bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of the depth of the acetabular component during simulated acetabulum reaming in total hip arthroplasty
Authors: Zuo Jianlin , Xu Meng , Zhao Xin , Shen Xianyue , Gao Zhongli , Xiao Jianlin 
Published: May 2021

AbstractWe aimed to evaluate whether there are differences in the rotation center, cup coverage, and biomechanical effects between conventional and anatomical technique. Computed tomography scans of 26 normal hips were used to simulate implantation of acetabular component. The hip rotation center and acetabular component coverage rate were calculated. Moreover, a finite element model of the hip joint was generated to simulate and evaluate the acetabular cup insertion. Micromotion and the peak stress distribution were used to quantify the biomechanical properties. The medial and superior shifts of the rotation center were 5.2 ± 1.8 mm and 1.6 ± 0.7 mm for the conventional reaming technique and 1.1 ± 1.5 mm and 0.8 ± 0.5 mm for anatomical technique, respectively. The acetabular component coverage rates for conventional reaming technique and anatomical technique were 86.8 ± 4% and 70.0 ± 7%, respectively. The micromotion of the cup with conventional reaming technique was greater than that with anatomical technique. The peak stress concentration was highest in the superior portion with conventional reaming technique, whereas with anatomical technique, there was no stress concentration. Paradoxically although the acetabular component coverage rate is larger with conventional reaming technique, anatomical technique provides less micromotion and stress concentration for initial cup stability. Thus, anatomical technique may be more suitable for acetabulum reaming during primary total hip arthroplasty.
Regulatory rare variants of the dopaminergic gene ANKK1 as potential risk factors for Parkinson’s disease
Authors: Pérez-Santamarina Estela , García-Ruiz Pedro , Martínez-Rubio Dolores , Ezquerra Mario , Pla-Navarro Irene , Puente Jorge , Martí María José , Palau Francesc , Hoenicka Janet 
Published: May 2021

AbstractParkinson’s disease (PD) is characterized by cerebral dopamine depletion that causes motor and cognitive deficits. The dopamine-related gene ANKK1 has been associated with neuropsychiatric disorders with a dopaminergic deficiency in the striatum. This study aims to define the contribution of ANKK1 rare variants in PD. We found in 10 out of 535 PD patients 6 ANKK1 heterozygous rare alleles located at the 5′UTR, the first exon, intron 1, and the nearby enhancer located 2.6 kb upstream. All 6 ANKK1 single nucleotide variants were located in conserved regulatory regions and showed significant allele-dependent effects on gene regulation in vitro. ANKK1 variant carriers did not show other PD-causing Mendelian mutations. Nevertheless, four patients were heterozygous carriers of rare variants of ATP7B gene, which is related to catecholamines. We also found an association between the polymorphic rs7107223 of the ANKK1 enhancer and PD in two independent clinical series (P = 0.007 and 0.021). rs7107223 functional analysis showed significant allele-dependent effects on both gene regulation and dopaminergic response. In conclusion, we have identified in PD patients functional variants at the ANKK1 locus highlighting the possible relevance of rare variants and non-coding regulatory regions in both the genetics of PD and the dopaminergic vulnerability of this disease.
Use of single guided Cas9 nickase to facilitate precise and efficient genome editing in human iPSCs
Authors: Li Pan P. , Margolis Russell L. 
Published: May 2021

AbstractCas9 nucleases permit rapid and efficient generation of gene-edited cell lines. However, in typical protocols, mutations are intentionally introduced into the donor template to avoid the cleavage of donor template or re-cleavage of the successfully edited allele, compromising the fidelity of the isogenic lines generated. In addition, the double-stranded breaks (DSBs) used for editing can introduce undesirable “on-target” indels within the second allele of successfully modified cells via non-homologous end joining (NHEJ). To address these problems, we present an optimized protocol for precise genome editing in human iPSCs that employs (1) single guided Cas9 nickase to generate single-stranded breaks (SSBs), (2) transient overexpression of BCL-XL to enhance survival post electroporation, and (3) the PiggyBac transposon system for seamless removal of dual selection markers. We have used this method to modify the length of the CAG repeat contained in exon 7 of PPP2R2B. When longer than 43 triplets, this repeat causes the neurodegenerative disorder spinocerebellar ataxia type 12 (SCA12); our goal was to seamlessly introduce the SCA12 mutation into a human control iPSC line. With our protocol, ~ 15% of iPSC clones selected had the desired gene editing without “on target” indels or off-target changes, and without the deliberate introduction of mutations via the donor template. This method will allow for the precise and efficient editing of human iPSCs for disease modeling and other purposes.
The combination of dantrolene and nimodipine effectively reduces 5-HT-induced vasospasms in diabetic rats
Authors: Román Marie , García Laura , Morales Myrna , Crespo María J. 
Published: May 2021

AbstractDiabetics have a higher risk of developing cerebral vasospasms (CVSP) after subarachnoid hemorrhagic stroke than non-diabetics. Serotonin (5-HT) is one of the key vasoconstrictors released in the hemorrhagic blood and an important contributor to the etiology of CVSP. The combination of the ryanodine receptor blocker dantrolene and the Ca2+ channel blocker nimodipine significantly reduces phenylephrine (PHE)-induced vascular contraction in both diabetic and nondiabetic rats, but the effectiveness of this drug combination in reducing 5-HT-induced contraction is unknown. Dose–response curves for the 5-HT-induced contraction (from 0.1 nM to 100 µM) were performed on aortic rings from diabetic and non-diabetic rats after a 30-min incubation period with dantrolene, nimodipine, and both drugs in combination. In diabetic rats, 10 μM of dantrolene alone failed to reduce 5-HT-induced maximal contraction (Emax), but 50 μM reduced this parameter by 34% (n = 7, p < 0.05). In non-diabetic rats, by contrast, dantrolene did not modify the vascular response to 5-HT. 50 nM of nimodipine alone, however, reduced this parameter by 57% in diabetic rats (n = 10, p < 0.05), and by 34% in non-diabetic rats (n = 10, p < 0.05). In addition, concomitant administration of dantrolene and nimodipine reduced vascular reactivity to a similar extent in both diabetic (~ 60% reduction, n = 10, p < 0.05) and non-diabetic rats (~ 70% reduction, n = 10, p < 0.05). Moreover, the combination of nimodipine with the higher concentration of dantrolene significantly increased the EC50 values for the 5-HT-induced contraction curves in both diabetics (from 10.31 ± 1.17 µM to 19.26 ± 2.82; n = 10, p < 0.05) and non-diabetic rats (5.93 ± 0.54 µM to 15.80 ± 3.24; n = 10, p < 0.05). These results suggest that simultaneous administration of dantrolene and nimodipine has a synergistic effect in reducing 5-HT-induced vascular contraction under both diabetic and non-diabetic conditions. If our findings with rats are applicable to humans, concomitant administration of these drugs may represent a promising alternative for the management of CVSP in both diabetics and non-diabetics.
Application of the targeted sequencing approach reveals the single nucleotide polymorphism (SNP) repertoire in microRNA genes in the pig genome
Authors: Pawlina-Tyszko Klaudia , Semik-Gurgul Ewelina , Gurgul Artur , Oczkowicz Maria , Szmatoła Tomasz , Bugno-Poniewierska Monika 
Published: May 2021

AbstractMicroRNAs (miRNAs) are recognized as gene expression regulators, indirectly orchestrating a plethora of biological processes. Single nucleotide polymorphism (SNP), one of the most common genetic variations in the genome, is established to affect miRNA functioning and influence complex traits and diseases. SNPs in miRNAs have also been associated with important production traits in livestock. Thus, the aim of our study was to reveal the SNP variability of miRNA genes in the genome of the pig, which is a significant farm animal and large-mammal human model. To this end, we applied the targeted sequencing approach, enabling deep sequencing of specified genomic regions. As a result, 73 SNPs localized in 50 distinct pre-miRNAs were identified. In silico analysis revealed that many of the identified SNPs influenced the structure and energy of the hairpin precursors. Moreover, SNPs localized in the seed regions were shown to alter targeted genes and, as a result, enrich different biological pathways. The obtained results corroborate a significant impact of SNPs on the miRNA processing and broaden the state of knowledge in the field of animal genomics. We also report the targeted sequencing approach to be a promising alternative for the whole genome sequencing in miRNA genes focused studies.
Diversification of the Balloon bushcrickets (Orthoptera, Hexacentrinae, Aerotegmina) in the East African mountains
Authors: Grzywacz Beata , Warchałowska-Śliwa Elżbieta , Kociński Maciej , Heller Klaus-Gerhard , Hemp Claudia 
Published: May 2021

AbstractEast African mountains constitute a network of isolated habitat islands among dry savannah and are thus ideal for studying species diversification processes. This study elucidated the phylogenetic and phylogeographic relationships of all bushcricket species comprising the genusAerotegmina. Our analysis indicated that large-scale climatic and topographic processes in Africa are likely to have driven speciation in this group, and revealed the cytogenetic traits of the species. Molecular phylogeny supported the monophyly ofAerotegminaand showed that the genus probably originated in the old Eastern Arc Mountains of Tanzania and Kenya. Two lineages were distinguished: small- and large-sized species with geographically distinct habitats. The underlying processes are thought to be eight dispersals, ten vicariance events, and one extinction event linked to repeated fragmentation of the African rainforest. Those processes, in conjunction with habitat change, probably also led to the spatial separation of the species into a northern clade with a diploid number of chromosomes 2n = 32 + X0 or 2n = 30 + neo-XY and a southern clade with a reduced number of chromosomes (2n = 28 + X0 or 24 + neo-X1X2Y). Karyotype analysis suggests thatAerotegminais currently in the process of speciation.
Role of hydrogen bond alternation and charge transfer states in photoactivation of the Orange Carotenoid Protein
Authors: Yaroshevich Igor A. , Maksimov Eugene G. , Sluchanko Nikolai N. , Zlenko Dmitry V. , Stepanov Alexey V. , Slutskaya Ekaterina A. , Slonimskiy Yury B. , Botnarevskii Viacheslav S. , Remeeva Alina , Gushchin Ivan , Kovalev Kirill , Gordeliy Valentin I. , Shelaev Ivan V. , Gostev Fedor E. , Khakhulin Dmitry , Poddubnyy Vladimir V. , Gostev Timofey S. , Cherepanov Dmitry A. , Polívka Tomáš , Kloz Miroslav , Friedrich Thomas , Paschenko Vladimir Z. , Nadtochenko Victor A. , Rubin Andrew B. , Kirpichnikov Mikhail P. 
Published: May 2021

AbstractHere, we propose a possible photoactivation mechanism of a 35-kDa blue light-triggered photoreceptor, the Orange Carotenoid Protein (OCP), suggesting that the reaction involves the transient formation of a protonated ketocarotenoid (oxocarbenium cation) state. Taking advantage of engineering an OCP variant carrying the Y201W mutation, which shows superior spectroscopic and structural properties, it is shown that the presence of Trp201 augments the impact of one critical H-bond between the ketocarotenoid and the protein. This confers an unprecedented homogeneity of the dark-adapted OCP state and substantially increases the yield of the excited photoproduct S*, which is important for the productive photocycle to proceed. A 1.37 Å crystal structure of OCP Y201W combined with femtosecond time-resolved absorption spectroscopy, kinetic analysis, and deconvolution of the spectral intermediates, as well as extensive quantum chemical calculations incorporating the effect of the local electric field, highlighted the role of charge-transfer states during OCP photoconversion.
ARP-T1-associated Bazex–Dupré–Christol syndrome is an inherited basal cell cancer with ciliary defects characteristic of ciliopathies
Authors: Park Hyun-Sook , Papanastasi Eirini , Blanchard Gabriela , Chiticariu Elena , Bachmann Daniel , Plomann Markus , Morice-Picard Fanny , Vabres Pierre , Smahi Asma , Huber Marcel , Pich Christine , Hohl Daniel 
Published: May 2021

AbstractActin-Related Protein-Testis1 (ARP-T1)/ACTRT1gene mutations cause the Bazex-Dupré-Christol Syndrome (BDCS) characterized by follicular atrophoderma, hypotrichosis, and basal cell cancer. Here, we report an ARP-T1 interactome (PXD016557) that includes proteins involved in ciliogenesis, endosomal recycling, and septin ring formation. In agreement, ARP-T1 localizes to the midbody during cytokinesis and the basal body of primary cilia in interphase. Tissue samples from ARP-T1-associated BDCS patients have reduced ciliary length. The severity of the shortened cilia significantly correlates with the ARP-T1 levels, which was further validated by ACTRT1 knockdown in culture cells. Thus, we propose that ARP-T1 participates in the regulation of cilia length and that ARP-T1-associated BDCS is a case of skin cancer with ciliopathy characteristics.
Identification of a peptide motif that potently inhibits two functionally distinct subunits of Shiga toxin
Authors: Watanabe-Takahashi Miho , Tamada Masakazu , Senda Miki , Hibino Masahiro , Shimizu Eiko , Okuta Akiko , Miyazawa Atsuo , Senda Toshiya , Nishikawa Kiyotaka 
Published: May 2021

AbstractShiga toxin (Stx) is a major virulence factor of enterohemorrhagic Escherichia coli, which causes fatal systemic complications. Here, we identified a tetravalent peptide that inhibited Stx by targeting its receptor-binding, B-subunit pentamer through a multivalent interaction. A monomeric peptide with the same motif, however, did not bind to the B-subunit pentamer. Instead, the monomer inhibited cytotoxicity with remarkable potency by binding to the catalytic A-subunit. An X-ray crystal structure analysis to 1.6 Å resolution revealed that the monomeric peptide fully occupied the catalytic cavity, interacting with Glu167 and Arg170, both of which are essential for catalytic activity. Thus, the peptide motif demonstrated potent inhibition of two functionally distinct subunits of Stx.
FMRP regulates STAT3 mRNA localization to cellular protrusions and local translation to promote hepatocellular carcinoma metastasis
Authors: Shen Zhifa , Liu Bowen , Wu Biting , Zhou Hongyin , Wang Xiangyun , Cao Jinling , Jiang Min , Zhou Yingying , Guo Feixia , Xue Chang , Wu Zai-Sheng 
Published: May 2021

AbstractMost hepatocellular carcinoma (HCC)-associated mortalities are related to the metastasis of cancer cells. The localization of mRNAs and their products to cell protrusions has been reported to play a crucial role in the metastasis. Our previous findings demonstrated that STAT3 mRNA accumulated in the protrusions of metastatic HCC cells. However, the underlying mechanism and functional significance of this localization of STAT3 mRNA has remained unexplored. Here we show that fragile X mental retardation protein (FMRP) modulates the localization and translation of STAT3 mRNA, accelerating HCC metastasis. The results of molecular analyses reveal that the 3′UTR of STAT3 mRNA is responsible for the localization of STAT3 mRNA to cell protrusions. FMRP is able to interact with the 3′UTR of STAT3 mRNA and facilitates its localization to protrusions. Importantly, FMRP could promote the IL-6-mediated translation of STAT3, and serine 114 of FMRP is identified as a potential phosphorylation site required for IL-6-mediated STAT3 translation. Furthermore, FMRP is highly expressed in HCC tissues and FMRP knockdown efficiently suppresses HCC metastasis in vitro and in vivo. Collectively, our findings provide further insights into the mechanism of HCC metastasis associated with the regulation of STAT3 mRNA localization and translation.
Bifidobacterium response to lactulose ingestion in the gut relies on a solute-binding protein-dependent ABC transporter
Authors: Yoshida Keisuke , Hirano Rika , Sakai Yohei , Choi Moonhak , Sakanaka Mikiyasu , Kurihara Shin , Iino Hisakazu , Xiao Jin-zhong , Katayama Takane , Odamaki Toshitaka 
Published: May 2021

AbstractThis study aims to understand the mechanistic basis underlying the response of Bifidobacterium to lactulose ingestion in guts of healthy Japanese subjects, with specific focus on a lactulose transporter. An in vitro assay using mutant strains of Bifidobacterium longum subsp. longum 105-A shows that a solute-binding protein with locus tag number BL105A_0502 (termed LT-SBP) is primarily involved in lactulose uptake. By quantifying faecal abundance of LT-SBP orthologues, which is defined by phylogenetic analysis, we find that subjects with 107 to 109 copies of the genes per gram of faeces before lactulose ingestion show a marked increase in Bifidobacterium after ingestion, suggesting the presence of thresholds between responders and non-responders to lactulose. These results help predict the prebiotics-responder and non-responder status and provide an insight into clinical interventions that test the efficacy of prebiotics.
Mitofusin-2 boosts innate immunity through the maintenance of aerobic glycolysis and activation of xenophagy in mice
Authors: Silwal Prashanta , Kim Jin Kyung , Jeon Sang Min , Lee June-Young , Kim Young Jae , Kim Yi Sak , Seo Yeji , Kim Jihye , Kim Soo Yeon , Lee Min Joung , Heo Jun Young , Jung Mi-Ja , Kim Hyun Sik , Hyun Dong-Wook , Han Jeong Eun , Whang Jake , Huh Yang Hoon , Lee Sang-Hee , Heo Won Do , Kim Jin-Man , Bae Jin-Woo , Jo Eun-Kyeong 
Published: May 2021

AbstractMitochondrial function and innate immunity are intimately linked; however, the mechanisms how mitochondrion-shaping proteins regulate innate host defense remains largely unknown. Herein we show that mitofusin-2 (MFN2), a mitochondrial fusion protein, promotes innate host defense through the maintenance of aerobic glycolysis and xenophagy via hypoxia-inducible factor (HIF)-1α during intracellular bacterial infection. Myeloid-specific MFN2 deficiency in mice impaired the antimicrobial and inflammatory responses against mycobacterial and listerial infection. Mechanistically, MFN2 was required for the enhancement of inflammatory signaling through optimal induction of aerobic glycolysis via HIF-1α, which is activated by mitochondrial respiratory chain complex I and reactive oxygen species, in macrophages. MFN2 did not impact mitophagy during infection; however, it promoted xenophagy activation through HIF-1α. In addition, MFN2 interacted with the late endosomal protein Rab7, to facilitate xenophagy during mycobacterial infection. Our findings reveal the mechanistic regulations by which MFN2 tailors the innate host defense through coordinated control of immunometabolism and xenophagy via HIF-1α during bacterial infection.
Mucosal ribosomal stress-induced PRDM1 promotes chemoresistance via stemness regulation
Authors: Kim Juil , Moon Yuseok 
Published: May 2021

AbstractThe majorities of colorectal cancer (CRC) cases are sporadic in origin and a large proportion of etiologies are associated with environmental stress responses. In response to external and internal stress, the ribosome stands sentinel and stress-driven ribosomal dysfunction triggers the cellular decision pathways via transcriptional reprogramming. In the present study, PR domain zinc finger protein (PRDM) 1, a master transcriptional regulator, was found to be closely associated with ribosomal actions in patients with CRC and the murine models. Stress-driven ribosomal dysfunction enhanced PRDM1 levels in intestinal cancer cells, which contributed to their survival and enhanced cancer cell stemness against cancer treatment. Mechanistically, PRDM1 facilitated clustering modulation of insulin-like growth factor (IGF) receptor-associated genes, which supported cancer cell growth and stemness-linked features. Ribosomal dysfunction-responsive PRDM1 facilitated signaling remodeling for the survival of tumor progenitors, providing compelling evidence for the progression of sporadic CRC.
Structural analogues in herbal medicine ginseng hit a shared target to achieve cumulative bioactivity
Authors: Zhang Wei , Tao Wei-Wei , Zhou Jing , Wu Cheng-Ying , Long Fang , Shen Hong , Zhu He , Mao Qian , Xu Jun , Li Song-Lin , Wu Qi-Nan 
Published: May 2021

AbstractBy a pilot trial on investigating immunomodulatory activity and target of ginsenosides, the major bioactive components of ginseng, here we report that structural analogues in herbal medicines hit a shared target to achieve cumulative bioactivity. A ginsenoside analogues combination with definite immunomodulatory activity in vivo was designed by integrating pharmacodynamics, serum pharmacochemistry and pharmacokinetics approaches. The cumulative bioactivity of the ginsenoside analogues was validated on LPS/ATP-induced RAW264.7 macrophages. The potentially shared target NLRP3 involved in this immunomodulatory activity was predicted by systems pharmacology. The steady binding affinity between each ginsenoside and NLRP3 was defined by molecular docking and bio-layer interferometry assay. The activation of NLRP3 inflammasomes in LPS/ATP-induced RAW264.7 was significantly suppressed by the combination, but not by any individual, and the overexpression of NLRP3 counteracted the immunomodulatory activity of the combination. All these results demonstrate that the ginsenoside analogues jointly hit NLRP3 to achieve cumulative immunomodulatory activity.
Supramolecular construction of a cyclobutane ring system with four different substituents in the solid state
Authors: Sinnwell Michael A. , Groeneman Ryan H. , Ingenthron Benjamin J. , Li Changan , MacGillivray Leonard R. 
Published: May 2021

AbstractMethods to form cyclobutane rings by an intermolecular [2 + 2] cross-photoreaction (CPR) with four different substituents are rare. These reactions are typically performed in the liquid phase, involve multiple steps, and generate product mixtures. Here, we report a CPR that generates a cyclobutane ring with four different aryl substituents. The CPR occurs quantitatively, without side products, and without a need for product purification. Generally, we demonstrate how face-to-face stacking interactions of aromatic rings can be exploited in the process of cocrystallization and the field of crystal engineering to stack and align unsymmetrical alkenes in CPRs to afford chiral cyclobutanes with up to four different aryl groups via binary cocrystals. Overall, we expect the process herein to be useful to generate chiral carbon scaffolds, which is important given the presence of four-membered carbocyclic rings as structural units in biological compounds and materials science.
Novel fidaxomicin antibiotics through site-selective catalysis
Authors: Dailler David , Dorst Andrea , Schäfle Daniel , Sander Peter , Gademann Karl 
Published: May 2021

AbstractFidaxomicin (FDX) is a marketed antibiotic for the treatment ofClostridioides difficileinfections (CDI). Fidaxomicin displays antibacterial properties against many Gram-positive bacteria, yet the application of this antibiotic is currently limited to treatment of CDI. Semisynthetic modifications present a promising strategy to improve its pharmacokinetic properties and also circumvent resistance development by broadening the structural diversity of the derivatives. Here, based on a rational design using cryo-EM structural analysis, we implement two strategic site-selective catalytic reactions with a special emphasis to study the role of the carbohydrate units. Site-selective introduction of various ester moieties on the noviose as well as a Tsuji–Trost type rhamnose cleavage allow the synthesis of novel fidaxomicin analogs with promising antibacterial activities againstC. difficileandMycobacterium tuberculosis.