Mesoporous silica-based dosage forms improve bioavailability of poorly soluble drugs in pigs: case example fenofibrate.

Objectives: Mesoporous silicas (SLC) have demonstrated considerable potential to improve bioavailability of poorly soluble drugs by facilitating rapid dissolution and generating supersaturation. The addition of certain polymers can further enhance the dissolution of these formulations by preventing drug precipitation. This study uses fenofibrate as a model drug to investigate the performance of an SLC-based formulation, delivered with hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a precipitation inhibitor, in pigs.

The Transcription Factor T-bet Limits Amplification of Type I IFN Transcriptome and Circuitry in T Helper 1 Cells.

Host defense requires the specification of CD4 helper T (Th) cells into distinct fates, including Th1 cells that preferentially produce interferon-γ (IFN-γ). IFN-γ, a member of a large family of anti-pathogenic and anti-tumor IFNs, induces T-bet, a lineage-defining transcription factor for Th1 cells, which in turn supports IFN-γ production in a feed-forward manner. Herein, we show that a cell-intrinsic role of T-bet influences how T cells perceive their secreted product in the environment.

BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency.

The transcriptional programs that guide lymphocyte differentiation depend on the precise expression and timing of transcription factors (TFs). The TF BACH2 is essential for T and B lymphocytes and is associated with an archetypal super-enhancer (SE). Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but BACH2 mutations that cause Mendelian monogenic primary immunodeficiency have not previously been identified.

A novel perfused porcine simulator for teaching aortic anastomosis increases resident interest in vascular surgery.

Objective: This report describes a novel simulator, euthanized pigs on cardiopulmonary bypass, and validates this simulator with a controlled trial in general surgery residents learning aortic anastomosis. We evaluated this novel simulator with the following hypothesis: our porcine perfused simulator is as good as or better than the standard rubber tubing, low-fidelity models used for vascular anastomotic training.

Methods: Euthanized pigs were placed on cardiopulmonary bypass, creating a perfused, ex vivo model on which to perform surgical procedures.

Extraordinary effects of unnatural pairings.

Engineered molecules based on human cytokines have potential uses in research and medicine.

Digital disease detection: A systematic review of event-based internet biosurveillance systems.

Background: Internet access and usage has changed how people seek and report health information. Meanwhile,infectious diseases continue to threaten humanity. The analysis of Big Data, or vast digital data, presents an opportunity to improve disease surveillance and epidemic intelligence.

Mechanisms and consequences of Jak-STAT signaling in the immune system.

Kinases of the Jak ('Janus kinase') family and transcription factors (TFs) of the STAT ('signal transducer and activator of transcription') family constitute a rapid membrane-to-nucleus signaling module that affects every aspect of the mammalian immune system. Research on this paradigmatic pathway has experienced breakneck growth in the quarter century since its discovery and has yielded a stream of basic and clinical insights that have profoundly influenced modern understanding of human health and disease, exemplified by the bench-to-bedside success of Jak inhibitors ('jakinibs') and pathway-targeting drugs. Here we review recent advances in Jak-STAT biology, focusing on immune cell function, disease etiology and therapeutic intervention, as well as broader principles of gene regulation and signal-dependent TFs.

Frenotomy for tongue-tie in newborn infants.

Background: Tongue-tie, or ankyloglossia, is a condition whereby the lingual frenulum attaches near the tip of the tongue and may be short, tight and thick. Tongue-tie is present in 4% to 11% of newborns. Tongue-tie has been cited as a cause of poor breastfeeding and maternal nipple pain.

Using data mining to predict success in a weight loss trial.

Background: Traditional methods for predicting weight loss success use regression approaches, which make the assumption that the relationships between the independent and dependent (or logit of the dependent) variable are linear. The aim of the present study was to investigate the relationship between common demographic and early weight loss variables to predict weight loss success at 12 months without making this assumption.

Methods: Data mining methods (decision trees, generalised additive models and multivariate adaptive regression splines), in addition to logistic regression, were employed to predict: (i) weight loss success (defined as ≥5%) at the end of a 12-month dietary intervention using demographic variables [body mass index (BMI), sex and age]; percentage weight loss at 1 month; and (iii) the difference between actual and predicted weight loss using an energy balance model.

In vitro dissolution models for the prediction of in vivo performance of an oral mesoporous silica formulation.

Drug release from mesoporous silica systems has been widely investigated in vitro using USP Type II (paddle) dissolution apparatus. However, it is not clear if the observed enhanced in vitro dissolution can forecast drug bioavailability in vivo. In this study, the ability of different in vitro dissolution models to predict in vivo oral bioavailability in a pig model was examined.

Studying the neural bases of prism adaptation using fMRI: A technical and design challenge.

Prism adaptation induces rapid recalibration of visuomotor coordination. The neural mechanisms of prism adaptation have come under scrutiny since the observations that the technique can alleviate hemispatial neglect following stroke, and can alter spatial cognition in healthy controls. Relative to non-imaging behavioral studies, fMRI investigations of prism adaptation face several challenges arising from the confined physical environment of the scanner and the supine position of the participants.

Targeting cytokine signaling in autoimmunity: back to the future and beyond.

Cytokines represent structurally diverse soluble factors with critical roles in normal immune function and the pathogenesis of autoimmunity. The emergence of many successful biological therapies targeting cytokines and cytokine receptors exemplifies the importance of cytokines in driving human autoimmune disease; unsurprisingly, there is no paucity of reviews on this subject. Nonetheless, many patients with autoimmune disease do not respond to biologicals, and cure remains an unmet goal.

Cardiac autonomic innervation of the western pygmy possum (Cercatetus concinnus) and golden bandicoot (Isoodon auratus).

Evidence for a functional ventricular parasympathetic innervation of the mammalian heart between and within taxa remains controversial. We have previously proposed that the presence of a functional parasympathetic innervation of the ventricle was indicative of heterothermy, and is essential for maintaining ventricular stability at low body temperature. However, it is possible that the presence of such an innervation is also representative of the primitive mammalian state.

Tofacitinib Ameliorates Murine Lupus and Its Associated Vascular Dysfunction.

Objective: Dysregulation of innate and adaptive immune responses contributes to the pathogenesis of systemic lupus erythematosus (SLE) and its associated premature vascular damage. No drug to date targets both systemic inflammatory disease and the cardiovascular complications of SLE. Tofacitinib is a JAK inhibitor that blocks signaling downstream of multiple cytokines implicated in lupus pathogenesis.

Folate-targeted amphiphilic cyclodextrin.siRNA nanoparticles for prostate cancer therapy exhibit PSMA mediated uptake, therapeutic gene silencing in vitro and prolonged circulation in vivo.

In this study, a folate targeted cyclodextrin (CD) nanoparticle was prepared by co-formulating CD.siRNA complexes with DSPE-PEG-folate to target the prostate specific membrane antigen (PSMA). Targeted formulations showed increased uptake, relative to untargeted controls, in two prostate cancer cell lines expressing PSMA (VCaP and LNCaP).

Identification of the STEMI-equivalent de Winter Electrocardiogram Pattern After Ventricular Fibrillation Cardiac Arrest: A Case Report.

Background: Patients with chest pain who have ST elevations on electrocardiogram (ECG) are at high risk for ST-elevation myocardial infarction (STEMI). Recent literature has reported various STEMI equivalents, which may be equally threatening. One STEMI equivalent, previously named the de Winter pattern, describes ECG changes where there are ST-segment depressions in the precordial leads in association with tall, symmetrical, hyperacute T-waves.

BACH2 regulates CD8(+) T cell differentiation by controlling access of AP-1 factors to enhancers.

T cell antigen receptor (TCR) signaling drives distinct responses depending on the differentiation state and context of CD8(+) T cells. We hypothesized that access of signal-dependent transcription factors (TFs) to enhancers is dynamically regulated to shape transcriptional responses to TCR signaling. We found that the TF BACH2 restrains terminal differentiation to enable generation of long-lived memory cells and protective immunity after viral infection.

Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality.

Innate lymphoid cells (ILCs) play key roles in host defense, barrier integrity, and homeostasis and mirror adaptive CD4(+) T helper (Th) cell subtypes in both usage of effector molecules and transcription factors. To better understand the relationship between ILC subsets and their Th cell counterparts, we measured genome-wide chromatin accessibility. We find that chromatin in proximity to effector genes is selectively accessible in ILCs prior to high-level transcription upon activation.

Signal transducer and activator of transcription 5 (STAT5) paralog dose governs T cell effector and regulatory functions.

The transcription factor STAT5 is fundamental to the mammalian immune system. However, the relationship between its two paralogs, STAT5A and STAT5B, and the extent to which they are functionally distinct, remain uncertain. Using mouse models of paralog deficiency, we demonstrate that they are not equivalent for CD4(+) 'helper' T cells, the principal orchestrators of adaptive immunity.

Unmasking Latent Inhibitory Connections in Human Cortex to Reveal Dormant Cortical Memories.

Balance of cortical excitation and inhibition (EI) is thought to be disrupted in several neuropsychiatric conditions, yet it is not clear how it is maintained in the healthy human brain. When EI balance is disturbed during learning and memory in animal models, it can be restabilized via formation of inhibitory replicas of newly formed excitatory connections. Here we assess evidence for such selective inhibitory rebalancing in humans.

Structural Basis of Duplex Thermodynamic Stability and Enhanced Nuclease Resistance of 5'-C-Methyl Pyrimidine-Modified Oligonucleotides.

Although judicious use of chemical modifications has contributed to the success of nucleic acid therapeutics, poor systemic stability remains a major hurdle. The introduction of functional groups around the phosphate backbone can enhance the nuclease resistance of oligonucleotides (ONs). Here, we report the synthesis of enantiomerically pure (R)- and (S)-5'-C-methyl (C5'-Me) substituted nucleosides and their incorporation into ONs.