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Encapsulation is a process in which a base material is encapsulated in a wall material that can protect it against external factors and/or improve its bioavailability. Among the different encapsulation techniques, ionic gelation stands out as being useful for thermolabile compounds. The aim of this work was to encapsulate Saccharomyces boulardii by ionic gelation using agavins (A) and whey protein (WP) as wall materials and to evaluate the morphostructural changes that occur during in vitro gastrointestinal digestion. Encapsulations at different levels of A and WP were analyzed using microscopic, spectroscopic and thermal techniques. Encapsulation efficiency and cell viability were evaluated. S. boulardii encapsulated at 5% A: 3.75% WP (AWB6) showed 88.5% cell survival after the simulated gastrointestinal digestion; the bead showed a significantly different microstructure from the controls. The mixture of A and WP increased in the survival of S. boulardii respect to those encapsulated with alginate, A or WP alone. The binary material mixture simultaneously allowed a controlled release of S. boulardii by mostly diffusive Fickian mechanisms and swelling. The cell-release time was found to control the increment of the Damköhler number when A and WP were substrates for S. boulardii, in this way allowing greater protection against gastrointestinal conditions. [ABSTRACT FROM AUTHOR]

Objective: To describe the behavior of pregnancy and congenital syphilis in Colombia between 2012 and 2018 according to national notifications records. Materials and Methods: An ecological exploratory study was conducted based on notifications to the public health surveillance system. The incidence rate and prevalence ratio were estimated for each department. Each estimate was established per ranges for 33 departments evaluated and expressed in grayscale maps based on rates and ratios evaluated. Epidemic curves by week of notification for pregnancy and congenital syphilis are also shown. Results: Arauca, Santander, Cesar and Caldas had the highest increase in pregnancy syphilis between 2012 and 2018 while Santander, Casanare and Amazonas had an increase in congenital syphilis during the same period. Other departments had a decrease in these events. Significant differences were found in case reporting from year to year in both events in the country (p<0.001). Conclusions: In Colombia, an increase in pregnancy syphilis was found while a variability with an increasing trend was found for congenital syphilis in recent years. [ABSTRACT FROM AUTHOR]

The rapid growth in the extraction of clinical events from unstructured clinical records has raised considerable challenges. In this paper, we propose the use of different features with a statical modeling method called conditional random fields, which is consider an algorithm for effectively solving problems of sequence tagging. Our goal is to determine which feature selection can affect the performance of four subtasks presented in SemEval Task-12: Clinical TempEval 2016. We applied a careful preprocessing, where the proposed method was tested on real clinical records from Task-12: Clinical TempEval 2016. The comparative analyses obtained indicate that our proposal achieves good results compared to the work presented in Task-12: Clinical TempEval 2016 challenges. [ABSTRACT FROM AUTHOR]

Recently, the extraction of clinical events from unstructured medical texts has attracted much attention of the research community. Machine learning approaches are popular for this task, due to their ability to solve the problem of sequence tagging effectively. It has been suggested previously that simple features, such as word unigrams, part-of-speech tags, chunk tags, among others, are sufficient for this task. We show that more careful preprocessing and feature selection can significantly improve the results. We used conditional random field classifier with more linguistically oriented features and outperformed the current state-of-the-art approaches. We also show that the popular and much simpler Viterbi algorithm (hidden Markov model-based classification algorithm) can produce competitive results, when its parameters are tuned using specific optimization techniques. We evaluate these algorithms for the task of extraction of medical events from the corpus developed for SemEval shared Task 12: Clinical TempEval (Temporal Evaluation) 2016, namely, for its two subtasks: (i) event detection and (ii) event classification based on contextual modality. [ABSTRACT FROM AUTHOR]

Osteomyelitis is a heterogeneous infection with regard to etiology and treatment, and currently no single management protocol exists. Management of the condition is typically an interdisciplinary approach between orthopedics and infectious disease; however, the orthopedist is often the person who manages treatment. The aim of the study was to determine differences in the outcome of osteomyelitis according to its treating specialty and to identify factors associated with the recurrence of the disease. An ambispective cohort study of 129 patients with osteomyelitis was conducted and the proportions for qualitative variables and central tendency and dispersion measures for quantitative variables were calculated; the latter were tested for normality using the Shapiro-Wilk test. A bivariate analysis was conducted with measures of association based on the chi square test and crude relative risk. A logistic regression model was applied and statistical significance was set at p < 0.05, including the model of relevant clinical variables that fit the Hosmer-Lemeshow test. We found that 70% of patients were treated either by orthopedics or infectious disease. Patients who were treated by an orthopedist alone presented a greater risk of relapse or reinfection (RR = 4.6; 95% CI 2.3;8.9). Risk factors of osteomyelitis recurrence as determined in the regression model included the following: age of 57 years or older (RR = 1.3; 95% 0.3;5.2), long bones (RR = 1.9; 95% CI 0.5;7.1), fracture (RR = 5.0; 95% CI 0.4;51.4), monotherapy (RR = 3.0; 95% CI 0.6;14.5), receiving less than 4 weeks of antibiotics (RR = 1.5; 95% CI 0.2;10.1), inadequate treatment (RR = 3.1; 95% CI 0.4;20.1), and receiving orthopedics treatment (RR = 5.5; 95% CI 1.6;18.2). Most patients evaluated jointly by orthopedics and infectious disease received adequate treatment for osteomyelitis and had fewer relapses. [ABSTRACT FROM AUTHOR]

There are different models that explain growth during development. One model is based on insect and amphibian regeneration studies. This model proposes that growth is directed by pattern, and growth takes place by intercalation at a growth discontinuity; therefore, proliferation should surround the discontinuity. Currently, this model, apart from regenerative studies on mostly adult patterning, has not found supporting evidence in Drosophila that shows proliferation surrounding a discontinuity. Despite this lack of evidence, the importance of discontinuities has been shown in different experiments, even under wt conditions, more specifically in the formation of the leg joints because of the occurrence of cell death at their boundaries. Here, we show the existence of a sharp discontinuity in Decapentaplegic (Dpp) in the genital discs at the third larvae stage (L3), which determines the upregulation in the Jun-NH2-Terminal-Kinase (JNK) pathway, reaper (rpr), head involution defective (hid) and active caspases from its boundaries. The proliferation and cell death surrounding the discontinuity suggest that growth can proceed by intercalation and competitive death takes place in this area. Finally, we show that the Rpr, Grim and Hid (RGH) products are a few of the factors that define the growth discontinuity because they are negative regulators of growth, a new function that is unique from their known functions in apoptosis. [ABSTRACT FROM AUTHOR]

Latency-associated nuclear antigen (LANA), a multifunctional protein expressed by the Kaposi sarcoma-associated herpesvirus (KSHV) in latently infected cells, is required for stable maintenance of the viral episome. This is mediated by two interactions: LANA binds to specific sequences (LBS1 and LBS2) on viral DNA and also engages host histones, tethering the viral genome to host chromosomes in mitosis. LANA has also been suggested to affect host gene expression, but both the mechanism(s) and role of this dysregulation in KSHV biology remain unclear. Here, we have examined LANA interactions with host chromatin on a genome-wide scale using chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) and show that LANA predominantly targets human genes near their transcriptional start sites (TSSs). These host LANA-binding sites are generally found within transcriptionally active promoters and display striking overrepresentation of a consensus DNA sequence virtually identical to the LANA-binding site 1 (LBS1) motif in KSHV DNA. Comparison of the ChIP-seq profile with whole-transcriptome (high-throughput sequencing of RNA transcripts [RNA-seq]) data reveals that few of the genes that are differentially regulated in latent infection are occupied by LANA at their promoters. This suggests that direct LANA binding to promoters is not the prime determinant of altered host transcription in KSHV-infected cells. Most surprisingly, the association of LANA to both host and viral DNA is strongly disrupted during the lytic cycle of KSHV. This disruption can be prevented by the inhibition of viral DNA synthesis, suggesting the existence of novel and potent regulatory mechanisms linked to either viral DNA replication or late gene expression. [ABSTRACT FROM AUTHOR]

Productive herpesvirus infection requires a profound, time-controlled remodeling of the viral transcriptome and proteome. To gain insights into the genomic architecture and gene expression control in Kaposi's sarcoma-associated herpesvirus (KSHV), we performed a systematic genome-wide survey of viral transcriptional and translational activity throughout the lytic cycle. Using mRNA-sequencing and ribosome profiling, we found that transcripts encoding lytic genes are promptly bound by ribosomes upon lytic reactivation, suggesting their regulation is mainly transcriptional. Our approach also uncovered new genomic features such as ribosome occupancy of viral non-coding RNAs, numerous upstream and small open reading frames (ORFs), and unusual strategies to expand the virus coding repertoire that include alternative splicing, dynamic viral mRNA editing, and the use of alternative translation initiation codons. Furthermore, we provide a refined and expanded annotation of transcription start sites, polyadenylation sites, splice junctions, and initiation/termination codons of known and new viral features in the KSHV genomic space which we have termed KSHV 2.0. Our results represent a comprehensive genome-scale image of gene regulation during lytic KSHV infection that substantially expands our understanding of the genomic architecture and coding capacity of the virus. [ABSTRACT FROM AUTHOR]

In response to numerous signals, latent herpesvirus genomes abruptly switch their developmental program, aborting stable host-cell colonization in favor of productive viral replication that ultimately destroys the cell. To achieve a rapid gene expression transition, newly minted capped, polyadenylated viral mRNAs must engage and reprogram the cellular translational apparatus. While transcriptional responses of viral genomes undergoing lytic reactivation have been amply documented, roles for cellular translational control pathways in enabling the latent-lytic switch have not been described. Using PEL-derived B-cells naturally infected with KSHV as a model, we define efficient reactivation conditions and demonstrate that reactivation substantially changes the protein synthesis profile. New polypeptide synthesis correlates with 4E-BP1 translational repressor inactivation, nuclear PABP accumulation, eIF4F assembly, and phosphorylation of the capbinding protein eIF4E by Mnk1. Significantly, inhibiting Mnk1 reduces accumulation of the critical viral transactivator RTA through a post-transcriptional mechanism, limiting downstream lytic protein production, and impairs reactivation efficiency. Thus, herpesvirus reactivation from latency activates the host cap-dependent translation machinery, illustrating the importance of translational regulation in implementing new developmental instructions that drastically alter cell fate. [ABSTRACT FROM AUTHOR]

Objective: In light of the health promotion approaches and strategies proposed in the Ottawa Charter, endorsed by the World Health Organization, it was analyzed how the national health authorities of Colombia, Brazil and Mexico, which have health systems structured differently, conceptualize and guide health promotion. Methodology: Documentary analysis of official information from the agencies in charge of health promotion in each country. Subsequently, a coherence analysis around this concept was carried out. Results: There are different levels of coherence regarding health promotion: in Colombia the concept is transmuted into individual risk management through the documents that implement the Ten-Year Public Health Plan; in Brazil, the concept of health promotion is applied coherently although operational priorities are focused on individual aspects, and each state and municipality implements it according to their needs and capabilities; in Mexico, health promotion is institutionalized, but the access of citizens to the service depends on insurance and individual agency. Conclusions: Health promotion is done within a framework of health service provision focused on individual risk control. Officially, the three countries showed coherence with the health promotion postulates set out in the Ottawa Charter, without adequate coherence in its implementation. [ABSTRACT FROM AUTHOR]

Although picornavirus RNA genomes contain a 3'-terminal poly(A) tract that is critical for their replication, the impact of encephalomyocarditis virus (EMCV) infection on the host poly(A)-binding protein (PABP) remains unknown. Here, we establish that EMCV infection stimulates site-specific PABP proteolysis, resulting in accumulation of a 45-kDa N-terminal PABP fragment in virus-infected cells. Expression of a functional EMCV 3C proteinase was necessary and sufficient to stimulate PABP cleavage in uninfected cells, and bacterially expressed 3C cleaved recombinant PABP in vitro in the absence of any virus-encoded or eukaryotic cellular cofactors. N-terminal sequencing of the resulting C-terminal PABP fragment identified a 3Cpro cleavage site on PABP between amino acids Q437 and G438, severing the C-terminal protein-interacting domain from the N-terminal RNA binding fragment. Single amino acid substitution mutants with changes at Q437 were resistant to 3Cpro cleavage in vitro and in vivo, validating that this is the sole detectable PABP cleavage site. Finally, while ongoing protein synthesis was not detectably altered in EMCV-infected cells expressing a cleavage-resistant PABP variant, viral RNA synthesis and infectious virus production were both reduced. Together, these results establish that the EMCV 3C proteinase mediates site-specific PABP cleavage and demonstrate that PABP cleavage by 3C regulates EMCV replication. [ABSTRACT FROM AUTHOR]

Despite their self-sufficient ability to generate capped mRNAs from cytosolic DNA genomes, poxviruses must commandeer the critical eukaryotic translation initiation factor 4F (eIF4F) to recruit ribosomes. While eIF4F integrates signals to control translation, precisely how poxviruses manipulate the multisubunit eIF4F, composed of the cap-binding eIF4E and the RNA helicase eIF4A assembled onto an eIF4G platform, remains obscure. Here, we establish that the poxvirus infection of normal, primary human cells destroys the translational repressor eIF4E binding protein (4E-BP) and promotes eIF4E assembly into an active eIF4F complex bound to the cellular polyadenylate-binding protein (PABP). Stimulation of the eIF4G-associated kinase Mnk1 promotes eIF4E phosphorylation and enhances viral replication and protein synthesis. Remarkably, these eIF4F architectural alterations are accompanied by the concentration of eIF4E and eIF4G within cytosolic viral replication compartments surrounded by PABP. This demonstrates that poxvirus infection redistributes, assembles, and modifies core and associated components of eIF4F and concentrates them within discrete subcellular compartments. Furthermore, it suggests that the subcellular distribution of eIF4F components may potentiate the complex assembly. [ABSTRACT FROM AUTHOR]

In the efforts of viruses to dominate and control critical cellular pathways, viruses generate considerable intracellular stress within their hosts. In particular, the capacity of resident endoplasmic reticulum (ER) chaperones to properly process the acute increase in client protein load is significantly challenged. Such alterations typically induce the unfolded protein response, one component of which acts through IRE1 to restore ER homeostasis by expanding the folding capabilities, whereas the other arm activates the eIF-2α (αsubunit of eukaryotic initiation factor 2) kinase PERK to transiently arrest production of new polypeptide clientele. Viruses, such as herpes simplex virus type 1 (HSV-1), however, go to great lengths to prevent the inhibition of translation resulting from eIF-2α phosphorylation. Here, we establish that PERK, but not IRE1, resists activation by acute ER stress in HSV-1-infected cells. This requires the ER luminal domain of PERK, which associates with the viral glycoprotein gB. Strikingly, gB regulates viral protein accumulation in a PERK-dependent manner. This is the first description of a virus-encoded PERK-specific effector and defines a new strategy by which viruses are able to maintain ER homeostasis. [ABSTRACT FROM AUTHOR]

ia careful control of multiple kinases that inactivate the critical translation initiation factor eIF2 by phosphorylation of its alpha subunit, the cellular translation machinery can rapidly respond to a spectrum of environmental stresses, including viral infection. Indeed, virus replication produces a battery of stresses, such as endoplasmic reticulum (ER) stress resulting from misfolded proteins accumulating within the lumen of this organelle, which could potentially result in eIF2α phosphorylation and inhibit translation. While cellular translation is exquisitely sensitive to ER stress-inducing agents, protein synthesis in herpes simplex virus type 1 (HSV-1)-infected cells is notably resistant. Sustained translation in HSV-1-infected cells exposed to acute ER stress does not involve the interferon-induced, double-stranded RNA-responsive eIF2α kinase PKR, and it does not require either the PKR inhibitor encoded by the Us11 gene or the eIF2α phosphatase component specified by the γ134.5 gene, the two viral functions known to regulate eIF2α phosphorylation. In addition, although ER stress potently induced the GADD34 cellular eIF2α phosphatase subunit in uninfected cells, it did not accumulate to detectable levels in HSV-1-infected cells under identical exposure conditions. Significantly, resistance of translation to the acute ER stress observed in infected cells requires HSV-1 gene expression. Whereas blocking entry into the true late phase of the viral developmental program does not abrogate ER stress-resistant translation, the presence of viral immediate-early proteins is sufficient to establish a state permissive of continued polypeptide synthesis in the presence of ER stress-inducing agents. Thus, one or more previously uncharacterized viral functions exist to counteract the accumulation of phosphorylated eIF2α in response to ER stress in HSV-1-infected cells. [ABSTRACT FROM AUTHOR]

The stimuli-triggered cell attachment/detachment from responsive polymer-coated surfaces is influenced by several parameters including electrostatic interactions, wettability and swelling of the polymer coating. Herein, the supported dual thermo- and pH-responsive cationic poly(N-isopropylacrylamide) microgel, surface-functionalized with polyethylene glycol (PEG) or poly-2-dimethylaminoethylmethacrylate (PDMAEMA), were used as substrates to investigate the role of these parameters on the cell behavior. The microgel were covalently immobilized on glass coverslips and their stimuli-triggered cell detachment ability towards cultured bEnd.3, MCF7 and U138 cell lineages was investigated. The microgel surface-functionalized with PEG chains presented cell adhesion and proliferation rates comparable to controls, while providing the best thermo-triggered detachment performance with MCF7 and U138 cells. This behavior was associated with a preserved hydrophilic character of the microgel surface regardless of the temperature and pH. The swelling behavior of all microgels tuned by pH gave rise to significant cellular detachment only for U138 cells. However, bEnd.3 cell detachment could not be triggered neither by temperature nor pH, regardless of the microgel surface coating. [Display omitted] • Responsive microgel coatings modulate the attachment/detachment behavior of cells. • Cell attachment and proliferation on microgel coatings is similar to the controls. • Triggered cell detachment is favored on microgels surface-functionalized with PEG. • Detachment could not be triggered by any responsive microgel for bEnd.3 cells. [ABSTRACT FROM AUTHOR]

Background: There is no effective therapy for the severe acute respiratory syndrome by coronavirus 2 (SARS-CoV2) responsible for the Coronavirus disease 2019 (Covid-19). To date, dexamethasone has shown a decrease in mortality in patients who require oxygen, especially those with invasive mechanical ventilation. However, it is unknown if another corticosteroid can be used, the optimal dose and its duration, to achieve a better clinical outcome. The objective of the study was to compare the differences in clinical outcome and laboratory results in hospitalized patients with severe SARS-CoV2 Pneumonia treated with dexamethasone at 6 mg doses versus patients treated with high-dose methylprednisolone. Materials and methods: Ambispective cohort study with survival analysis of 216 patients diagnosed with severe Covid-19 pneumonia confirmed by polymerase chain reaction for SARS-CoV2 by Berlin protocol, who were hospitalized in a high-complexity clinic in Medellín, Colombia. The patients should also have supplementary oxygen and radiological confirmation of Pneumonia by chest tomography. Sample size was not calculated since the total population that met the inclusion criteria was evaluated. 111 patients were treated with the institutional protocol with intravenous dexamethasone 6 mg QD for seven to 10 days if they required oxygen. Since September 15, 2020, the hospitalization protocol of the clinic was modified by the Infectious Diseases and Pulmonology service, recommending a high dose of methylprednisolone of 250 to 500 mg every day for three days with a subsequent change to oral prednisone 50 mg every day for 14 days. The protocol was not applied in the intensive care unit, where dexamethasone continued to be administered. The clinical outcome and differences in laboratory results of the patients who received dexamethasone vs. the prospective cohort that received methylprednisolone from September 15 to October 31, 2020, were evaluated. Follow-up was carried out by outpatient consultation one month after discharge or by telephone, inquiring about readmission or living-dead status. Results: 216 patients had Covid-19 pneumonia documented by ground-glass imaging and alveolar pressure / inspired oxygen fraction (PaFi) less than 300. 111 patients received dexamethasone (DXM) and 105 received methylprednisolone (MTP). Patients in the DXM group evolved to severe ARDS in a higher proportion (26.1% vs 17.1% than the MTP group). Upon completion 4 days of treatment with parenteral corticosteroid, laboratory markers of severity decreased significantly in the group that received MTP, CRP 2.85 (2.3–3.8) vs 7.2 (5.4–9.8), (p-value < 0.0001), D-dimer 691 (612–847) vs 1083 (740–1565) (p-value = 0.04) and DHL 273 (244–289) vs 355 (270.6–422) (p-value = 0.01). After starting the corticosteroid, transfer to the intensive care unit (4.8% vs. 14.4%) and mortality (9,5% vs. 17.1%) was lower in the group that received MTP. Recovery time was shorter in patients treated with MTP, three days (3–4) vs. DXM 6 days (5–8) (p-value < 0.0001). At 30-day follow-up, 88 (92.6%) were alive in MTP vs 58 (63.1%) of those who received dexamethasone. Conclusions: In this study, the treatment of severe Covid-19 Pneumonia with high-dose methylprednisolone for three days followed by oral prednisone for 14 days, compared with 6 mg dexamethasone for 7 to 10 days, statistically significantly decreased the recovery time, the need for transfer to intensive care and the severity markers C-reactive protein (CRP), D-dimer and LDH. Randomized controlled studies with methylprednisolone are required to corroborate its effect, and studies in a population hospitalized in intensive care wards. [ABSTRACT FROM AUTHOR]

The current SARS‐CoV‐2 pandemic is wreaking havoc throughout the world and has rapidly become a global health emergency. A central question concerning COVID‐19 is why some individuals become sick and others not. Many have pointed already at variation in risk factors between individuals. However, the variable outcome of SARS‐CoV‐2 infections may, at least in part, be due also to differences between the viral subspecies with which individuals are infected. A more pertinent question is how we are to overcome the current pandemic. A vaccine against SARS‐CoV‐2 would offer significant relief, although vaccine developers have warned that design, testing and production of vaccines may take a year if not longer. Vaccines are based on a handful of different designs (i), but the earliest vaccines were based on the live, attenuated virus. As has been the case for other viruses during earlier pandemics, SARS‐CoV‐2 will mutate and may naturally attenuate over time (ii). What makes the current pandemic unique is that, thanks to state‐of‐the‐art nucleic acid sequencing technologies, we can follow in detail how SARS‐CoV‐2 evolves while it spreads. We argue that knowledge of naturally emerging attenuated SARS‐CoV‐2 variants across the globe should be of key interest in our fight against the pandemic. [ABSTRACT FROM AUTHOR]

Background: The relationship of religious affiliation and mental health is complex, and being part of a minority religious group could have negative effects on mental health. In this study, we assessed the association between religious affiliation and major depressive episode (MDE) in older adults (> = 60 years) from China, Ghana, India, Mexico, Russia and South Africa.Methods: We conducted a secondary analysis of data from the Study on global Ageing and adult health (SAGE), with six nationally-representative community-based samples (n = 21,410). Religious affiliation was self-reported by participants, and we defined MDE based on ICD-10 classification. We estimated the association of MDE with religious affiliation versus no religious affiliation, and minority versus majority affiliation.Results: We observed no association between having a religious affiliation (vs. no affiliation) and the odds of MDE in older adults. In most cases minorities had higher odds of MDE as compared with the majority religion, but the associations were only significant for Muslims in Ghana and for Muslims, Hindus and Other in South Africa.Conclusions: While the results were significant only for two countries, we observed higher odds of MDE among minorities in most of them. Older adults who are members of religious minorities might be at risk for mental health problems, and there is a need for public health interventions aimed at them. [ABSTRACT FROM AUTHOR]

The rapid spread of Zika virus (ZIKV) and its association with abnormal brain development constitute a global health emergency. Congenital ZIKV infection produces a range of mild to severe pathologies, including microcephaly. To understand the pathophysiology of ZIKV infection, we used models of the developing brain that faithfully recapitulate the tissue architecture in early to midgestation. We identify the brain cell populations that are most susceptible to ZIKV infection in primary human tissue, provide evidence for a mechanism of viral entry, and show that a commonly used antibiotic protects cultured brain cells by reducing viral proliferation. In the brain, ZIKV preferentially infected neural stem cells, astrocytes, oligodendrocyte precursor cells, and microglia, whereas neurons were less susceptible to infection. These findings suggest mechanisms for microcephaly and other pathologic features of infants with congenital ZIKV infection that are not explained by neural stem cell infection alone, such as calcifications in the cortical plate. Furthermore, we find that blocking the glia-enriched putative viral entry receptor AXL reduced ZIKV infection of astrocytes in vitro, and genetic knockdown of AXL in a glial cell line nearly abolished infection. Finally, we evaluate 2,177 compounds, focusing on drugs safe in pregnancy. We show that the macrolide antibiotic azithromycin reduced viral proliferation and virus-induced cytopathic effects in glial cell lines and human astrocytes. Our characterization of infection in the developing human brain clarifies the pathogenesis of congenital ZIKV infection and provides the basis for investigating possible therapeutic strategies to safely alleviate or prevent the most severe consequences of the epidemic. [ABSTRACT FROM AUTHOR]

The article presents a study that determines the potential of cyclin-dependent kinase 9 (CDK9) and MYC/BRD4 in inducing growth arrest and apoptosis of cancer cells.

Treatment and follow-up in Hereditary Tyrosinemia type 1 (HT-1) patients require comprehensive clinical and dietary management, which involves drug therapy with NTBC and the laboratory monitoring of parameters, including NTBC levels, succinylacetone (SA), amino acids, and various biomarkers of liver and kidney function. Good adherence to treatment and optimal adjustment of the NTBC dose, according to clinical manifestations and laboratory parameters, can prevent severe liver complications such as hepatocarcinogenesis (HCC). We analyzed several laboratory parameters for 15 HT-1 patients over one year of follow-up in a cohort that included long-term NTBC-treated patients (more than 20 years), as well as short-term patients (one year). Based on this analysis, we described the overall adherence by our cohort of 70% adherence to drug and dietary treatment. A positive correlation was found between blood and plasma NTBC concentration with a conversion factor of 2.57. Nonetheless, there was no correlation of the NTBC level with SA levels, αFP, liver biomarkers, and amino acids in paired samples analysis. By separating according to the range of the NTBC concentration, we therefore determined the mean concentration of each biochemical marker, for NTBC ranges above 15–25 μmol/L. SA in urine and αFP showed mean levels within controlled parameters in our group of patients. Future studies analyzing a longer follow-up period, as well as SA determination in the blood, are encouraged to confirm the present findings. [ABSTRACT FROM AUTHOR]

Chilean newborn screening program began in 1984 through of a covenant between the National Ministry of Health and the Chilean University through its Institute of Nutrition and Food Technology (INTA) with the aim of implementing a pilot study for neonatal detection of phenylketonuria (PKU) in Santiago's central area. In 1989 a program for neonatal diagnosis of PKU and congenital hypothyroidism (HC) was initiated by INTA along with Santiago's occidental health ministry rural area, which covered 20% of newborn population. PKU and HC had an incidence of 1:14,640 and 1:2000 living newborns respectively. These findings allowed the establishment of a favorable cost/benefit ratio which validated the implementation of a program with National character. In 1992 the Chilean Ministry of Health ruled the initiation of PKU and HC newborn screening program and by 1998 the coverage across the country was achieved. INTA is the National Reference Center for confirmation and long term treatment for PKU and HC patients. A follow-up program consists of medical, nutritional, neurological and psychological outcome evaluations as well as periodic biochemical testing in order to guarantee normal patient growth and development. To date 184 children have been diagnosed with classic or moderate PKU, all of them follow a strict monitoring program. [ABSTRACT FROM AUTHOR]

Summary: Using genome-wide approaches, we have elucidated the regulatory circuitry governed by the XBP1 transcription factor, a key effector of the mammalian unfolded protein response (UPR), in skeletal muscle and secretory cells. We identified a core group of genes involved in constitutive maintenance of ER function in all cell types and tissue- and condition-specific targets. In addition, we identified a cadre of unexpected targets that link XBP1 to neurodegenerative and myodegenerative diseases, as well as to DNA damage and repair pathways. Remarkably, we found that XBP1 regulates functionally distinct targets through different sequence motifs. Further, we identified Mist1, a critical regulator of differentiation, as an important target of XBP1, providing an explanation for developmental defects associated with XBP1 loss of function. Our results provide a detailed picture of the regulatory roadmap governed by XBP1 in distinct cell types as well as insight into unexplored functions of XBP1. [Copyright &y& Elsevier]

Uncovering viral gene functions requires the modulation of gene expression through overexpression or loss-of-function. CRISPR interference (CRISPRi), a modification of the CRISPR-Cas9 gene editing technology, allows specific and efficient transcriptional silencing without genetic ablation. CRISPRi has been used to silence eukaryotic and prokaryotic genes at the single-gene and genome-wide levels. Here, we report the use of CRISPRi to silence latent and lytic viral genes, with an efficiency of ~80–90%, in epithelial and B-cells carrying multiple copies of the Kaposi's sarcoma-associated herpesvirus (KSHV) genome. Our results validate CRISPRi for the analysis of KSHV viral elements, providing a functional genomics tool for studying virus–host interactions. [ABSTRACT FROM AUTHOR]