Mechanism-based inactivators of sirtuin 5: A focused structure-activity relationship study.

Sirtuin 5 (SIRT5) is a lysine deacylase enzyme that cleaves negatively charged ε-N-acyllysine posttranslational modifications, arising from short dicarboxylic acids. Inhibition of SIRT5 has been suggested as a target for treatment of leukemia and breast cancer. In this work, we performed a focused structure-activity relationship study that identified highly potent inhibitors of SIRT5.

Sulfur(VI) Fluoride Exchange Chemistry in Solid-Phase Synthesis of Compound Arrays: Discovery of Histone Deacetylase Inhibitors.

Multistep synthesis performed on solid support is a powerful means to generate small-molecule libraries for the discovery of chemical probes to dissect biological mechanisms as well as for drug discovery. Therefore, expansion of the collection of robust chemical transformations amenable to solid-phase synthesis is desirable for achieving chemically diverse libraries for biological testing. Here, we show that sulfur(VI) fluoride exchange (SuFEx) chemistry, exemplified by pairing phenols with aryl fluorosulfates, can be used for the solid-phase synthesis of biologically active compounds.

Contemporary Applications of Thioamides and Methods for Their Synthesis.

Thioamides are naturally occurring isosteres of amide bonds in which the chalcogen atom of the carbonyl is changed from oxygen to sulfur. This substitution gives rise to altered nucleophilicity and hydrogen bonding properties with importance for both chemical reactivity and non-covalent interactions. As such, thioamides have been introduced into biologically active compounds to achieve improved target affinity and/or stability towards hydrolytic enzymes but have also been applied as probes of protein and peptide folding and dynamics.

Substrates and Cyclic Peptide Inhibitors of the Oligonucleotide-Activated Sirtuin 7.

The sirtuins are NAD -dependent lysine deacylases, comprising seven isoforms (SIRT1-7) in humans, which are involved in the regulation of a plethora of biological processes, including gene expression and metabolism. The sirtuins share a common hydrolytic mechanism but display preferences for different ϵ-N-acyllysine substrates. SIRT7 deacetylates targets in nuclei and nucleoli but remains one of the lesser studied of the seven isoforms, in part due to a lack of chemical tools to specifically probe SIRT7 activity.

Aryl Fluorosulfate Based Inhibitors That Covalently Target the SIRT5 Lysine Deacylase.

The sirtuin enzymes are a family of lysine deacylases that regulate gene transcription and metabolism. Sirtuin 5 (SIRT5) hydrolyzes malonyl, succinyl, and glutaryl ϵ-N-carboxyacyllysine posttranslational modifications and has recently emerged as a vulnerability in certain cancers. However, chemical probes to illuminate its potential as a pharmacological target have been lacking.

Investigating GIPR (ant)agonism: A structural analysis of GIP and its receptor.

The glucose-dependent insulinotropic polypeptide (GIP) is a 42-residue metabolic hormone that is actively being targeted for its regulatory role of glycemia and energy balance. Limited structural data of its receptor has made ligand design tedious. This study investigates the structure and function of the GIP receptor (GIPR), using a homology model based on the GLP-1 receptor.

A trial comparing continuous positive airway pressure (CPAP) devices in preterm infants.

Objective: To test the hypothesis that infants born <30 weeks' gestation supported by Seattle-PAP will have lower rates of continuous positive airway pressure (CPAP) failure than infants supported with conventional, Fisher&Paykel-CPAP (FP-CPAP).

Study Design: Randomized trial (3/2017-01/2019) at 5 NICUs. The primary outcome was CPAP failure; subgroup analyses (gestational age, receipt antenatal corticosteroids) were performed.

Evaluating the efficacy of Seattle-PAP for the respiratory support of premature neonates: study protocol for a randomized controlled trial.

Background: At birth, the majority of neonates born at <30 weeks of gestation require respiratory support to facilitate transition and ensure adequate gas exchange. Although the optimal approach to the initial respiratory management is uncertain, the American Academy of Pediatrics endorses noninvasive respiratory support with nasal continuous positive airway pressure (nCPAP) for premature neonates with respiratory insufficiency. Despite evidence for its use, nCPAP failure, requiring intubation and mechanical ventilation, is common.

Short term evaluation of respiratory effort by premature infants supported with bubble nasal continuous airway pressure using Seattle-PAP and a standard bubble device.

Background: Almost one million prematurely born infants die annually from respiratory insufficiency, predominantly in countries with limited access to respiratory support for neonates. The primary hypothesis tested in the present study was that a modified device for bubble nasal continuous positive airway pressure (Bn-CPAP) would provide lower work of spontaneous breathing, estimated by esophageal pressure-rate products.

Methods: Infants born <32 weeks gestation and stable on Bn-CPAP with FiO2 <0.

Automated extraction of DNA from biological stains on fabric from crime cases. A comparison of a manual and three automated methods.

The presence of PCR inhibitors in extracted DNA may interfere with the subsequent quantification and short tandem repeat (STR) reactions used in forensic genetic DNA typing. DNA extraction from fabric for forensic genetic purposes may be challenging due to the occasional presence of PCR inhibitors that may be co-extracted with the DNA. Using 120 forensic trace evidence samples consisting of various types of fabric, we compared three automated DNA extraction methods based on magnetic beads (PrepFiler Express Forensic DNA Extraction Kit on an AutoMate Express, QIAsyphony DNA Investigator kit either with the sample pre-treatment recommended by Qiagen or an in-house optimized sample pre-treatment on a QIAsymphony SP) and one manual method (Chelex) with the aim of reducing the amount of PCR inhibitors in the DNA extracts and increasing the proportion of reportable STR-profiles.

Hematological clozapine monitoring with a point-of-care device: a randomized cross-over trial.

Clozapine remains the drug of choice for patients with treatment-resistant schizophrenia, who show a response rate of about 50% despite their unresponsiveness to other antipsychotics. Although treatment with clozapine can lead to considerable savings on bed days, the drug is underutilized for several reasons, perhaps most importantly because of the mandatory hematological monitoring. The Chempaq Express Blood Counter (Chempaq XBC) is a point-of-care device providing counts of white blood cells (WBC) and granulocytes based on a capillary blood sampling.

Effective gas exchange in paralyzed juvenile rabbits using simple, inexpensive respiratory support devices.

We have developed two devices: a high-amplitude bubble continuous positive airway pressure (HAB-CPAP) and an inexpensive bubble intermittent mandatory ventilator (B-IMV) to test the hypotheses that simple, inexpensive devices can provide gas exchange similar to that of bubble CPAP (B-CPAP) and conventional mechanical ventilation (CMV). Twelve paralyzed juvenile rabbits were intubated, stabilized on CMV, and then switched to CPAP. On identical mean airway pressures (MAPs), animals were unable to maintain pulse oximeter oxygen saturation (SpO2) >80% on conventional B-CPAP, but all animals oxygenated well (97.

[Health status and degree of traumatisation among newly arrived asylum seeker--secondary publication].

An unknown number of asylum seekers arriving in Denmark have been exposed to torture. Amnesty International's Danish Medical Group examined 142 asylum seekers, of whom 45% had been exposed to torture. Physical and psychological symptoms were 2-3 times as frequent among torture survivors as among non-tortured asylum seekers.

Global report on preterm birth and stillbirth (3 of 7): evidence for effectiveness of interventions.

Introduction: Interventions directed toward mothers before and during pregnancy and childbirth may help reduce preterm births and stillbirths. Survival of preterm newborns may also be improved with interventions given during these times or soon after birth. This comprehensive review assesses existing interventions for low- and middle-income countries (LMICs).

Noninvasive respiratory support of juvenile rabbits by high-amplitude bubble continuous positive airway pressure.

Bubble continuous positive airway pressure (B-CPAP) applies small-amplitude, high-frequency oscillations in airway pressure (DeltaPaw) that may improve gas exchange in infants with respiratory disease. We developed a device, high-amplitude B-CPAP (HAB-CPAP), which provides greater DeltaPaw than B-CPAP provides. We studied the effects of different operational parameters on DeltaPaw and volumes of gas delivered to a mechanical infant lung model.

Quantitative miRNA expression analysis: comparing microarrays with next-generation sequencing.

Recently, next-generation sequencing has been introduced as a promising, new platform for assessing the copy number of transcripts, while the existing microarray technology is considered less reliable for absolute, quantitative expression measurements. Nonetheless, so far, results from the two technologies have only been compared based on biological data, leading to the conclusion that, although they are somewhat correlated, expression values differ significantly. Here, we use synthetic RNA samples, resembling human microRNA samples, to find that microarray expression measures actually correlate better with sample RNA content than expression measures obtained from sequencing data.

Early career development in academic pediatrics of participants in the APS-SPR Medical Student Research Program.

To recruit and train the next generations of pediatric clinician-scientists, the American Pediatric Society and Society for Pediatric Research initiated a program in 1991 to support medical students with interests in research and pediatrics to conduct research at institutions other than their respective medical schools. Since 1991, the American Pediatric Society-Society for Pediatric Research Medical Student Research Program (MSRP) has funded 732 of 2209 applicants from 132 US or Canadian medical schools for 8-12 wk of research under the direction of experienced investigators. PubMed-attributable publications tabulated in 2001 for MSRP applicants through 2000 indicated that participants had published more actively than had nonparticipant applicants.

Asylum seekers in Denmark--a study of health status and grade of traumatization of newly arrived asylum seekers.

Background: An unknown number of asylum seekers arriving in Denmark have been exposed to torture or have experienced other traumatising events in their country of origin. The health of traumatised asylum seekers, both physically and mentally, is affected upon arrival to Denmark, and time in asylum centres leads to further deterioration in health.

Methods: One hundred forty-two (N=142) newly arrived asylum seekers were examined at Center Sandholm by Amnesty International Danish Medical Group from the 1st of September until the 31st of December 2007.

Altered expressions of fibroblast growth factor receptors and alveolarization in neonatal mice exposed to 85% oxygen.

In the present study, we tested the hypothesis that exposure of newborn mice to sublethal hyperoxia would alter lung development and expressions of fibroblast growth factor receptors (FGFRs)-3 and FGFR-4. Newborn FVB mice were exposed to 85% O2 or maintained in room air for up to 14 d. No animal mortality was observed, and body weight gains were not affected by hyperoxia.

Large acoustic transients induced by nonthermal melting of InSb.

We have observed large-amplitude strain waves following a rapid change in density of InSb due to nonthermal melting. The strain has been measured in real time via time-resolved x-ray diffraction, with a temporal resolution better than 2 ps. The change from the solid to liquid density of the surface layer launches a high-amplitude strain wave into the crystalline material below.

Thioredoxin-related mechanisms in hyperoxic lung injury in mice.

Reduction of glutathione disulfide (GSSG) to glutathione (GSH) by glutathione reductase (GR) enhances the efficiency of GSH-dependent antioxidant activities. However, GR-deficient (a1Neu) mice are less susceptible to acute lung injury from continuous exposure to > 95% O(2) (96 h: 6.9 +/- 0.