The University of Michigan School of Public Health Preventive Medicine Residency (UMSPH PMR) Integrative Medicine Program (IMP) was developed to incorporate integrative medicine (IM), public health, ...and preventive medicine principles into a comprehensive curriculum for preventive medicine residents and faculty. The objectives of this project were to (1) increase the preventive medicine workforce skill sets based in complementary and alternative medicine and IM that would address individual and population health issues; (2) address the increasing demand for evidence-based IM by training physicians to implement cost-effective primary and secondary prevention services and programs; and (3) share lessons learned, curriculum evaluations, and best practices with the larger cohort of funded IM PMR programs. The UMSPH PMR collaborated with University of Michigan IM faculty to incorporate existing IM competencies with those already established for preventive medicine and public health residency training as the first critical step for IMP curriculum integration. Essential teaching strategies incorporated didactic and practicum methods, and made use of seasoned IM faculty, along with newly minted preventive medicine integrative teaching faculty, and PMR resident learners as IM teachers. The major components of the IMP curriculum included resident participation in IMP Orientation Sessions, resident leadership in epidemiology graduate IM seminars, resident rotations in IM month-long clinical practicums, resident participation in interprofessional health system–wide IM clinical case conferences, and PMR faculty enrollment in the renowned Faculty Scholars Program in Integrative Healthcare. This paper describes the novel interdisciplinary collaborations and key curriculum components that resulted in the IMP, as well as evaluation of strengths, weaknesses, and lessons learned.
The enzyme alpha1,3-galactosyltransferase (alpha1,3GT or GGTA1) synthesizes alpha1,3-galactose (alpha1,3Gal) epitopes (Galalpha1,3Galbeta1,4GlcNAc-R), which are the major xenoantigens causing ...hyperacute rejection in pig-to-human xenotransplantation. Complete removal of alpha1,3Gal from pig organs is the critical step toward the success of xenotransplantation. We reported earlier the targeted disruption of one allele of the alpha1,3GT gene in cloned pigs. A selection procedure based on a bacterial toxin was used to select for cells in which the second allele of the gene was knocked out. Sequencing analysis demonstrated that knockout of the second allele of the alpha1,3GT gene was caused by a T-to-G single point mutation at the second base of exon 9, which resulted in inactivation of the alpha1,3GT protein. Four healthy alpha1,3GT double-knockout female piglets were produced by three consecutive rounds of cloning. The piglets carrying a point mutation in the alpha1,3GT gene hold significant value, as they would allow production of alpha1,3Gal-deficient pigs free of antibiotic-resistance genes and thus have the potential to make a safer product for human use.
Several systematic reviews have reviewed the evidence relating to nature on aspects of children and adolescent's health and wellbeing; however, none have looked at the associations or effectiveness ...of attending nature-based early childhood education (ECE). The main objective is to systematically review and synthesise the evidence to determine if nature-based ECE enhances children's health, wellbeing and development.
We will search the following electronic databases (from inception onwards): MEDLINE, Scopus, PsycINFO, ERIC, SportDiscus, Australian Education Index, British Education Index, Child Development and Adolescent studies, and Applied Social Sciences Index and Abstracts. Grey literature will be identified searching dissertations and reports (e.g. Open Grey, Dissertations Theses Database ProQuest, and Google Scholar). All types of studies (quantitative and qualitative) conducted in children (aged 2-7 years old) attending ECE who had not started education at primary or elementary school will be included. The exposure of interest will be nature-based ECE settings that integrate nature into their philosophy and/or curriculum and environment. The outcomes of interest will be all aspects of the child's physical, cognitive, social and emotional health wellbeing and development. Two reviewers will independently screen full-text articles. The study methodological quality (or bias) will be appraised using appropriate tools. If feasible, a meta-analysis will be conducted using a random-effect model for studies similar in exposure and outcome. Where studies cannot be included in a meta-analysis, findings will be summarised based on the effect directions and a thematic analysis will be conducted for qualitative studies.
This systematic review will capture the state of the current literature on nature-based ECE for child health, wellbeing and development. The results of this study will be of interest to multiple audiences (including researchers and policy makers). Results will be published in a peer-reviewed journal. Gaps for future research will be identified and discussed.
PROSPERO CRD42019152582.
Rationale
Chronic cocaine exposure produces unconditioned enhancement in impulsive decision making; however, little is known about the effects of cocaine-paired conditioned stimuli on this behavior. ...Thus, this study explored the effects of cocaine-paired contextual stimuli on impulsive decision making and the contribution of nicotinic acetylcholine receptors (nAChRs) to this phenomenon.
Methods
Rats were trained to achieve stable performance on a delay discounting task, which involved lever press-based choice between a single food pellet (small reward) available immediately and three food pellets (large reward) available after a 10-, 20-, 40-, or 60-s time delay. Rats then received Pavlovian context-cocaine (15 mg/kg, i.p.) and context-saline (1 ml/kg, i.p.) pairings in two other, distinct contexts. Subsequently, delay discounting task performance was assessed in the previously cocaine-paired or saline-paired context following pretreatment with saline or cocaine (15 mg/kg, Experiment 1) or with saline or the nAChR antagonist, mecamylamine (0.2 and 2 mg/kg, Experiment 2), using counterbalanced within-subjects testing designs.
Results
Independent of cocaine pretreatment, rats exhibited greater decrease in preference for the large reward as a function of delay duration in the cocaine-paired context, relative to the saline-paired context. Furthermore, systemic mecamylamine pretreatment dose-dependently attenuated the decrease in preference for the large reward in the cocaine-paired context, but not in the saline-paired context, as compared to saline.
Conclusion
Cocaine-paired contextual stimuli evoke a state of impulsive decision making, which requires nAChR stimulation. Drug context-induced impulsivity likely increases the propensity for drug relapse in cocaine users, making the nAChR an interesting target for drug relapse prevention.
While the HIV-1-glycan shield is known to shelter Env from the humoral immune response, its quantitative impact on antibody elicitation has been unclear. Here, we use targeted deglycosylation to ...measure the impact of the glycan shield on elicitation of antibodies against the CD4 supersite. We engineered diverse Env trimers with select glycans removed proximal to the CD4 supersite, characterized their structures and glycosylation, and immunized guinea pigs and rhesus macaques. Immunizations yielded little neutralization against wild-type viruses but potent CD4-supersite neutralization (titers 1: >1,000,000 against four-glycan-deleted autologous viruses with over 90% breadth against four-glycan-deleted heterologous strains exhibiting tier 2 neutralization character). To a first approximation, the immunogenicity of the glycan-shielded protein surface was negligible, with Env-elicited neutralization (ID50) proportional to the exponential of the protein-surface area accessible to antibody. Based on these high titers and exponential relationship, we propose site-selective deglycosylated trimers as priming immunogens to increase the frequency of site-targeting antibodies.
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•Engineered diverse prefusion-closed selectively deglycosylated HIV-Env trimers•Exponential relationship between exposed protein surface and Env immunogenicity•Broad and potent neutralization by vaccine-elicited sera of glycan-deleted viruses•Site-specific deglycosylated trimers to prime in a lineage-independent manner
Zhou et al. engineer diverse HIV-Env trimers with selective glycans removed around the CD4-receptor-binding site. They demonstrate the impact of the glycan shield on immunogenicity, uncover an exponential relationship between exposed antibody-accessible protein surface and Env immunogenicity, and achieve vaccine-elicited neutralization of glycan-deleted viruses.
ABSTRACT
The functional integrity of the nucleus accumbens (NAC) core and shell is necessary for contextual cocaine‐seeking behavior in the reinstatement animal model of drug relapse; however, the ...neuropharmacological mechanisms underlying this phenomenon are poorly understood. The present study evaluated the contribution of metabotropic glutamate receptor subtype 1 (mGluR1) and α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)/kainate receptor populations to drug context‐induced reinstatement of cocaine‐seeking behavior. Rats were trained to lever press for un‐signaled cocaine infusions in a distinct context followed by extinction training in a different context. Cocaine‐seeking behavior (non‐reinforced active lever pressing) was then assessed in the previously cocaine‐paired and extinction contexts after JNJ16259685 (mGluR1 antagonist: 0.0, 0.6, or 30 pg/0.3 µl/hemisphere) or CNQX (AMPA/kainate receptor antagonist: 0.0, 0.03, or 0.3 µg/0.3 µl /hemisphere) administration into the NAC core, medial or lateral NAC shell, or the ventral caudate‐putamen (vCPu, anatomical control). JNJ16259685 or CNQX in the NAC core dose‐dependently impaired contextual cocaine‐seeking behavior relative to vehicle. Conversely, CNQX, but not JNJ16259685, in the lateral or medial NAC shell attenuated, whereas CNQX or JNJ16259685 in vCPu failed to inhibit, this behavior. The manipulations failed to alter instrumental behavior in the extinction context, general motor activity or food‐reinforced instrumental behavior in control experiments. Thus, glutamate‐mediated changes in drug context‐induced motivation for cocaine involve distinct neuropharmacological mechanisms within the core and shell subregions of the NAC, with the stimulation of mGlu1 and AMPA/kainate receptors in the NAC core and the stimulation of AMPA/kainate, but not mGlu1, receptors in the NAC shell being necessary for this phenomenon.
Amniotic and allantoic fluid volumes and composition change dynamically throughout gestation. Cattle that are pregnant with
somatic cell nuclear transfer (NT) fetuses show a high incidence of ...abnormal fluid accumulation (particularly hydrallantois)
and fetal mortality from approximately midgestation. To investigate fetal fluid homeostasis in these pregnancies, Na, K, Cl,
urea, creatinine, Ca, Mg, total PO 4 , glucose, fructose, lactate, total protein, and osmolalities were measured in amniotic and allantoic fluids collected at
Days 50, 100, and 150 of gestation from NT pregnancies and those generated by the transfer of in vitro-produced embryos or
by artificial insemination. Deviations in fetal fluid composition between NT and control pregnancies were apparent after placental
and fetal organ development, even when no gross morphological abnormalities were observed. Individual NT fetuses were affected
to varying degrees. Elevated allantoic Na was associated with lower K and increased allantoic fluid volume or edema of the
fetal membranes. Total PO 4 levels in NT allantoic and amniotic fluid were elevated at Days 100 and 150. This was not accompanied by hypophosphatemia
at Day 150, suggesting that PO 4 acquisition by NT fetuses was adequate but that its readsorption by the kidneys may be impaired. Excessive NT placental weight
was associated with low allantoic glucose and fructose as well as high lactate levels. However, the fructogenic ability of
the NT placenta appeared to be normal. The osmolality of the fetal fluids was maintained within a narrow range, suggesting
that the regulation of fluid composition, but not osmolality, was impaired in NT pregnancies.
Abstract
The ability of cloned cattle conceptuses to regulate amniotic and allantoic fluid composition is impaired
Ventricular arrhythmia is an important cause of mortality in patients with ischemic left ventricular dysfunction. Revascularization with coronary artery bypass graft or percutaneous coronary ...intervention is often recommended for these patients before implantation of a cardiac defibrillator because it is assumed that this may reduce the incidence of fatal and potentially fatal ventricular arrhythmias, although this premise has not been evaluated in a randomized trial to date.
Patients with severe left ventricular dysfunction, extensive coronary disease, and viable myocardium were randomly assigned to receive either percutaneous coronary intervention (PCI) plus optimal medical and device therapy (OMT) or OMT alone. The composite primary outcome was all-cause death or aborted sudden death (defined as an appropriate implantable cardioverter defibrillator therapy or a resuscitated cardiac arrest) at a minimum of 24 months, analyzed as time to first event on an intention-to-treat basis. Secondary outcomes included cardiovascular death or aborted sudden death, appropriate implantable cardioverter defibrillator (ICD) therapy or sustained ventricular arrhythmia, and number of appropriate ICD therapies.
Between August 28, 2013, and March 19, 2020, 700 patients were enrolled across 40 centers in the United Kingdom. A total of 347 patients were assigned to the PCI+OMT group and 353 to the OMT alone group. The mean age of participants was 69 years; 88% were male; 56% had hypertension; 41% had diabetes; and 53% had a clinical history of myocardial infarction. The median left ventricular ejection fraction was 28%; 53.1% had an implantable defibrillator inserted before randomization or during follow-up. All-cause death or aborted sudden death occurred in 144 patients (41.6%) in the PCI group and 142 patients (40.2%) in the OMT group (hazard ratio, 1.03 95% CI, 0.82-1.30;
=0.80). There was no between-group difference in the occurrence of any of the secondary outcomes.
PCI was not associated with a reduction in all-cause mortality or aborted sudden death. In patients with ischemic cardiomyopathy, PCI is not beneficial solely for the purpose of reducing potentially fatal ventricular arrhythmias.
URL: https://www.
gov; Unique identifier: NCT01920048.
The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing ...Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers approximately 99% of the euchromatic genome and is accurate to an error rate of approximately 1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human genome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead.
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