoidance was conceptualized as a transdiagnostic dimension common to various human problems. Then, the story of the participant was reviewed and the assessment of the case was done by the Parental Acceptance and Action Questionnaire (PAAQ) and a record length of conduct, based on all functional analysis of the case was conducted. Subsequently, Acceptance and Commitment Therapy (ACT) was applied in order to break the avoidant repertoire and route the path of life towards the valued actions, after that three follow-ups were conducted. Finally, the results obtained from topographic and functional successful benefits were analyzed and discussed, contingent on the application of ACT in the field of eating behavior problems.