A
bstract
The cross section for the production of Z
γ
in proton-proton collisions at 8 TeV is measured based on data collected by the CMS experiment at the LHC corresponding to an integrated ...luminosity of 19.5 fb
−1
. Events with an oppositely-charged pair of muons or electrons together with an isolated photon are selected. The differential cross section as a function of the photon transverse momentum is measured inclusively and exclusively, where the exclusive selection applies a veto on central jets. The observed cross sections are compatible with the expectations of next-to-next-to-leading-order quantum chromodynamics. Limits on anomalous triple gauge couplings of ZZ
γ
and Z
γγ
are set that improve on previous experimental results obtained with the charged lepton decay modes of the Z boson.
•Summary of the biological mechanisms and processes underpinning hepatotoxicity.•Description of experimental approaches to support the prediction of hepatotoxicity.•Discussion of the role of in ...silico approaches highlighting challenges to the adoption of these methods.•Proposed framework for the integration of in silico and experimental information.
Hepatotoxicity is one of the most frequently observed adverse effects resulting from exposure to a xenobiotic. For example, in pharmaceutical research and development it is one of the major reasons for drug withdrawals, clinical failures, and discontinuation of drug candidates. The development of faster and cheaper methods to assess hepatotoxicity that are both more sustainable and more informative is critically needed. The biological mechanisms and processes underpinning hepatotoxicity are summarized and experimental approaches to support the prediction of hepatotoxicity are described, including toxicokinetic considerations. The paper describes the increasingly important role of in silico approaches and highlights challenges to the adoption of these methods including the lack of a commonly agreed upon protocol for performing such an assessment and the need for in silico solutions that take dose into consideration. A proposed framework for the integration of in silico and experimental information is provided along with a case study describing how computational methods have been used to successfully respond to a regulatory question concerning non-genotoxic impurities in chemically synthesized pharmaceuticals.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Glaucoma is a distinct neuropathy characterized by the chronic and progressive death of retinal ganglion cells (RGCs). The etiology of RGC death remains unknown. Risk factors for glaucomatous RGC ...death are elevated intraocular pressure and glial production of tumor necrosis factor-alpha (TNF-α). Previously, the authors showed that glaucoma causes a rapid upregulation of a neurotrophin receptor truncated isoform lacking the kinase domain, TrkC.T1, in retina. Here they examined the biological role of TrkC.T1 during glaucoma progression.
Rat and mouse models of chronic ocular hypertension were used. Immunofluorescence Western blot analysis and in situ mRNA hybridization were used to identify cells upregulating TrkC.T1. A genetic model of engineered mice lacking TrkC.T1 (TrkC.T1(-/-)) was used to validate a role for this receptor in glaucoma. Pharmacologic studies were conducted to evaluate intravitreal delivery of agonists or antagonists of TrkC.T1, compared with controls, during glaucoma. Surviving RGCs were quantified by retrograde-labeling techniques. Production of neurotoxic TNF-α and α2 macroglobulin were quantified.
TrkC.T1 was upregulated in retinal glia, with a pattern similar to that of TNF-α. TrkC.T1(-/-) mice had normal retinas. However, during experimental glaucoma, TrkC.T1(-/-) mice had lower rates of RGC death and produced less TNF-α than wild-type littermates. In rats with glaucoma, the pharmacologic use of TrkC antagonists delayed RGC death and reduced the production of retinal TNF-α.
TrkC.T1 is implicated in glaucomatous RGC death through the control of glial TNF-α production. Overall, the data point to a paracrine mechanism whereby elevated intraocular pressure upregulated glial TrkC.T1 expression in glia; TrkC.T1 controlled glial TNF-α production, and TNF-α caused RGC death.
A within-subjects experiment explored how the number of online, hyperlinked stories available for individuals to choose from affects cognitive processing of a selected story. Participants chose and ...read unpleasant online news stories from a Web page containing either 5 or 15 headline/photo hyperlinks. Heart rate data indicated more cognitive resources were allocated to reading stories selected from the larger array of hyperlinks. This increased allocation of cognitive resources also led to more accurate story recognition. Results of this study provide insight into information processing of interactive, online news as well as limited suggestions for the design of news Web sites.
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BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, PRFLJ, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
Polymorphisms in
MSH3
gene confer risk of esophageal cancer when in combination with tobacco smoke exposure. The purpose of this study was to investigate the methylation status of
MSH3
gene ...in esophageal cancer patients in order to further elucidate possible role of
MSH3
in esophageal tumorigenesis.
Methods
We applied nested methylation-specific polymerase chain reaction to investigate the methylation status of the
MSH3
promoter in tumors and matching adjacent normal-looking tissues of 84 esophageal cancer patients from a high-risk South African population. The Cancer Genome Atlas data were used to examine DNA methylation profiles at 17 CpG sites located in the
MSH3
locus.
Results
Overall, promoter methylation was detected in 91.9 % of tumors, which was significantly higher compared to 76.0 % in adjacent normal-looking esophageal tissues (
P
= 0.008). When samples were grouped according to different demographics (including age, gender and ethnicity) and smoking status of patients, methylation frequencies were found to be significantly higher in tumor tissues of Black subjects (
P
= 0.024), patients of 55–65 years of age (
P
= 0.032), males (
P
= 0.037) and tobacco smokers (
P
= 0.015). Furthermore, methylation of the
MSH3
promoter was significantly more frequent in tumor samples from smokers compared to tumor samples from non-smokers odds ratio (OR) = 31.9,
P
= 0.031. The TCGA data confirmed significantly higher DNA methylation level at the
MSH3
promoter region in tumors (
P
= 0.0024). In addition, we found evidence of an aberrantly methylated putative
MSH3
-associated distal enhancer element.
Conclusion
Our results suggest that methylation of
MSH3
together with exposure to tobacco smoke is involved in esophageal carcinogenesis. Due to the active role of the MSH3 protein in modulating chemosensitivity of cells, methylation of
MSH3
should further be examined in association with the outcome of esophageal cancer treatment using anticancer drugs.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Human infections caused by viral pathogens trigger a complex gamut of host responses that limit disease, resolve infection, generate immunity, and contribute to severe disease or death. Here, we ...present experimental methods and multi-omics data capture approaches representing the global host response to infection generated from 45 individual experiments involving human viruses from the Orthomyxoviridae, Filoviridae, Flaviviridae, and Coronaviridae families. Analogous experimental designs were implemented across human or mouse host model systems, longitudinal samples were collected over defined time courses, and global multi-omics data (transcriptomics, proteomics, metabolomics, and lipidomics) were acquired by microarray, RNA sequencing, or mass spectrometry analyses. For comparison, we have included transcriptomics datasets from cells treated with type I and type II human interferon. Raw multi-omics data and metadata were deposited in public repositories, and we provide a central location linking the raw data with experimental metadata and ready-to-use, quality-controlled, statistically processed multi-omics datasets not previously available in any public repository. This compendium of infection-induced host response data for reuse will be useful for those endeavouring to understand viral disease pathophysiology and network biology.
Obesity is a chronic relapsing disorder that is caused by an excess of caloric intake relative to energy expenditure. There is growing recognition that food motivation is altered in people with ...obesity. However, it remains unclear how brain circuits that control food motivation are altered in obese animals.
Using a novel behavioral assay that quantifies work during food seeking, in vivo and ex vivo cell-specific recordings, and a synaptic blocking technique, we tested the hypothesis that activity of circuits promoting appetitive behavior in the core of the nucleus accumbens (NAc) is enhanced in the obese state, particularly during food seeking.
We first confirmed that mice made obese with ad libitum exposure to a high fat diet work harder than lean mice to obtain food, consistent with an increase in food motivation in obese mice. We observed greater activation of D
receptor-expressing NAc spiny projection neurons (NAc D1
) during food seeking in obese mice relative to lean mice. This enhanced activity was not observed in D
receptor-expressing neurons (D2
). Consistent with these in vivo findings, both intrinsic excitability and excitatory drive onto D1
were enhanced in obese mice relative to lean mice, and these measures were selective for D1
. Finally, blocking synaptic transmission from D1
, but not D2
, in the NAc core decreased physical work during food seeking and, critically, attenuated high fat diet-induced weight gain.
These experiments demonstrate the necessity of NAc core D1
in food motivation and the development of diet-induced obesity, establishing these neurons as a potential therapeutic target for preventing obesity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Carbon-donated hydrogen bonds (CDHBs) are weak forms of hydrogen bonding (0.5-1.0kcalmol-1) that are difficult to detect, and thus their roles in the structure and functionality of chemical systems ...often go unrecognized. Utilizing a computational approach, the existence of a structurally significant CDHB in the medically relevant protein Streptococcus pneumoniae hyaluronate lyase (SpnHL) is affirmed. The structure of a tetrapeptide fragment model containing the CDHB was optimized with second-order perturbation theory. From this, a CDHB with bond distance and angle consistent with previously discovered CDHBs and comparable to neighboring traditional HBs in the fragment model was found. The CDHB competes with another donor T253 OH, whereby the two alternate in strength between protein conformations, imbuing alphaHelix3 appreciable flexibility. The CDHB seems to exist in spite of torsional and steric strain on the donor methyl group. It is postulated that the CDHB could aid in either counteracting the macrodipole of alphaHelix3 or protecting the A249 CO from destabilizing interactions with the adjacent solvent. Employing the energy gradients from the optimization, the torque generated by the fragment model was computed, which accurately predicts the direction of rotation of alphaHelix3 observed from experiment. A strongly correlated motion between alphaHelix3 and alphaHelices2, 4, and 5 was noted, which the interactions of the fragment model help drive by generating a torque much larger than necessary to rotate just alphaHelix3. Considering these results, we conclude that CDHBs should be considered as possible beneficial components of chemical and biological phenomena. PUBLICATION ABSTRACT
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
A search for a standard-model-like Higgs boson in the H→WW and H→ZZ decay channels is reported, for Higgs boson masses in the range 145<
m
H
<1000 GeV. The search is based upon proton–proton ...collision data samples corresponding to an integrated luminosity of up to 5.1 fb
−1
at
and up to 5.3 fb
−1
at
, recorded by the CMS experiment at the LHC. The combined upper limits at 95 % confidence level on products of the cross section and branching fractions exclude a standard-model-like Higgs boson in the range 145<
m
H
<710 GeV, thus extending the mass region excluded by CMS from 127–600 GeV up to 710 GeV.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: There is paucity of data regarding prevalence and key harms of non-medical cannabis use in surgical patients. We investigated whether cannabis use in patients undergoing surgery or ...interventional procedures patients was associated with a higher degree of post-procedural healthcare utilisation. Methods: 210,639 adults undergoing non-cardiac surgery between January 2008 and June 2020 at an academic healthcare network in Massachusetts, USA, were included. The primary exposure was use of cannabis, differentiated by reported ongoing non-medical use, self-identified during structured, preoperative nursing/physician interviews, or diagnosis of cannabis use disorder based on International Classification of Diseases, 9th/10th Revision, diagnostic codes. The main outcome measure was the requirement of advanced post-procedural healthcare utilisation (unplanned intensive care unit admission, hospital re-admission or non-home discharge). Findings: 16,211 patients (7.7%) were identified as cannabis users. The prevalence of cannabis use increased from 4.9% in 2008 to 14.3% by 2020 (p < 0.001). Patients who consumed cannabis had higher rates of psychiatric comorbidities (25.3 versus 16.8%; p < 0.001) and concomitant non-tobacco substance abuse (30.2 versus 7.0%; p < 0.001). Compared to non-users, patients with a diagnosis of cannabis use disorder had higher odds of requiring advanced post-procedural healthcare utilisation after adjusting for patient characteristics, concomitant substance use and socioeconomic factors (aOR adjusted odds ratio 1.16; 95% CI 1.02–1.32). By contrast, patients with ongoing non-medical cannabis use had lower odds of advanced post-procedural healthcare utilisation (aOR 0.87; 95% CI 0.81–0.92, compared to non-users). Interpretation: One in seven patients undergoing surgery or interventional procedures in 2020 reported cannabis consumption. Differential effects on post-procedural healthcare utilisation were observed between patients with non-medical cannabis use and cannabis use disorder. Funding: This work was supported by an unrestricted philantropic grant from Jeff and Judy Buzen to Maximilian S. Schaefer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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