Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of mortality worldwide. Recent genome-wide association studies (GWAS) have identified robust susceptibility loci associated ...with COPD. However, the mechanisms mediating the risk conferred by these loci remain to be found. The goal of this study was to identify causal genes/variants within susceptibility loci associated with COPD. In the discovery cohort, genome-wide gene expression profiles of 500 non-tumor lung specimens were obtained from patients undergoing lung surgery. Blood-DNA from the same patients were genotyped for 1,2 million SNPs. Following genotyping and gene expression quality control filters, 409 samples were analyzed. Lung expression quantitative trait loci (eQTLs) were identified and overlaid onto three COPD susceptibility loci derived from GWAS; 4q31 (HHIP), 4q22 (FAM13A), and 19q13 (RAB4B, EGLN2, MIA, CYP2A6). Significant eQTLs were replicated in two independent datasets (n = 363 and 339). SNPs previously associated with COPD and lung function on 4q31 (rs1828591, rs13118928) were associated with the mRNA expression of HHIP. An association between mRNA expression level of FAM13A and SNP rs2045517 was detected at 4q22, but did not reach statistical significance. At 19q13, significant eQTLs were detected with EGLN2. In summary, this study supports HHIP, FAM13A, and EGLN2 as the most likely causal COPD genes on 4q31, 4q22, and 19q13, respectively. Strong lung eQTL SNPs identified in this study will need to be tested for association with COPD in case-control studies. Further functional studies will also be needed to understand the role of genes regulated by disease-related variants in COPD.
A highly luminescent Zn4L6 tetrahedron is reported with 3.8 nm perylene bisimide edges and hexadentate ZnII–imine chelate vertices. Replacing FeII and monoamines commonly utilized in subcomponent ...self‐assembly with ZnII and tris(2‐aminoethyl)amine provides access to a metallosupramolecular host with the rare combination of structural integrity at concentrations <10−7 mol L−1 and an exceptionally high fluorescence quantum yield of Φem=0.67. Encapsulation of multiple perylene or coronene guest molecules is accompanied by strong luminescence quenching. We anticipate this self‐assembly strategy may be generalized to improve access to brightly fluorescent coordination cages tailored for host–guest light‐harvesting, photocatalysis, and sensing.
FeII‐free and fluorescent: A highly luminescent (Φem=0.67) Zn4L6 tetrahedron with perylene bisimide edges and hexadentate zinc–imine chelate vertices is accessed by dynamic imine–metal coordination self‐assembly. Encapsulation of multiple perylene or coronene guest molecules is detected by quenching of the host emission. The chelate may be generalized to other dyes, improving access to brightly luminescent metallosupramolecular cages.
Sport specialization is a training method now commonly used by young athletes who hope to achieve elite-level success. This may be defined as (1) choosing a main sport, (2) quitting all other sports ...to focus on 1 sport, and (3) year-round training (greater than 8 months per year). A number of sports medicine organizations have published recommendations based on the limited evidence available on this topic. The objective of this article was to perform a narrative review of the currently available evidence and sports medicine organizational recommendations regarding sport specialization and its effects on health to guide athletic trainers and sports medicine providers. To accomplish this goal, we conducted a narrative review of articles and position statements on sport specialization published from 1990 through 2018. Injury, overuse injury, serious overuse injury, and lower extremity injury were likely associated with higher degrees of sport specialization in various populations. Sports medicine organizations in general recommended against sport specialization in young athletes and instead promoted multisport participation for physical and psychological benefits. Few long-term data suggest that sport specialization has negative health-related quality-of-life consequences. Higher degrees of sport specialization likely pose risks of overuse injury; however, the age of specialization at which this risk occurs is not known. Because different populations and sports activities may put children at risk for certain injuries, future researchers should monitor large populations with sport-specific prospective active surveillance.
Individual plant cells have a genetic circuit, the circadian clock, that times key processes to the day-night cycle. These clocks are aligned to the day-night cycle by multiple environmental signals ...that vary across the plant. How does the plant integrate clock rhythms, both within and between organs, to ensure coordinated timing? To address this question, we examined the clock at the sub-tissue level across Arabidopsis thaliana seedlings under multiple environmental conditions and genetic backgrounds. Our results show that the clock runs at different speeds (periods) in each organ, which causes the clock to peak at different times across the plant in both constant environmental conditions and light-dark (LD) cycles. Closer examination reveals that spatial waves of clock gene expression propagate both within and between organs. Using a combination of modeling and experiment, we reveal that these spatial waves are the result of the period differences between organs and local coupling, rather than long-distance signaling. With further experiments we show that the endogenous period differences, and thus the spatial waves, can be generated by the organ specificity of inputs into the clock. We demonstrate this by modulating periods using light and metabolic signals, as well as with genetic perturbations. Our results reveal that plant clocks can be set locally by organ-specific inputs but coordinated globally via spatial waves of clock gene expression.
Hexaxim is a hexavalent vaccine approved as primary and booster vaccination in infants 6 weeks and older, protecting against diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B and Haemophilus ...influenzae type b.
To evaluate the immunogenicity and reactogenicity (safety) of Hexaxim (Hexyon, Hexacima) in primary and booster vaccine schedules; long-term antibody persistence; concomitant use with other childhood vaccines and use in immunocompromised infants. Hexaxim was found to be noninferior to other licensed hexavalent vaccines, being highly immunogenic for all toxoids/antigens and with an acceptable safety profile. It can be administered concomitantly with other childhood vaccines. Hexaxim can be given as a booster for infants primed with Infanrix Hexa and given in a pentavalent-hexavalent-pentavalent series. Hexaxim elicits a similar immune response and safety profile in human immunodeficiency virus (HIV) positive infants. It has the benefit of being a ready-to-use liquid formulation, minimizing dosage errors and preparation time.
Hexaxim has an acceptable safety profile and provides immunity against all six targeted diseases. It is an acceptable alternative to other hexavalent vaccines on the market. Further studies are required on the use of immunocompromised patients as well as the antibody persistence of each of the vaccine components.
The involvement of host immunity in the gut microbiota-mediated colonization resistance to Clostridioides difficile infection (CDI) is incompletely understood. Here, we show that interleukin (IL)-22, ...induced by colonization of the gut microbiota, is crucial for the prevention of CDI in human microbiota-associated (HMA) mice. IL-22 signaling in HMA mice regulated host glycosylation, which enabled the growth of succinate-consuming bacteria Phascolarctobacterium spp. within the gut microbiome. Phascolarctobacterium reduced the availability of luminal succinate, a crucial metabolite for the growth of C. difficile, and therefore prevented the growth of C. difficile. IL-22-mediated host N-glycosylation is likely impaired in patients with ulcerative colitis (UC) and renders UC-HMA mice more susceptible to CDI. Transplantation of healthy human-derived microbiota or Phascolarctobacterium reduced luminal succinate levels and restored colonization resistance in UC-HMA mice. IL-22-mediated host glycosylation thus fosters the growth of commensal bacteria that compete with C. difficile for the nutritional niche.
IgG antibodies play a role in malaria immunity, but whether and how IgM protects from malaria and the biology of Plasmodium falciparum (Pf)-specific IgM B cells is unclear. In a Mali cohort spanning ...infants to adults, we conducted longitudinal analyses of Pf- and influenza-specific B cells. We found that Pf-specific memory B cells (MBCs) are disproportionally IgM+ and only gradually shift to IgG+ with age, in contrast to influenza-specific MBCs that are predominantly IgG+ from infancy to adulthood. B cell receptor analysis showed Pf-specific IgM MBCs are somatically hypermutated at levels comparable to influenza-specific IgG B cells. During acute malaria, Pf-specific IgM B cells expand and upregulate activation/costimulatory markers. Finally, plasma IgM was comparable to IgG in inhibiting Pf growth and enhancing phagocytosis of Pf by monocytes in vitro. Thus, somatically hypermutated Pf-specific IgM MBCs dominate in children, expand and activate during malaria, and produce IgM that inhibits Pf through neutralization and opsonic phagocytosis.
Abstract
We study the (characteristic) Cauchy problem for the Maxwell‐Bloch equations of light‐matter interaction via asymptotics, under assumptions that prevent the generation of solitons. Our ...analysis clarifies some features of the sense in which physically‐motivated initial‐boundary conditions are satisfied. In particular, we present a proper Riemann‐Hilbert problem that generates the unique
causal
solution to the Cauchy problem, that is, the solution vanishes outside of the light cone. Inside the light cone, we relate the leading‐order asymptotics to self‐similar solutions that satisfy a system of ordinary differential equations related to the Painlevé‐III (PIII) equation. We identify these solutions and show that they are related to a family of PIII solutions recently discovered in connection with several limiting processes involving the focusing nonlinear Schrödinger equation. We fully explain a resulting boundary layer phenomenon in which, even for smooth initial data (an incident pulse), the solution makes a sudden transition over an infinitesimally small propagation distance. At a formal level, this phenomenon has been described by other authors in terms of the PIII self‐similar solutions. We make this observation precise and for the first time we relate the PIII self‐similar solutions to the Cauchy problem. Our analysis of the asymptotic behavior satisfied by the optical field and medium density matrix reveals slow decay of the optical field in one direction that is actually inconsistent with the simplest version of scattering theory. Our results identify a precise generic condition on an optical pulse incident on an initially‐unstable medium sufficient for the pulse to stimulate the decay of the medium to its stable state.
The recent success of cancer immunotherapies has highlighted the benefit of harnessing the immune system for cancer treatment. Vaccines have a long history of promoting immunity to pathogens and, ...consequently, vaccines targeting cancer neoantigens have been championed as a tool to direct and amplify immune responses against tumours while sparing healthy tissue. In recent years, extensive preclinical research and more than one hundred clinical trials have tested different strategies of neoantigen discovery and vaccine formulations. However, despite the enthusiasm for neoantigen vaccines, proof of unequivocal efficacy has remained beyond reach for the majority of clinical trials. In this Review, we focus on the key obstacles pertaining to vaccine design and tumour environment that remain to be overcome in order to unleash the true potential of neoantigen vaccines in cancer therapy.
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