Taxonomic changes in the gut microbiota are associated with cartilage damage independent of adiposity, high fat diet, and joint injury

Abstract Lipodystrophic mice are protected from cartilage damage following joint injury. This protection can be reversed by the implantation of a small adipose tissue graft. The purpose of this study was to evaluate the relationship between the gut microbiota and knee cartilage damage while controlling for adiposity, high fat diet, and joint injury using lipodystrophic (LD) mice. LD and littermate control (WT) mice were fed a high fat diet, chow diet, or were rescued with fat implantation, then challenged with destabilization of the medial meniscus surgery to induce osteoarthritis (OA). 16S rRNA sequencing was conducted on feces. MaAslin2 was used to determine associations between taxonomic relative abundance and OA severity. While serum LPS levels between groups were similar, synovial fluid LPS levels were increased in both limbs of HFD WT mice compared to all groups, except for fat transplanted animals. The Bacteroidetes:Firmicutes ratio of the gut microbiota was significantly reduced in HFD and OA-rescued animals when compared to chow. Nine novel significant associations were found between gut microbiota taxa and OA severity. These findings suggest the presence of causal relationships the gut microbiome and cartilage health, independent of diet or adiposity, providing potential therapeutic targets through manipulation of the microbiome

Catheter-based intervention for pulmonary vein stenosis due to fibrosing mediastinitis: The Mayo Clinic experience

AbstractIntroductionFibrosing mediastinitis (FM) is a rare but fatal disease characterized by an excessive fibrotic reaction in the mediastinum, which can lead to life-threatening stenosis of the pulmonary veins (PV). Catheter-based intervention is currently the only viable option for therapy. However, the current literature on how best to manage these difficult cases, especially in regards to sequential interventions and their potential complications is very limited.MethodsWe searched through a database of all patients who have undergone PV interventions at the Earl H. Wood Cardiac Catheterization Laboratory in Mayo Clinic, Rochester. From this collection, we selected patients that underwent PV intervention to relieve stenosis secondary to FM.ResultsEight patients were identified, with a mean age of 41years (24–59years). Five were men, and three were women. Three patients underwent balloon angioplasty alone, and five patients had stents placed. The majority of patients had acute hemodynamic and symptomatic improvement. More than one intervention was required in five patients, four patients had at least one episode of restenosis, and four patients died within four weeks of their first PV intervention.ConclusionsWe describe the largest reported case series of catheter-based intervention for PV stenosis in FM. Although catheter-based therapy improved hemodynamics, short-term vascular patency, and patient symptoms, the rate of life-threatening complications, restenosis, and mortality associated with these interventions was found to be high. Despite these associated risks, catheter-based intervention is the only palliative option available to improve quality of life in severely symptomatic patients with PV stenosis and FM. Patients with PV stenosis and FM (especially those with bilateral disease) have an overall poor prognosis in spite of undergoing these interventions due to the progressive and recalcitrant nature of the disease. This underscores the need for further innovative approaches to manage this disease

Cetuximab as Second-Line Therapy in Patients with Metastatic Esophageal Adenocarcinoma: A Phase II Southwest Oncology Group Study (S0415)

IntroductionEsophageal adenocarcinomas commonly express the epidermal growth factor receptor. This trial assessed the 6-month overall survival probability in metastatic esophageal cancer patients treated with cetuximab as second-line therapy.MethodsThis was a multicenter, open-label phase II study of single-agent cetuximab for metastatic esophageal adenocarcinoma patients who failed one prior chemotherapy regimen. Adequate organ function and Zubrod performance status of 0 to 2 were required. Patients received cetuximab 400 mg/m2 intravenously (IV) on week 1 and 250 mg/m2 IV weekly thereafter. The primary objective was to determine 6-month overall survival. Secondary end points included progression-free survival, response rate, and toxicity. Tumor tissue was collected for correlative studies.ResultsSixty-three patients were registered, with eight ineligible or never treated. Fifty-five eligible patients (49 men, 6 women; median age = 61.2 years [range, 30.7–88.5]) were enrolled. Twenty patients survived more than 6 months for a 6-month overall survival rate of 36% (95% confidence interval [CI]: 24–50%). The median overall survival was 4.0 months (95% CI: 3.2–5.9). Median progression-free survival was 1.8 months (95% CI: 1.7–1.9). One partial response and two unconfirmed partial responses were observed. Two patients experienced grade 4 fatigue. There was one treatment-related death due to pneumonitis. Germline polymorphisms of epidermal growth factor receptor, epidermal growth factor, interleukin (IL)-8, cyclooxygenase (COX)-2, vascular epidermal growth factor receptor (VEGF), CCND1, neuropilin 1 (NRP1), and K-ras mutational status were not associated with response or survival.ConclusionsThe 6-month overall survival rate of 36% observed on this study failed to meet the primary survival objective. Thus, cetuximab alone cannot be recommended in the second-line treatment of metastatic esophageal cancer

A Study of Thymidylate Synthase Expression as a Biomarker for Resectable Colon Cancer: Alliance (Cancer and Leukemia Group B) 9581 and 89803.

PurposeTumor levels of thymidylate synthase (TS), a target of 5-fluorouracil (5-FU)-based chemotherapy for colorectal cancer, have been studied as a predictive or prognostic biomarker with mixed results.Patients and methodsTumor TS levels were prospectively evaluated in two adjuvant therapy trials for patients with resected stage II or III colon cancer. TS expression was determined by standard immunohistochemistry and by automated quantitative analysis. Tumor mismatch repair deficiency (MMR-D) and BRAF c.1799T > A (p.V600E) mutation status were also examined. Relationships between tumor TS, MMR-D, and BRAF mutation status, overall survival (OS), and disease-free survival (DFS) were investigated in the subset of stage III patients.ResultsPatients whose tumors demonstrated high TS expression experienced better treatment outcomes, with DFS hazard ratio (HR) = 0.67, 95% confidence interval (CI) = 0.53, 0.84; and OS HR = 0.68, 95% CI = 0.53, 0.88, for high versus low TS expression, respectively. No significant interaction between TS expression and stage was observed (DFS: interaction HR = 0.94; OS: interaction HR = 0.94). Tumors with high TS expression were more likely to demonstrate MMR-D (22.2% vs. 12.8%; p =  .0003). Patients whose tumors demonstrated both high TS and MMR-D had a 7-year DFS of 77%, compared with 58% for those whose tumors had low TS and were non-MMR-D (log-rank p =  .0006). Tumor TS expression did not predict benefit of a particular therapeutic regimen.ConclusionThis large prospective analysis showed that high tumor TS levels were associated with improved DFS and OS following adjuvant therapy for colon cancer, although tumor TS expression did not predict benefit of 5-FU-based chemotherapy. The Oncologist 2017;22:107-114Implications for Practice: This study finds that measurement of tumor levels of thymidylate synthase is not helpful in assigning specific adjuvant treatment for colorectal cancer. It also highlights the importance of using prospective analyses within treatment clinical trials as the optimal method of determining biomarker utility

Top mass dependent alpha_s^3 corrections to B-meson mixing in the MSSM

We compute the top mass dependent NLO strong interaction matching conditions to the Delta F=2 effective Hamiltonian in the general MSSM. We study the relevance of such corrections, comparing its size with that of previously known NLO corrections in the limit mt->0, in scenarios with degeneracy, alignment, and hierarchical squarks. We find that, while these corrections are generally small, there are regions in the parameter space where the contributions to the Wilson coefficients C1 and C4 could partially overcome the expected suppression m_t/M_SUSY.Comment: 15 pages, 6 figure

Protein complexes in cells by AI-assisted structural proteomics

Abstract Accurately modeling the structures of proteins and their complexes using artificial intelligence is revolutionizing molecular biology. Experimental data enable a candidate‐based approach to systematically model novel protein assemblies. Here, we use a combination of in‐cell crosslinking mass spectrometry and co‐fractionation mass spectrometry (CoFrac‐MS) to identify protein–protein interactions in the model Gram‐positive bacterium Bacillus subtilis. We show that crosslinking interactions prior to cell lysis reveals protein interactions that are often lost upon cell lysis. We predict the structures of these protein interactions and others in the SubtiWiki database with AlphaFold‐Multimer and, after controlling for the false‐positive rate of the predictions, we propose novel structural models of 153 dimeric and 14 trimeric protein assemblies. Crosslinking MS data independently validates the AlphaFold predictions and scoring. We report and validate novel interactors of central cellular machineries that include the ribosome, RNA polymerase, and pyruvate dehydrogenase, assigning function to several uncharacterized proteins. Our approach uncovers protein–protein interactions inside intact cells, provides structural insight into their interaction interfaces, and is applicable to genetically intractable organisms, including pathogenic bacteria

Model-independent extraction of ∣Vtq∣|V_{tq}| matrix elements from top-quark measurements at hadron colliders

Current methods to extract the quark-mixing matrix element $|V_{tb}|$ from single-top production measurements assume that $|V_{tb}|\gg |V_{td}|, |V_{ts}|$: top quarks decay into $b$ quarks with 100% branching fraction, s-channel single-top production is always accompanied by a $b$ quark and initial-state contributions from $d$ and $s$ quarks in the $t$-channel production of single top quarks are neglected. Triggered by a recent measurement of the ratio $R=\frac{|V_{tb}|^{2}}{|V_{td}|^{2}+|V_{ts}|^{2}+|V_{tb}|^{2}}=0.90 \pm 0.04$ performed by the D0 collaboration, we consider a $|V_{tb}|$ extraction method that takes into account non zero d- and s-quark contributions both in production and decay. We propose a strategy that allows to extract consistently and in a model-independent way the quark mixing matrix elements $|V_{td}|$, $|V_{ts}|$, and $|V_{tb}|$ from the measurement of $R$ and from single-top measured event yields. As an illustration, we apply our method to the Tevatron data using a CDF analysis of the measured single-top event yield with two jets in the final state one of which is identified as a $b$-quark jet. We constrain the $|V_{tq}|$ matrix elements within a four-generation scenario by combining the results with those obtained from direct measurements in flavor physics and determine the preferred range for the top-quark decay width within different scenarios.Comment: 36 pages, 17 figure

Footprints of the Beyond in flavor physics: Possible role of the Top Two Higgs Doublet Model

The B-factories results provide an impressive confirmation of the Standard Model (SM) description of flavor and CP violation. Nevertheless, as more data were accumulated, deviations in the 2.5-3.5 sigma range have emerged pointing to the exciting possibility of new CP-odd phase(s) and flavor violating parameters in B-decays. Primarily this seems to be the case in the time dependent CP asymmetries in penguin dominated modes (e.g. B -> phi (eta') Ks). We discuss these and other deviations from the SM and, as an illustration of possible new physics scenarios, we examine the role of the Top Two Higgs Doublet Model. This is a simple extension of the SM obtained by adding second Higgs doublet in which the Yukawa interactions of the two Higgs doublets are assigned in order to naturally account for the large top-quark mass. Of course, many other extensions of the Standard Model could also account for these experimental deviations. Clearly if one takes these deviations seriously then some new particles in the 300 GeV to few TeV with associated new CP-odd phase(s) are needed.Comment: 40 pages, 17 figures (png format), uses pdflate

Implications of large dimuon CP asymmetry in B_{d,s} decays on minimal flavor violation with low tan beta

The D0 collaboration has recently announced evidence for a dimuon CP asymmetry in B_{d,s} decays of order one percent. If confirmed, this asymmetry requires new physics. We argue that for minimally flavor violating (MFV) new physics, and at low tan beta=v_u/v_d, there are only two four-quark operators (Q_{2,3}) that can provide the required CP violating effect. The scale of such new physics must lie below 260 GeV sqrt{tan beta}. The effect is universal in the B_s and B_d systems, leading to S_{psi K}~sin(2beta)-0.15 and S_{psi phi}~0.25. The effects on epsilon_K and on electric dipole moments are negligible. The most plausible mechanism is tree-level scalar exchange. MFV supersymmetry with low tan beta will be excluded. Finally, we explain how a pattern of deviations from the Standard Model predictions for S_{psi phi}, S_{psi K} and epsilon_K can be used to test MFV and, if MFV holds, to probe its structure in detail.Comment: 11 pages. v2: References adde

Neutral Gauge Boson Contributions to the Dimuon Charge Asymmetry in B Decays

Recently, the D0 Collaboration measured the CP-violating like-sign dimuon charge asymmetry in neutral B decays, finding a 3.2sigma difference from the standard-model (SM) prediction. A non-SM charge asymmetry a_sl^s suggests a new-physics (NP) contribution to Bs-Bsbar mixing. In this case, in order to explain the measured value of a_sl^s within its 1sigma range, NP must be present in Gamma_12^s, the absorptive part of the mixing. In this paper, we examine whether such an explanation is possible in models with flavor-changing Z (ZFCNC) or Z' (Z'FCNC) gauge bosons. The models must also reproduce the measured values of the indirect CP asymmetry S_psi-phi in Bs -> J/psi phi, and Delta Gamma_s, the Bs-Bsbar width difference. We find that the ZFCNC model cannot reproduce the present measured values of S_psi-phi and a_sl^s within their 1sigma ranges. On the other hand, in the Z'FCNC model, the values of all three observables can be simultaneously reproduced.Comment: 18 pages, 7 figures, JHEP format. Some ZFCNC equations corrected, ZFCNC analysis redone, references added, conclusions unchange