bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants
Authors: Jensen Sanne Brun , Fahnøe Ulrik , Pham Long V. , Serre Stéphanie Brigitte Nelly , Tang Qi , Ghanem Lubna , Pedersen Martin Schou , Ramirez Santseharay , Humes Daryl , Pihl Anne Finne , Filskov Jonathan , Sølund Christina Søhoel , Dietz Julia , Fourati Slim , Pawlotsky Jean‐Michel , Sarrazin Christoph , Weis Nina , Schønning Kristian , Krarup Henrik , Bukh Jens , Gottwein Judith Margarete
Published: April 2019

Protease inhibitors (PIs) are important components of treatment regimens for patients with chronic hepatitis C virus (HCV) infection. However, emergence and persistence of antiviral resistance could reduce their efficacy. Thus, defining resistance determinants is highly relevant for efforts to control HCV. Here, we investigated patterns of PI resistance–associated substitutions (RASs) for the major HCV genotypes and viral determinants for persistence of key RASs. We identified protease position 156 as a RAS hotspot for genotype 1‐4, but not 5 and 6, escape variants by resistance profiling using PIs grazoprevir and paritaprevir in infectious cell culture systems. However, except for genotype 3, engineered 156‐RASs were not maintained. For genotypes 1 and 2, persistence of 156‐RASs depended on genome‐wide substitution networks, co‐selected under continued PI treatment and identified by next‐generation sequencing with substitution linkage and haplotype reconstruction. Persistence of A156T for genotype 1 relied on compensatory substitutions increasing replication and assembly. For genotype 2, initial selection of A156V facilitated transition to 156L, persisting without compensatory substitutions. The developed genotype 1, 2, and 3 variants with persistent 156‐RASs had exceptionally high fitness and resistance to grazoprevir, paritaprevir, glecaprevir, and voxilaprevir. A156T dominated in genotype 1 glecaprevir and voxilaprevir escape variants, and pre‐existing A156T facilitated genotype 1 escape from clinically relevant combination treatments with grazoprevir/elbasvir and glecaprevir/pibrentasvir. In genotype 1 infected patients with treatment failure and 156‐RASs, we observed genome‐wide selection of substitutions under treatment. Conclusion: Comprehensive PI resistance profiling for HCV genotypes 1‐6 revealed 156‐RASs as key determinants of high‐level resistance across clinically relevant PIs. We obtained in vitro proof of concept for persistence of highly fit genotype 1‐3 156‐variants, which might pose a threat to clinically relevant combination treatments.
Comparative genetic profiling aids diagnosis and clinical decision making in challenging cases of CUP syndrome
Authors: Bochtler Tilmann , Endris Volker , Leichsenring Jonas , Reiling Anna , Neumann Olaf , Volckmar Anna‐Lena , Kirchner Martina , Allgäuer Michael , Schirmacher Peter , Krämer Alwin , Stenzinger Albrecht
Published: April 2019

Cancer of unknown primary (CUP) denotes cancer cases where metastatic spread is histologically confirmed, but no respective primary tumor can be identified. The challenging diagnosis of CUP is further complicated in cases with previously identified malignancies or with dubious clonal relationship between metastatic sites due to ambiguous histology. Our study aims at elucidating clonal relationships by comparing the respective mutational spectra. Targeted next‐generation sequencing (NGS) employing formalin‐fixed and paraffin‐embedded (FFPE) tumor tissue was performed on 174 consecutive CUP patients. Among these, 43/174 (24.7%) patients had a documented prior malignancy. Data on pairwise targeted NGS testing to address clonal relationships between the previous malignancy and the presumed CUP (n = 11) or between different CUP metastatic sites (n = 7) was available in 18 patients. NGS could clarify clonal relationships in 16/18 cases. Among the 11 CUP patients with antecedent malignancies, four cases were clonally independent of the previous malignancy but harbored deleterious germline mutations in BRCA/BAP1/ATM genes. Seven CUP cases were clonally related to the antecedent malignancy, changing the CUP diagnosis to relapse of the prior malignancy. In the seven CUP cases, with doubtfully related metastatic sites, NGS confirmed clonal relationship in five cases and was inconclusive in two. In conclusion, NGS proved an efficient tool to elucidate clonal relationships in clinically challenging CUP cases. Our study cautions against a premature diagnosis of CUP. Relapses of antecedent malignancies should be carefully considered. CUPs clonally independent from the antecedent malignancy should raise a red flag of a potential cancer‐predisposing germline mutation.
Long noncoding RNA HOTAIR promotes invasion of breast cancer cells through chondroitin sulfotransferase CHST15
Authors: Liu Liang‐Chih , Wang Yuan‐Liang , Lin Pei‐Le , Zhang Xiang , Cheng Wei‐Chung , Liu Shu‐Hsuan , Chen Chih‐Jung , Hung Yu , Jan Chia‐Ing , Chang Ling‐Chu , Qi Xiaoyang , Hsieh‐Wilson Linda C. , Wang Shao‐Chun
Published: April 2019

The long noncoding RNA HOTAIR plays significant roles in promoting cancer metastasis. However, how it conveys an invasive advantage in cancer cells is not clear. Here we identify the chondroitin sulfotransferase CHST15 (GalNAc4S‐6ST) as a novel HOX transcript antisense intergenic RNA (HOTAIR) target gene using RNA profiling and show that CHST15 is required for HOTAIR‐mediated invasiveness in breast cancer cells. CHST15 catalyzes sulfation of the C6 hydroxyl group of the N‐acetyl galactosamine 4‐sulfate moiety in chondroitin sulfate to form the 4,6‐disulfated chondroitin sulfate variant known as the CS‐E isoform. We show that HOTAIR is necessary and sufficient for CHST15 transcript expression. Inhibition of CHST15 by RNA interference abolished cell invasion promoted by HOTAIR but not on HOTAIR‐mediated migratory activity. Conversely, reconstitution of CHST15 expression rescued the invasive activity of HOTAIR‐depleted cells. In corroboration with this mechanism, blocking cell surface chondroitin sulfate using a pan‐CS antibody or an antibody specifically recognizes the CS‐E isoform significantly suppressed HOTAIR‐induced invasion. Inhibition of CHST15 compromised tumorigenesis and metastasis in orthotopic breast cancer xenograft models. Furthermore, the expression of HOTAIR closely correlated with the level of CHST15 protein in primary as well as metastatic tumor lesions. Our results demonstrate a novel mechanism underlying the function of HOTAIR in tumor progression through programming the context of cell surface glycosaminoglycans. Our results further establish that the invasive and migratory activities downstream of HOTAIR are distinctly regulated, whereby CHST15 preferentially controls the arm of invasiveness. Thus, the HOTAIR‐CHST15 axis may provide a new avenue toward novel therapeutic strategies and prognosis biomarkers for advanced breast cancer.
MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma
Authors: Wang Yezhong , Xia Yong , Hu Kunhua , Zeng Minling , Zhi Cheng , Lai Miaoling , Wu Liqiang , Liu Sisi , Zeng Shulian , Huang Ziyan , Ma Shanshan , Yuan Zhongmin
Published: April 2019

JNK activity has been implicated in the malignant proliferation, invasion and drug‐resistance of glioma cells (GCs), but the molecular mechanisms underlying JNK activation are currently unknown. Here, we reported that MKK7, not MKK4, directly activates JNK in GCs and exerts oncogenic effects on tumor formation. Notably, MKK7 expression in glioma tissues was closely correlated with the grade of the glioma and JNK/c‐Jun activation. Mechanistically, MKK7 transcription critically depends on the complexes formed by HDAC4 and the transcriptional factors SP1 and Krüppel‐like factor‐5 (KLF5), wherein HDAC4 directly deacetylates both SP1 and KLF5 and synergistically upregulates MKK7 transcription through two SP1 sites located on its promoter. In contrast, the increases in acetylated‐SP1 and acetylated‐KLF5 after HDAC4 inhibition switched to transcriptionally suppress MKK7. Selective inhibition of HDAC4 by LMK235, siRNAs or blockage of SP1 and KLF5 by the ectopic dominant‐negative SP1 greatly reduced the malignant capacity of GCs. Furthermore, suppression of both MKK7 expression and JNK/c‐Jun activities was involved in the tumor‐growth inhibitory effects induced by LMK235 in U87‐xenograft mice. Interestingly, HDAC4 is highly expressed in glioma tissues, and the rate of HDAC4 nuclear import is closely correlated with glioma grade, as well as with MKK7 expression. Collectively, these findings demonstrated that highly expressed MKK7 contributes to JNK/c‐Jun signaling‐mediated glioma formation. MKK7 transcription, regulated by SP1 and KLF5, critically depends on HDAC4 activity, and inhibition of HDAC4 presents a potential strategy for suppressing the oncogenic roles of MKK7/JNK/c‐Jun signaling in GCs.
Impacts of school‐wide positive behaviour support: Results from National Longitudinal Register Data
Authors: Borgen Nicolai T. , Kirkebøen Lars J. , Ogden Terje , Raaum Oddbjørn , Sørlie Mari‐Anne
Published: April 2019

Problem behaviour in schools may have detrimental effects both on students' well‐being and academic achievement. A large literature has consistently found that school‐wide positive behaviour support (SWPBS) successfully addresses social and behavioural problems. In this paper, we used population‐wide longitudinal register data for all Norwegian primary schools and a difference‐in‐difference (DiD) design to evaluate effects of SWPBS on a number of primary and secondary outcomes, including indicators of externalising behaviour, school well‐being, pull‐out instruction, and academic achievement. Indications of reduced classroom noise were found. No other effects were detected. Analyses revealed important differences in outcomes between the intervention and control schools, independent of the implementation of SWPBS, and that a credible design like DiD is essential to handle such school differences.
Impact of infant crying on mothers with a diagnosis of borderline personality disorder: A qualitative study
Authors: Geerling Ingrid , Roberts Rachel M. , Sved Williams Anne
Published: April 2019

Mothers with borderline personality disorder (BPD) and their infants often have compromised relationships. To further understand the complexities, this study explored (a) the experiences of mothers with BPD in response to infant crying and (b) how these parenting responses impact on mothers’ interpersonal functioning with significant others. Six mothers with clinical BPD were recruited from a mother–baby psychiatric unit and interviewed using an interpretative phenomenological analysis (IPA) approach. Transcripts of the semistructured interviews were coded for themes and subthemes. Dominant themes revealed that mothers with BPD entered motherhood in a psychologically fragile state, hypersensitive to experiencing intense physiological–emotional pain and cognitive chaos in response to infant crying. Automatic maladaptive flight–fright responses including suicide attempts were common. A novel theme revealed some mothers’ split identity, and only the “mother” part could attend to infant crying. Finally, the data provided an understanding of the detrimental domino effect on close family. Mothers also highlighted gaps in accessibility of current mental health services and parenting programs, and their desire to prevent the intergenerational transmission of attachment problems and BPD symptoms to offspring. Clinical implications include antenatal BPD screening, psychoeducation about infant crying, and greater access for programs supporting the whole family to improve outcomes.
Decellularized human liver scaffold‐based three‐dimensional culture system facilitate hepatitis B virus infection
Authors: Zhang ZhenZhen , Xu HongMei , Mazza Giuseppe , Zhang MingMan , Frenguelli Luca , Liu QuanBo , Al‐Akkad Walid , Ren JiHua , Zhao RuiQiu , Ren Fang , Chen Xin , Huang AiLong , Chen Juan
Published: April 2019

Hepatitis B virus (HBV) study is hampered by lacking of idea cell model which support effective HBV infection and meanwhile recapitulate hepatocyte biology function in vivo. In this study, we developed decellularized human liver scaffolds for cell culture and further applied for HBV infection. As a result, primary human hepatocytes (PHHs) engrafted into liver scaffolds and maintained differentiation with stable albumin secretion and liver‐specific gene expression. Comparing to mono‐layer cell culture, scaffold‐based three‐dimensional (3D) culture system significantly augment HBV DNA (including cccDNA), RNA level as well as HBsAg secretion. Moreover, HepG2‐NTCP cells cultured on 3D system exhibited higher infection efficiency and longer infection period in vitro. In addition, HBV DNA level was suppressed when anti‐HBV medicine Entecavir (ETV) introduced into HepG2‐NTCP 3D system. Herein, we evaluated the potential of decellularized human liver scaffold‐based in 3D cell culture and disclosed that scaffold‐based 3D culture system can facilitate HBV infection in vitro. This 3D culture system could be further applied in HBV‐related study. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1744–1753, 2019.
Inhibition of didscoidin domain receptor 1 reduces epithelial–mesenchymal transition and induce cell‐cycle arrest and apoptosis in prostate cancer cell lines
Authors: Azizi Reza , Salemi Zahra , Fallahian Faranak , Aghaei Mahmoud
Published: April 2019

Didscoidin domain receptor 1 (DDR1) is involved in the progression of prostate cancer metastasis through stimulation of epithelial–mesenchymal transition (EMT). So DDR1 inhibition can be a helpful target for cancer metastasis prevention. So, we studied the effects of DDR1 inhibition on EMT as well as induction of cell‐cycle arrest and apoptosis in prostate cancer cell lines. DDR1 expression was evaluated using reverse‐transcription polymerase chain reaction and western blot analysis. The EMT‐associated protein expression was determined using the western blot analysis and immunocytochemistry following treatment with various concentrations of DDR1 inhibitor. The activation of DDR1 and also downstream‐signaling molecules Pyk2 and MKK7 were determined using western blot analysis. Cell survival and proliferation after DDR1 inhibition were evaluated using 3‐(4,5‐dimethylthiazole‐2‐yl)‐2,5‐diphenyltetrazolium bromide, bromodeoxyuridine, and colony formation assays. Flow cytometry analysis was used to determine the effects of DDR1 inhibition on cell‐cycle arrest and apoptosis using annexin V/propidium iodide‐based flow cytometry. Results showed that the protein expression of N‐cadherin and vimentin were decreased whereas protein expression of E‐cadherin was increased after DDR1 inhibition. Results of our western blot analysis indicated that DDR1 inhibitor effectively downregulated P‐DDR1, P‐Pyk2, and P‐MKK7 levels. This result also showed that DDR1 inhibition decreased cell survival and proliferation, induced G1 cell‐cycle arrest, induced apoptosis by an increase in the Bax/Bcl‐2 ratio and depletion of the mitochondrial membrane potential, and also by reactive oxygen species creation in prostate cancer cells. These data show that DDR1 inhibition can result in the EMT prevention via inhibition of Pyk2 and MKK7 signaling pathway and induces cell‐cycle arrest and apoptosis in prostate cancer cell lines. Thus, this study identifies DDR1 as an important target for modulating EMT and induction of apoptosis in prostate cancer cells.
FNDC3B circular RNA promotes the migration and invasion of gastric cancer cells via the regulation of E‐cadherin and CD44 expression
Authors: Hong Yuling , Qin Haifeng , Li Yin , Zhang Yuhai , Zhuang Xunrong , Liu Lei , Lu Kun , Li Long , Deng Xiaoling , Liu Fan , Shi Songlin , Liu Guoyan
Published: April 2019

Circular RNAs (circRNAs) are a new class of RNAs, and many studies have identified thousands of circRNAs in tumor cells. Fibronectin type III domain‐containing protein 3B (FNDC3B) circular RNA (circFNDC3B, circBase ID: hsa_circ_0006156) circularizes with exons 5 and 6. Gibson Assembly DNA technology was used to construct a circFNDC3B expression vector without a splice site and restriction enzyme site. We showed that circFNDC3B increased migration and invasion in gastric cancer (GC). Ectopic expression of circFNDC3B reduced the level of E‐cadherin protein to promote the epithelial–mesenchymal transition in GC. RNA immunoprecipitation assays and RNA pull‐down assays confirmed that circFNC3B increased CD44 expression, which was associated with cell adhesion, via the formation of a ternary complex of circFNDC3B‐IGF2BP3‐CD44 mRNA. These results indicated that circFNDC3B was associated with the degree of malignancy to highlight the specific characteristics of cell invasion.
Competing endogenous RNA network and prognostic nomograms for hepatocellular carcinoma patients who underwent R0 resection
Authors: Li Yuntong , Ma Bingfen , Yin Zhenyu , Liu Pingguo , Liu Jianming , Li Jie , Wang Fuqiang , Chen Huimin
Published: April 2019

The prognosis of hepatocellular carcinoma (HCC) after R0 resection is unsatisfactory due to the high rate of recurrence. In this study, we investigated the recurrence‐related RNAs and the underlying mechanism. The long noncoding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA) expression data and clinical information of 247 patients who underwent R0 resection patients with HCC were obtained from The Cancer Genome Atlas. Comparing the 1‐year recurrence group (n = 56) with the nonrecurrence group (n = 60), we detected 34 differentially expressed lncRNAs (DElncRNAs), five DEmiRNAs, and 216 DEmRNAs. Of these, three DElncRNAs, hsa‐mir‐150‐5p, and 11 DEmRNAs were selected for constructing the competing endogenous RNA (ceRNA) network. Next, two nomogram models were constructed based separately on the lncRNAs and mRNAs that were further selected by Cox and least absolute shrinkage and selection operator regression analysis. The two nomogram models that showed a high prediction accuracy for disease‐free survival with the concordance indexes at 0.725 and 0.639. Further functional enrichment analysis of DEmRNAs showed that the mRNAs in the ceRNA network and nomogram models were associated with immune pathways. Hence, we constructed a hsa‐mir‐150‐5p‐centric ceRNA network and two effective nomogram prognostic models, and the related RNAs may be useful as potential biomarkers for predicting recurrence in patients with HCC.
Male parental assistance in embryo hatching of barred‐chin blenny Rhabdoblennius nitidus
Authors: Sano Kaori , Yokoyama Risa , Kitano Takako , Takegaki Takeshi , Kitazawa Nobumasa , Kaneko Toyoji , Nishino Yoshihide , Yasumasu Shigeki , Kawaguchi Mari
Published: April 2019

Most teleostean embryos develop and hatch without parental assistance, though some receive parental care. We focused on a paternal brood‐care species, the barred‐chin blenny (Rhabdoblennius nitidus [Günther, 1861]). As hatching approached, fanning behavior by the male parent drastically increased and then embryos hatch. In the absence of the male parent, most embryos failed to hatch. However, the hatching rate was greatly assisted by introducing an artificial water current, suggesting that paternal assistance other than for aeration is required for successful embryo hatching. Next, we analyzed genes for the hatching enzyme and egg‐envelope protein, which were successfully cloned from barred‐chin blenny, and found the expression patterns differed from those of other euteleosts. Generally, high choriolytic enzyme swells the intact egg envelope, and then low choriolytic enzyme solubilizes the swollen envelope. The expression levels of both the enzymes, but especially the latter, were much lower in barred‐chin blenny that is known in most other oviparous species. In addition, the main component of the egg envelope was changed into ChgHm and choriogenin L (ChgL) in barred‐chin blenny, whereas ChgH and ChgL for other euteleosts. These in barred‐chin blenny would result in ineffective egg‐envelope digestion because the posthatching egg envelopes were observed to be swollen but not solubilized. Male parental assistance by fanning until hatching may compensate for this insufficiency. Our study illustrates an example of the evolution of parent‐embryo interaction built on a novel relationship: Degradation of the hatching enzyme/egg‐envelope digestion system, accompanied by male parental hatching assistance.
Genetic counseling, 2030: An on‐demand service tailored to the needs of a price conscious, genetically literate, and busy world
Authors: Rashkin Misha D. , Bowes Johnathan , Dunaway Keith , Dhaliwal Jasmine , Loomis Erick , Riffle Stephen , Washington Nicole L. , Ziegler Chris , Lu James , Levin Elissa
Published: April 2019

The practice of genetic counseling is going to be impacted by the public's expectation that goods, services, information, and experiences happen on demand, wherever and whenever people want them. Building from trends that are currently taking shape, this article looks just over a decade into the future—to 2030—to provide a description of how the field of genetics and genetic counseling will be changed, as well as advice for genetic counselors for how to prepare. We build from the prediction that a large portion of the general public will have access to their digitized whole genome sequence anytime, any place, on any device. We focus on five topics downstream of this prediction: public health, personal autonomy, polygenic scores (PGS), evolving clinical practices, and genetic privacy.
Parenteral Nutrition Drug Shortages: A Single‐Center Experience With Rapid Process Change
Authors: Nystrom Erin M. , Bergquist Whitney J. , Wieruszewski Patrick M. , McMahon M. Molly , Barreto Erin F.
Published: April 2019

Disruptions in the medication supply chain and consequent drug product shortages, including shortages of parenteral products used for parenteral nutrition (PN) compounding, have become an increasingly common occurrence. The amino acid solution shortage that resulted from the devastating impact of Hurricanes Maria and Irma on manufacturing facilities in Puerto Rico in 2017 necessitated a rapid, coordinated shift from use of compounded PN to commercial multichamber‐bag PN (MCB‐PN) at our hospitals. We describe our experience operationalizing this intervention via a framework that may be adapted for addressing other drug product shortages to promote rapid yet safe use of therapeutic alternatives.
Optical Nanofabrication of Concave Microlens Arrays
Authors: Liu Xue‐Qing , Yu Lei , Yang Shuang‐Ning , Chen Qi‐Dai , Wang Lei , Juodkazis Saulius , Sun Hong‐Bo
Published: April 2019

For the simple and versatile fabrication of nanosmooth finished microlens arrays on hard materials, an approach combining femtosecond laser modification with subsequent ion beam etching is demonstrated. This method is based on the dependence of the plasma etching rate on the laser fluence used to modify the surface. The fabricated microlenses exhibit a low surface roughness of approximately 2.5 nm, due to the high precision of the plasma etching and benefit from the smooth interface between the laser‐modified and pristine subsurface regions. Microlenses with focal lengths ranging from 60 to 100 µm are realized by controlling the laser fluence, exposure dose, and etching time. Uniform square and hexagonal microlens arrays are fabricated on both hard and ultrahard materials and glasses (fused silica, GaAs, SiC, diamond) by the same process and deliver high‐quality focusing and imaging.
Physicians’ Perspectives on Palliative Care for Patients With End‐Stage Liver Disease: A National Survey Study
Authors: Ufere Nneka N. , Donlan John , Waldman Lauren , Patel Arpan , Dienstag Jules L. , Friedman Lawrence S. , Corey Kathleen E. , Hashemi Nikroo , Carolan Peter , Mullen Alan C. , Thiim Michael , Bhan Irun , Nipp Ryan , Greer Joseph , Temel Jennifer , Chung Raymond T. , El‐Jawahri Areej
Published: April 2019

Specialty palliative care (PC) is underused for patients with end‐stage liver disease (ESLD). We sought to examine attitudes of hepatologists and gastroenterologists about PC for patients with ESLD. We conducted a cross‐sectional survey of these specialists who provide care to patients with ESLD. Participants were recruited from the American Association for the Study of Liver Diseases membership directory. Using a questionnaire adapted from prior studies, we examined physicians’ attitudes about PC and whether these attitudes varied based on patients’ candidacy for liver transplantation. We identified predictors of physicians’ attitudes about PC using linear regression. Approximately one‐third of eligible physicians (396/1236, 32%) completed the survey. Most (95%) believed that centers providing care to patients with ESLD should have PC services, and 86% trusted PC clinicians to care for their patients. Only a minority reported collaborating frequently with inpatient (32%) or outpatient (11%) PC services. Most believed that when patients hear the term PC, they feel scared (94%) and anxious (87%). Most (83%) believed that patients would think nothing more could be done for their underlying disease if a PC referral was suggested. Physicians who believed that ESLD is a terminal condition (B = 1.09; P = 0.006) reported more positive attitudes about PC. Conversely, physicians with negative perceptions of PC for transplant candidates (B = –0.22; standard error = 0.05; P < 0.001) reported more negative attitudes toward PC. In conclusion, although most hepatologists and gastroenterologists believe that patients with ESLD should have access to PC, they reported rarely collaborating with PC teams and had substantial concerns about patients’ perceptions of PC. Interventions are needed to overcome misperceptions of PC and to promote collaboration with PC clinicians for patients with ESLD.
Computational 1H NMR: Part 1. Theoretical background
Authors: Krivdin Leonid B.
Published: April 2019

This is the first one of the three closely interrelated reviews to be published in Magnetic Resonance in Chemistry dealing with accordingly theoretical background, chemical applications, and biochemical studies of and by means of computational 1H NMR. Presented in the first part of the review is a general outline of the modern theoretical methods and accuracy factors of computational 1H NMR involving locally dense basis set schemes, solvent effects, vibrational corrections, and relativistic effects performed at the density functional theory and/or nonempirical levels. This review is dedicated to Prof. Stephan Sauer in view of his invaluable contribution to the field of computational nuclear magnetic resonance.
An Organic Zeolite With 10 Å Diameter Pores Assembles From a Soluble and Flexible Building Block by Non‐Covalent Interactions
Authors: Plater M. John , Harrison William T. A.
Published: April 2019

Two similar molecular building blocks, which both contain a hydrogen‐bonded nitro group, have been prepared and crystallised. One structure has more flexibility with a butyl side chain which allows an open framework organic zeolite to form with large 10 Å diameter pores, whereas the other structure has less flexibility with an aryl side chain and is close packed. The pore size is comparable with those of the aluminophosphate VPI‐5 (12 Å). It is concluded that some flexibility in the design of the building block for porous organic molecular materials was beneficial.
A method for determining the flow front velocity of a plastic melt in an injection molding process
Authors: Mensler Holger , Zhang Shujun , Win Thomas
Published: April 2019

During the filling phase of an injection molding process, the flow front velocity of the plastics melt has a decisive influence on the form part quality. It has been believed that a constant flow front velocity of the melt leads to distortion‐free and residual stress‐free form parts. A process control strategy based on a constant flow front velocity of the melt, however, requires the full understanding of the flow front position as a function of the screw position of the injection molding machine. With current methods, this can only be achieved by direct measurements using a number of sensors inside the mold, which leads to complicated structure, great efforts, and high cost for the tooling equipment. This article proposes, designs, and develops an innovative method for determining the flow front velocity of a plastic melt in an injection molding using only one pressure sensor at the front of the screw and based on the idea of mapping a simulated filling process to a real injection molding process. The mapping ensues that the characteristic event points are identified and matched for both the simulated and real filling process. The results of the simulation analysis and experimental evaluation show that the proposed method can be used to determine the flow front position and the resulting flow front velocity of the melt within the cavity of the mold and provide evidence that the new method offers great potential to process control strategies based on machine independent parameters. POLYM. ENG. SCI., 59:1132–1145 2019. © 2019 Society of Plastics Engineers
Substituent effects at nitrogen/phosphorus atoms of dialkaline earth metal complexes: Excess electron and large second‐hyperpolarizability
Authors: Banerjee Paramita , Hatua Kaushik , Mondal Avijit , Nandi Prasanta K.
Published: April 2019

A number of imido‐, amido‐, and phosphido‐bridged dialkaline earth metal (M = Be, Mg, and Ca) complexes and their alkali metal (Li and Na) derivatives have been considered to study the ground state structure and the second‐hyperpolarizability. The calculated ground state geometries contain four‐membered MN(P)MN(P) ring having either planar or butterfly‐like bent structure. The second‐hyperpolarizability has been calculated at the HF and CCSD(T) levels using Sadlej's pol and aug‐pc‐2 basis sets, respectively. The addition of second hydrogen/alkali metal atom on nitrogen/phosphorus (N/P) atom substantially reduces the charge transfer from the alkaline earth metal atoms as the high negative charge on N/P exerts stronger push effect on the outermost electron pair in the “ns” sub‐shell of M. The excess electron density on the alkaline earth metal atoms plays a crucial role in the enhancement of second‐hyperpolarizability. The sum‐over‐state method calculated two‐photon contribution of second‐hyperpolarizability has been found to be significant. The variation of second‐hyperpolarizability has been explained satisfactorily in terms of the TD‐CAMB3LYP calculated spectroscopic properties in the light of two‐state model. The calculated mean second‐hyperpolarizabilities of alkali substituted amido‐ and phosphido‐bridged complexes are in the order of 107 au.
Formic acid catalyzed keto‐enol tautomerizations for C2and C3enols: Implications in atmospheric and combustion chemistry
Authors: Monge‐Palacios Manuel , Grajales‐González Edwing , Sarathy Subram M.
Published: April 2019

Enols are important species in atmospheric and combustion chemistry. However, their implications in these environments are not well established due to a lack of accurate rate constants and mechanisms to determine their fate. In this work, we investigate the formic acid catalyzed keto‐enol tautomerizations converting vinyl alcohol, propen‐2‐ol and 1‐propenol into acetaldehyde, acetone and propanal, respectively. High‐level ab initio and multistructural torsional variational transition state theory calculations are performed with small‐curvature tunneling corrections to obtain rate constants in the temperature range 200 K‐3000 K. Tunneling is shown to be pronounced as a consequence of very narrow adiabatic potential energy curves, and indicates a need to revisit previous calculations. We show the implications of the studied reactions on the fate of enols under combustion relevant conditions by detailed kinetic modeling simulations. The yield of vinyl alcohol predicted by our calculated rate constants may be useful to lessen the underestimation of organic acids concentrations in current atmospheric models.
Current state and future possibilities of ovarian tissue transplantation
Authors: Takae Seido , Suzuki Nao
Published: April 2019

Background

As a result of recent developments in cancer treatment, cancer survivorship and survivors' quality of life have been emphasized. Although ovarian tissue cryopreservation (OTC) is an experimental technique, it would be the sole technique for fertility preservation treatment for girls with malignant disease. Indeed, OTC requires ovarian tissue transplantation (OTT) for conception. As for OTC, there is room to investigate OTT. The present review focused on the current state and progress of OTT.

Method

The literature regarding OTT, which is currently under development, was reviewed.

Main findings

To improve the outcome of OTT, both efficacy and safety are important. Good surgical technique and the optimal site are important surgical factors, with orthotopic transplantation increasing. Treatment of growth factors, gonadotropins, antioxidants, apoptosis suppression factors, and cell therapy may improve the efficacy of OTT by inducing neo‐angiogenesis and preventing damage. Artificial ovaries, complete in vitro primordial follicle culture technique, and non‐invasive ovarian imaging techniques, such as optical coherence tomography, to select the best ovarian tissue are future possibilities.

Conclusion

Improving neo‐angiogenesis and preventing damage with optimization, as well as investigation of future techniques, may bring us to the next stage of a fertility preservation strategy.
On structure constants with two spinning twist-two operators
Authors: Bianchi Marco S.
Published: April 2019

Abstract

I consider three-point functions of one protected and two unprotected twist-two operators ccwith spin in

$$ \mathcal{N}=4 $$

N
=
4

SYM at weak coupling. At one loop I formulate an empiric conjecture for the dependence of the corresponding structure constants on the spins of the operators. Using such an ansatz and some input from explicit perturbative results, I fix completely various infinite sets of one-loop structure constants of these three-point functions. Finally, I determine the two-loop corrections to the structure constants for a few fixed values of the spins of the operators.
Spontaneous Retroperitoneal and Rectus Sheath Hemorrhage—Management, Risk Factors and Outcomes
Authors: Baekgaard Josefine S. , Eskesen Trine G. , Lee Jae Moo , Yeh D. Dante , Kaafarani Haytham M. A. , Fagenholz Peter J. , Avery Laura , Saillant Noelle , King David R. , Velmahos George C.
Published: April 2019

Background

Spontaneous retroperitoneal and rectus sheath hemorrhage (SRRSH) is associated with high mortality in the literature, but studies on the subject are lacking. The objective of this study was to identify early predictors of the need for angiographic or surgical intervention (ASI) in patients with SRRSH and define risk factors for mortality.

Methods

We conducted a retrospective cohort study at a tertiary academic hospital. All patients with computed tomography‐identified SRRSH between 2012 to 2017 were included. Exclusion criteria were age below 18 years, possible mechanical cause of SRRSH, aortic aneurysm rupture or dissection, and traumatic or iatrogenic sources of SRRSH. The primary outcome was the incidence of ASI and/or mortality.

Results

Of 100 patients included (median age 70 years, 52% males), 33% were transferred from another hospital, 82% patients were on therapeutic anticoagulation, and 90% had serious comorbidities. Overall mortality was 22%, but SRRSH‐related mortality was only 6%. Sixteen patients underwent angiographic intervention (n = 10), surgical intervention (n = 5), or both (n = 1). Flank pain (OR 4.15, 95% CI 1.21–14.16, p = 0.023) and intravenous contrast extravasation (OR 3.89, 95% CI 1.23–12.27, p = 0.020) were independent predictors of ASI. Transfer from another hospital (OR 3.72, 95% CI 1.30–10.70, p = 0.015), age above 70 years (OR 4.24, 95% CI 1.25–14.32, p = 0.020), and systolic blood pressure below 110 mmHg at the time of diagnosis (OR 4.59, 95% CI 1.19–17.68, p = 0.027) were independent predictors of mortality.

Conclusions

SRRSH is associated with high mortality but is typically not the direct cause. Most SRRSHs are self‐limited and require no intervention. Pattern identification of ASI is hard.
Adverse childhood experiences, epigenetics and telomere length variation in childhood and beyond: a systematic review of the literature
Authors: Lang Jason , McKie Judith , Smith Helen , McLaughlin Angela , Gillberg Christopher , Shiels Paul G. , Minnis Helen
Published: April 2019

A systematic review following PRISMA guidelines was conducted to answer the question: What epigenetic, telomeric and associated biological changes are associated with exposure to adverse childhood experiences (ACEs) in the under 12s? Using PRISMA guidelines, appropriate databases were searched. 190 papers were returned with 38 articles fully reviewed. Articles were each independently quality rated by two authors using the Crowe Critical Appraisal Tool and data were extracted. Of the 38 articles, 23 were rated as very high quality. Most study participants were adults (n = 7769) with n = 727 child participants. Only seven of the very/high-quality studies were prospective and involved children. Methylation was the most studied method of epigenetic modification. There is some evidence supporting epigenetic modification of certain markers in participants exposed to ACEs measured in adulthood. Research is lacking on non-coding aspects of the epigenome and on coding aspects other than DNA methylation. There is some evidence of a more powerful effect on telomere length if physical neglect was involved. Much further work is required to model biological and psychological effects of epigenetic changes during childhood using prospective study designs. The effect of ACEs on the cellular ageing process during childhood is inadequately investigated and relies solely on measure of telomere length. Future research suggestions are proposed.
The where of bodily awareness
Authors: Mandrigin Alisa
Published: April 2019

In bodily awareness body parts are felt to occupy locations relative to the rest of the body. Bodily sensations are felt to be, in Brian O’Shaughnessy’s terms ‘in-a-certain-body-part-at-a-position-in-body-relative-physical-space’. In this paper I put forward a dispositional account of the structure of the spatial content of bodily awareness, which takes inspiration from Gareth Evans’s account of egocentric spatial content in The Varieties of Reference (1982). On the Dispositional View, bodily awareness experiences have spatial content in virtue of a set of connections having been established between somatosensory and proprioceptive inputs on the one hand, and motor outputs on the other hand. This kind of account, according to which spatial content depends constitutively on bodily action, has been challenged by a set of neurological cases and behavioural studies on healthy subjects. The evidence has been used to motivate a functional distinction between two kinds of body representation: representations for perception and representations for action. I review and assess some of the main sources of evidence for this distinction, arguing that the evidence presents a challenge to the dispositional view only if we accept the unjustified assumption that differences in task performance can only be explained in terms of a difference in representation. I close by proposing, and offering some empirical support for, an alternative explanation of the empirical results. The availability of the alternative explanation means that further work is needed to establish whether or not there is any challenge to the Dispositional View.
The Effect of Bariatric Surgery Prior to Lower-Extremity Total Joint Arthroplasty: A Systematic Review
Authors: Gu Alex , Cohen Jordan S. , Malahias Michael-Alexander , Lee Danny , Sculco Peter K. , McLawhorn Alexander S.
Published: April 2019

Background

Obesity is an independent risk factor for osteoarthritis and has been associated with increased rate of complications following lower-extremity total joint arthroplasty (TJA). Bariatric surgery (BS) is a surgical option for weight loss and for reducing obesity-related comorbidities in morbidly obese patients.

Purpose/Questions

The goal of this systematic review was to answer the following questions: (1) Does BS prior to TJA correlate with lower post-operative complication rates in morbidly obese patients undergoing TJA? (2) Does BS have an impact on revision rates following TJA?

Methods

Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and checklist, a systematic review of medical databases (PubMed/ MEDLINE, Cochrane Library, Web of Science, and Clinicaltrials.gov ) was undertaken for articles published in English from January 1990 to September 2018. Inclusion criteria were studies that included at least ten patients who underwent BS prior to TJA, collected data on complications or other outcomes, and followed patients for at least 90 days after TJA. A descriptive and critical analysis of the results was performed.

Results

From 799 studies, 13 met inclusion criteria. A total of 11, 770 patients who had undergone bariatric surgery prior to TJA were analyzed. The quality of the evidence ranged between moderate and high. There was no consensus on the effect of previous BS on early- to short-term outcomes reported after TJA.

Conclusion

The literature remains conflicted on the impact of BS prior to TJA on early, short-term, and long-term complications after TJA. Additional well-matched, observational studies may further our understanding of the impact of BS prior to TJA on outcomes. In particular the effect of various types of BS prior to TJA on outcomes has yet to be elucidated. Ideally, prospective studies with higher level of evidence will be more definitive on the effects of BS prior to TJA. Prospero Registration Number: CRD42016043025.
White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): Knowledge gaps and opportunities
Authors: Alber Jessica , Alladi Suvarna , Bae Hee‐Joon , Barton David A. , Beckett Laurel A. , Bell Joanne M. , Berman Sara E. , Biessels Geert Jan , Black Sandra E. , Bos Isabelle , Bowman Gene L. , Brai Emanuele , Brickman Adam M. , Callahan Brandy L. , Corriveau Roderick A. , Fossati Silvia , Gottesman Rebecca F. , Gustafson Deborah R. , Hachinski Vladimir , Hayden Kathleen M. , Helman Alex M. , Hughes Timothy M. , Isaacs Jeremy D. , Jefferson Angela L. , Johnson Sterling C. , Kapasi Alifiya , Kern Silke , Kwon Jay C. , Kukolja Juraj , Lee Athene , Lockhart Samuel N. , Murray Anne , Osborn Katie E. , Power Melinda C. , Price Brittani R. , Rhodius‐Meester Hanneke F.M. , Rondeau Jacqueline A. , Rosen Allyson C. , Rosene Douglas L. , Schneider Julie A. , Scholtzova Henrieta , Shaaban C. Elizabeth , Silva Narlon C.B.S. , Snyder Heather M. , Swardfager Walter , Troen Aron M. , van Veluw Susanne J. , Vemuri Prashanthi , Wallin Anders , Wellington Cheryl , Wilcock Donna M. , Xie Sharon Xiangwen , Hainsworth Atticus H.
Published: April 2019

White matter hyperintensities (WMHs) are frequently seen on brain magnetic resonance imaging scans of older people. Usually interpreted clinically as a surrogate for cerebral small vessel disease, WMHs are associated with increased likelihood of cognitive impairment and dementia (including Alzheimer's disease [AD]). WMHs are also seen in cognitively healthy people. In this collaboration of academic, clinical, and pharmaceutical industry perspectives, we identify outstanding questions about WMHs and their relation to cognition, dementia, and AD. What molecular and cellular changes underlie WMHs? What are the neuropathological correlates of WMHs? To what extent are demyelination and inflammation present? Is it helpful to subdivide into periventricular and subcortical WMHs? What do WMHs signify in people diagnosed with AD? What are the risk factors for developing WMHs? What preventive and therapeutic strategies target WMHs? Answering these questions will improve prevention and treatment of WMHs and dementia.
Prosecutor v. Jean-Pierre Bemba Gombo
Authors: Sadat Leila Nadya
Published: April 2019

On June 8, 2018, in a surprising turn, the Appeals Chamber of the International Criminal Court (ICC) reversed the conviction of Jean-Pierre Bemba Gombo and acquitted him of crimes against humanity and war crimes. The four separate opinions, raising questions about Pre-Trial and Trial Chamber procedures, the standard of Appellate Chamber review, and the scope of command responsibility, have revealed sharp disagreements between ICC judges and created considerable confusion over the state of ICC law and procedure.
Obligation to Negotiate Access to the Pacific Ocean (Bolivia v. Chile)
Authors: Dunkelberg Alonso Gurmendi
Published: April 2019

More than thirteen decades after Chile annexed Bolivia's coastal regions, the International Court of Justice (ICJ) denied Bolivia's longstanding claim that Chile had undertaken a legal obligation to negotiate granting it sovereign access to the Pacific Ocean.
Paganism in the Greek World at the End of Antiquity: The Case of Rural Anatolia and Greece
Authors: Trombley Frank R.
Published: April 2019

I propose to discuss what might be called the “mechanics of conversion” in the countryside of the sixth-century later Roman Empire. This process consisted fundamentally in implanting monasteries in districts where few villages had been Christianized, or where the population was nominally Christian but so badly instructed that earlier pagan cult practices persisted. There is considerable evidence for rural conditions in the hagiographic lives of monks and in the ecclesiastical histories of this period. One of the principal difficulties in this sort of study is the geographic distribution of the sources. Hagiographic texts are, in effect, local histories, largely confined to the environs of the monastery. Thus, we are reasonably well informed about western Asia Minor and Galatia in the sixth century, for which sources like this exist, but hardly know anything about paganism in Greece until the tenth century, when monasteries finally began to appear in rural districts.
The Career of John Abernethy (1680–1740) Father of Nonsubscription in Ireland and Defender of Religious Liberty
Authors: Barlow Richard B.
Published: April 2019

The British theological world was stirred at the beginning of the eighteenth century by what the learned and staunchly orthodox Presbyterian historian James Seaton Reid has called “latitudinarian notions on the inferiority of dogmatic belief and the nature of religious liberty.” In the 1690s John Locke had published his Reasonableness of Christianity and Letters on Toleration, followed by John Toland's Christianity Not Mysterious. In 1710 “Honest Will” Whitson, Sir Isaac Newton's successor as Professor of Mathematics at Cambridge, was expelled from the University for embracing Arian views. His departure was accompanied by rumors—long since substantiated—about his great predecessor's heterodox theology. Traditional theologians were shocked next by the appearance of Dr. Samuel Clark's Scripture Doctrine of the Trinity which resulted in the author's arraignment before Convocation of the Church of England in 1714. The very same year John Simson, Professor of Divinity in the University of Glasgow, was first tried before the General Assembly of the Scottish Presbyterian Church for teaching Arian and Pelagian errors. In 1729, after three more trials, Simson was suspended from his professorship for denying the numerical oneness of the Trinity. Fierce doctrinal contentions also began to occupy English Presbyterians, Congregationalists, and Baptists, erupting during the famous Salters’ Hall meeting early in 1719.