A Molecular Mechanics Knowledge Base Applied to Template Based Structure Prediction

Predicting protein structure using its primary sequence has always been a challenging topic in biochemistry. Although it seems as simple as finding the minimal energy conformation, it has been quite difficult to provide an accurate yet reliable solution for the problem. On the one hand, the lack of understanding of the hydrophobic effect as well as the relationship between different stabilizing forces, such as hydrophobic interaction, hydrogen bonding and electronic static interaction prevent the scientist from developing potential functions to estimate free energy. On the other hand, structure databases are limited with redundant structures, which represent a noncontinuous, sparsely-sampled conformational space, and preventing the development of a method suitable for high-resolution, high-accuracy structure prediction that can be applied for functional annotation of an unknown protein sequence. Thus, in this study, we use molecular dynamics simulation as a tool to sample conformational space. Structures were generated with physically realistic conformations that represented the properties of ensembles of native structures. First, we focused our study on the relationship among different factors that stabilize protein structure. Using a wellcharacterized mutation system of the B-hairpin, a fundamental building block of protein, we were able to identify the effect of terminal ion-pairs (salt-bridges) on the stability of the beta-hairpin, and its relationship with hydrophobic interactions and hydrogen bonds. In the same study, we also correlated our theoretical simulations qualitatively with experimental results. Such analysis provides us a better understanding of beta-hairpin stability and helps us to improve the protein engineering method to design more stable hairpins. Second, with large-scale simulations of different representative protein folds, we were able to conduct a fine-grained analysis by sampling the continuous conformational space to characterize the relationship among backbone conformation, side-chain conformation and side-chain packing. Such information is valuable for improving high-resolution structure prediction. Last, with this information, we developed a new prediction algorithm using packing information derived from the conserved relative packing groups. Based on its performance in CASP7, we were able to draw the conclusion that our simulated dataset as well as our packing-oriented prediction method are useful for template based structure prediction

125I Radiotherapy combined with metronomic chemotherapy may boost the abscopal effect, leading to complete regression of liver metastasis in an SCLC patient with a 58.5-month OS: a case report

The liver is the most common and lethal metastatic site in patients with extensive-stage small-cell lung cancer (ES-SCLC), and median survival with current standard treatment is only 9–10 months from diagnosis. Clinical observations show that a complete response (CR) is extremely rare in ES-SCLC patients with liver metastasis. Moreover, to the best of our knowledge, complete regression of liver metastasis induced by the abscopal effect, boosted primarily by permanent radioactive iodine-125 seeds implantation (PRISI), combined with a low-dose metronomic temozolomide (TMZ) regimen, has not been recorded. Here, we present the case of a 54-year-old male patient who developed multiple liver metastases from ES-SCLC after multiple lines of chemotherapy. The patient was given partial PRISI therapy (two out of six tumor lesions; 38 iodine-125 seeds in one dorsal lesion and 26 seeds in one ventral lesion), which was combined with TMZ metronomic chemotherapy (50 mg/m2/day, days 1–21, every 28 days). The abscopal effect was observed for 1 month after PRISI treatment. After about 1 year, all the liver metastases had completely disappeared, and the patient experienced no relapse. The patient eventually died of malnutrition caused by a non-tumor intestinal obstruction and had an overall survival of 58.5 months after diagnosis. PRISI combined with TMZ metronomic chemotherapy might be considered a potential therapy to trigger the abscopal effect in patients with liver metastases

Identification and Molecular Characterization of a New Ovarian Cancer Susceptibility Locus at 17q21.31

Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3 ′ untranslated region at putative microRNA (miRNA) binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA binding site single nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (OR=1.12, P =10−8 ) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion ( P =10−10 ). Variation at 17q21.31 associates with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes

Multidifferential study of identified charged hadron distributions in ZZ-tagged jets in proton-proton collisions at s=\sqrt{s}=13 TeV

Jet fragmentation functions are measured for the first time in proton-proton collisions for charged pions, kaons, and protons within jets recoiling against a $Z$ boson. The charged-hadron distributions are studied longitudinally and transversely to the jet direction for jets with transverse momentum 20 $< p_{\textrm{T}} < 100$ GeV and in the pseudorapidity range $2.5 < \eta < 4$. The data sample was collected with the LHCb experiment at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 1.64 fb$^{-1}$. Triple differential distributions as a function of the hadron longitudinal momentum fraction, hadron transverse momentum, and jet transverse momentum are also measured for the first time. This helps constrain transverse-momentum-dependent fragmentation functions. Differences in the shapes and magnitudes of the measured distributions for the different hadron species provide insights into the hadronization process for jets predominantly initiated by light quarks.Comment: All figures and tables, along with machine-readable versions and any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-013.html (LHCb public pages

Study of the B−→Λc+Λˉc−K−B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-} decay

The decay $B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-}$ is studied in proton-proton collisions at a center-of-mass energy of $\sqrt{s}=13$ TeV using data corresponding to an integrated luminosity of 5 $\mathrm{fb}^{-1}$ collected by the LHCb experiment. In the $\Lambda_{c}^+ K^{-}$ system, the $\Xi_{c}(2930)^{0}$ state observed at the BaBar and Belle experiments is resolved into two narrower states, $\Xi_{c}(2923)^{0}$ and $\Xi_{c}(2939)^{0}$, whose masses and widths are measured to be $$m(\Xi_{c}(2923)^{0}) = 2924.5 \pm 0.4 \pm 1.1 \,\mathrm{MeV}, \\ m(\Xi_{c}(2939)^{0}) = 2938.5 \pm 0.9 \pm 2.3 \,\mathrm{MeV}, \\ \Gamma(\Xi_{c}(2923)^{0}) = \phantom{000}4.8 \pm 0.9 \pm 1.5 \,\mathrm{MeV},\\ \Gamma(\Xi_{c}(2939)^{0}) = \phantom{00}11.0 \pm 1.9 \pm 7.5 \,\mathrm{MeV},$$ where the first uncertainties are statistical and the second systematic. The results are consistent with a previous LHCb measurement using a prompt $\Lambda_{c}^{+} K^{-}$ sample. Evidence of a new $\Xi_{c}(2880)^{0}$ state is found with a local significance of $3.8\,\sigma$, whose mass and width are measured to be $2881.8 \pm 3.1 \pm 8.5\,\mathrm{MeV}$ and $12.4 \pm 5.3 \pm 5.8 \,\mathrm{MeV}$, respectively. In addition, evidence of a new decay mode $\Xi_{c}(2790)^{0} \to \Lambda_{c}^{+} K^{-}$ is found with a significance of $3.7\,\sigma$. The relative branching fraction of $B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-}$ with respect to the $B^{-} \to D^{+} D^{-} K^{-}$ decay is measured to be $2.36 \pm 0.11 \pm 0.22 \pm 0.25$, where the first uncertainty is statistical, the second systematic and the third originates from the branching fractions of charm hadron decays.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-028.html (LHCb public pages

Measurement of the ratios of branching fractions R(D∗)\mathcal{R}(D^{*}) and R(D0)\mathcal{R}(D^{0})

The ratios of branching fractions $\mathcal{R}(D^{*})\equiv\mathcal{B}(\bar{B}\to D^{*}\tau^{-}\bar{\nu}_{\tau})/\mathcal{B}(\bar{B}\to D^{*}\mu^{-}\bar{\nu}_{\mu})$ and $\mathcal{R}(D^{0})\equiv\mathcal{B}(B^{-}\to D^{0}\tau^{-}\bar{\nu}_{\tau})/\mathcal{B}(B^{-}\to D^{0}\mu^{-}\bar{\nu}_{\mu})$ are measured, assuming isospin symmetry, using a sample of proton-proton collision data corresponding to 3.0 fb${ }^{-1}$ of integrated luminosity recorded by the LHCb experiment during 2011 and 2012. The tau lepton is identified in the decay mode $\tau^{-}\to\mu^{-}\nu_{\tau}\bar{\nu}_{\mu}$. The measured values are $\mathcal{R}(D^{*})=0.281\pm0.018\pm0.024$ and $\mathcal{R}(D^{0})=0.441\pm0.060\pm0.066$, where the first uncertainty is statistical and the second is systematic. The correlation between these measurements is $\rho=-0.43$. Results are consistent with the current average of these quantities and are at a combined 1.9 standard deviations from the predictions based on lepton flavor universality in the Standard Model.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-039.html (LHCb public pages

Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

Background Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. Methods In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q Results The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p Conclusion These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.Peer reviewe

A new idea of modeling shear band in metallic glass based on the concept of distributed dislocation

Shear bands are closely linked with the plasticity and fracture behaviors of metallic glasses (MGs). This work proposes a new idea to predict shear bands by continuously distributed dislocations. The dislocations are unreal and used to model the plastic deformation of shear band. The possible positions of shear band initiation are determined based on the elastic stress field, and the direction and length of shear band propagation are determined by the distributed dislocation technique. Finite element simulations based on constitutive model are carried out to compare with the theoretical modeling. Two examples are considered, i.e., shear bands near a void and a notch under tensile loading. The results show that the theoretically predicted shear band morphology is well consistent with the finite element simulations, which verifies the validation of using distributed dislocations to predict shear bands. This work provides a new way to model shear band, and it has potential applications in predicting shear band morphology and fracture behaviors in MGs