bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trivalent PROTACs enhance protein degradation through cooperativity and avidity
Authors: Ciulli Alessio , Imaide Satomi , Riching Kristin , Vetma Vesna , Whitworth Claire , Hughes Scott , Trainor Nicole , Mahan Sarah , Murphy Nancy , Chan Kwok-Ho , Testa Andrea , Maniaci Chiara , Urh Marjeta , Daniels Danette 
Published: December 2020

Abstract
Bivalent small-molecule degraders, or proteolysis targeting chimeras (PROTACs), work by simultaneously binding a target protein and E3 ubiquitin ligase to produce a ternary complex. To drive target ubiquitination and degradation at low catalytic concentrations, degraders must form appropriately positioned complexes of sufficient stability, aided by intra-complex interactions. We hypothesized these molecular recognition features could be enhanced by increasing binding valency. Here we present trivalent PROTACs as a strategy to boost protein degradation. Our design for a trivalent PROTAC consisted of two BET bromodomain inhibitors and an E3 ligase ligand, each separately tethered via a branched linker. In screening, we identified SIM1, a VHL-based PROTAC, as a highly potent BET degrader, capable of low picomolar degradation for all family members, with preference for BRD2. In functional comparison studies to bivalent PROTACs or inhibitors, SIM1 showed more sustained anti-cancer activity across numerous therapeutically relevant cell lines. Biophysical, biochemical, and cellular mechanistic studies showed SIM1 induces conformational changes upon binding to the BET protein to simultaneously engage with high avidity both its bromodomains in a cis intramolecular fashion. The resulting 1:1:1 complex showed positive cooperativity, high stability and prolonged cellular residence time. We provide proof-of-concept for augmenting the binding valency of proximity-induced modalities as a strategy to leverage both cooperativity and avidity within the ternary complex to advance functional outcomes.
Long-term Prognosis of Vascular Access in Haemodialysis Patients with Systemic Lupus Erythematosus: A Retrospective Cohort Study
Authors: Chen Fan-Yu , Chen Chun-Fan , Tan Ann Charis , Chan Chia-Hao , Chen Fu-An , Liu Wen-Sheng , Chen Tz-Heng , Ou Shuo-Ming , Li Szu-Yuan , Tsai Ming-Tsun , Chen Yung-Tai , Lin Chih-Ching 
Published: December 2020

Abstract
Patients with systemic lupus erythematosus (SLE) have a higher risk of vascular complications. The objective of the study is to analyse the differences in the risk of arteriovenous fistula or graft (AVF/AVG) dysfunction in haemodialysis patients with and without SLE over a 10-year period. A final sample of 1366 SLE and 4098 non-SLE patients remained after propensity score matching. The outcome measure primarily evaluated is the incidence rate of AVF/AVG dysfunction. SLE patients had higher incidence rates of AVF/AVG dysfunction than non-SLE patients in all time periods. Three specific time periods that reached significant difference were the following: (1) after 1 year (incidence rates = 15.21, 13.01, respectively; subdistribution hazard ratio (SHR) = 1.15; P = 0.007), (2) 1st-to-10th-year period (incidence rates = 15.36 and 13.25, respectively; SHR = 1.16; P = 0.007), and (3) overall period (incidence rates = 23.53 and 21.66, respectively; SHR = 1.09; P = 0.027). In conclusion, there were significantly higher incidence rates of AVF/AVG dysfunction in SLE patients during the long-term follow-up period in this study.
Learning from retracted papers authored by the highly cited Iran-affiliated researchers: Revisiting research policies and a key message to Clarivate Analytics
Authors: Kamali Negin , Rahimi Farid , Abadi Amin Talebi Bezmin 
Published: December 2020

Abstract
Background The scientific literature is anticipated to self-correct with time. An integral part of this self-correction is the retraction notices identifying flawed scientific papers. Prevalence of retractions has been investigated in different countries and different scholarly disciplines, including surgery, biomedical sciences, and engineering. Reportedly retractions have increased with increasing number of papers from Iran. However, reasons underlying retractions of papers authored by the Iran-affiliated highly cited researchers (HCRs) have not been documented.Result Here, we report that 229 of the Iran-affiliated researchers were listed by the Clarivate Analytics as HCRs. In total, 51 retracted papers were authored by the HCRs as documented by the Retraction Watch Database interrogated from 2006 to 2019. Twenty-three of the 229 HCRs (10%) had at least one paper retracted. One of the listed HCRs had 22 papers retracted; 14 of the 23 (60.8%) had only one paper retracted. Of the 51 papers, 43 (84%) had a single retraction reason, whereas eight had multiple reasons. Among the 43 papers, 23 (53%) were retracted due to fake peer-review, eight (19%) were duplications, six (14%) had errors, four (9%) had plagiarism, and two (5%) were labelled as “limited or no information.” Duplication of data, which is easily preventable, amounted to 27%. The time from publication to retraction of the 51 papers ranged from one to 2,483 (mean 856.6) days.Conclusion Any publishing oversight committed by an HCR should not be tolerated because they represent the stakeholders of the scientific literature and stand as role-models for other peer researchers. Future policies supporting the Iranian academia should radically change by implementation of educational and awareness programs on publishing ethics to reduce the retraction rate.
The Anterior Capsule of the Hip Joint Is a Major Hindrance to the Surgical Treatment of Basicervical Intertrochanteric Fractures: A Single Center, Retrospective Observational Study
Authors: Shin Won Chul , Jang Jae Hoon , Jung Seok Jin , Moon Nam Hoon 
Published: December 2020

Abstract
Background: The basicervical intertrochanteric fracture has recently received considerable attention as one of the major risk factors for failure of internal fixation. We aimed to analyze the anatomical characteristics of basicervical intertrochanteric fractures related to their surgical outcomes using three-dimensional computed tomography (3D CT) and to determine the causes for the high failure rate of surgery.Methods: Between May 2015 and October 2019, 226 patients with intertrochanteric fracture of the femur including 58 basicervical types who were treated with femoral nail were evaluated. Following data were collected to find out the risk factors for surgical failure: fracture patterns (unstable or basicervical type), tip apex distance, type of postoperative reduction (acceptable or unacceptable), and continuity of anterior capsule for logistic regression analysis to determine the risk factors for surgical failuresResults: Union was achieved in 215 patients (95.1%), with 11 surgical failures (4.9%), including 10 non-unions (4.6%) and 1 osteonecrosis of the femoral head (0.4%). Seven surgical failures (8.7%) were identified in the unstable fracture group, 6 (10.3%) in the basicervical type group, and 10 (19.6%) in the unacceptable reduction group. Multivariate analysis showed that unstable fracture (OR 10.311, 95% CI 1.165 – 91.229, p = 0.036), basicervical type (OR 11.564, 95% CI 1.339 – 99.872, p = 0.026), and unacceptable reduction (OR 28.364, 95% CI 3.428 – 234.695, p = 0.002) were significant predictors for surgical failure. Unacceptable reduction (OR 13.180, 95% CI 1.336 – 130.059, p = 0.027) was the only risk factor for surgical failure in the basicervical intertrochanteric fracture group. A chi-square test showed that an intact anterior capsule was statistically correlated with surgical failure (p = 0.043) and unacceptable reduction (p = 0.008).Conclusion: Because the intact anterior capsule of the hip joint may hinder achieving acceptable reduction, the evaluation of the anterior capsule should be included as an important preoperative assessment for the surgical treatment of basicervical intertrochanteric fracture.Level of Evidence: Level III, retrospective cohort study
Airway management during out-of-hospital cardiac arrest; a prospective observational study comparing I-gel® and LTS-D ™
Authors: Lønvik Maja , Elden Odd Eirik , Lunde Mats , Nordseth Trond , Bakkelund Karin , Uleberg Oddvar 
Published: December 2020

Abstract
Background: Airway management in patients with out of hospital cardiac arrest (OHCA) is important and several methods are used. The establishment of a supraglottic airway device (SAD) is a common technique used during OHCA. Two types of SAD are routinely used in Norway; the Kings LTS-D™ and the I-gel®. The aim of this study was to compare the clinical performance of these two devices in terms of difficulty and number of attempts before successful insertion.Methods: All adult patients with OHCA, in whom ambulance personnel used a SAD over a one-year period in the ambulance services of Central Norway, were included. After the event, a questionnaire was completed and the personnel responsible for the airway management were interviewed. Primary outcomes were number of attempts until successful placement of SAD and graded difficulty of insertion. Secondary outcomes were specified challenges with the SAD at insertion. Intergroup differences were compared using Chi-square test for multiple groups.Results: Two hundred and fifty patients were included, of whom 191 received I-gel and 59 received LTS-D. Overall success rate was significantly higher in I-gel (86 %) compared to LTS-D (75%, p = 0,043). The difficulties of insertion were significantly lower among patients receiving I-gel (easy 80 %, medium 13 % and difficult 7 %) compared to LTS-D (easy 51 %, medium 22 % and difficult 27 %, p < 0,001). Conclusions: Overall success rate was significantly higher and the difficulty in insertion was significantly lower in the I-gel group compared to the LTS-D in patients with OHCA.
Substrate Stiffness-Dependent Regulatory Volume Decrease and Calcium Signaling in Chondrocytes
Authors: Zhang Quanyou , Zhang Min , Wu Xiaoan , Du Genlai , Wei Xiaochun , Chen Weiyi 
Published: December 2020

Abstract
The pericellular matrix stiffness is strongly associated with its biochemical and structural changes During the aging and osteoarthritis progresses of articular cartilage. However, how substrate stiffness modulates the chondrocyte regulatory volume decrease (RVD) and calcium signaling remains unknown. This study aims to investigate the effects of substrate stiffness on the chondrocyte RVD and calcium signaling by recapitulating the physiologically relevant substrate stiffness. Our results showed that substrate stiffness induced completely different dynamical deformation between the cell swelling and recovering progresses. Chondrocytes swelled faster on the soft substrate but recovered slower than the stiff substrate during the RVD response induced by the hypo-osmotic challenge. We found that stiff substrate enhanced the cytosolic Ca2+ oscillation of chondrocytes in the iso-osmotic medium. More importantly, chondrocytes exhibited a distinctive cytosolic Ca2+ oscillation during the RVD response. Soft substrate significantly improved the Ca2+ oscillation during the cell swelling whereas stiff substrate enhanced the cytosolic Ca2+ oscillation during the cell recovering. Our work also suggests that TRPV4 channel are involved in the chondrocyte sensing substrate stiffness and RVD response by mediating Ca2+ signaling in a stiffness-dependent manner. It helps to understand a previously unidentified relationship between substrate stiffness and RVD response under the hypo-osmotic challenge.
Colonisation of the Colonic Mucus Gel Layer With Butyrogenic and Hydrogenotropic Bacteria in Health and Ulcerative Colitis
Authors: Earley Helen , Lennon Grainne , Winter Desmond , Coffey Calvin , O'Connell Ronan 
Published: December 2020

Abstract
Butyrate is the primary energy source for colonocytes and is essential for mucosal integrity and repair. Butyrate deficiency as a result of colonic dysbiosis is a putative factor in ulcerative colitis (UC). Commensal microbes are butyrogenic, while others have an inhibitory effect, through hydrogenotropic activity. The aim of this study was to quantify butyrogenic and hydrogenotropic species and determine their relationship with inflammation within the colonic mucus gel layer (MGL).Mucosal brushings were obtained from 20 patients with active colitis (AC), 20 healthy controls (HC) and 14 with quiescent colitis (QUC). Abundance of each species was determined by RT-PCR. Inflammatory scores were available for each patient. Statistical analyses were performed using Mann-Whitney-U and Kruskall-Wallis tests.Butyrogenic R. hominis was more abundant in health than UC (p<0.005). Hydrogenotropic B. wadsworthia was reduced in AC compared to HC and QUC (p<0.005). An inverse correlation existed between inflammation and R. hominis (ρ -0.460, p >0.005) and B. wadsworthia (ρ -0.646, p >0.005). Other hydrogenotropic species did not widely colonise the MGL. These data support a role for butyrogenic and some species of hydrogenotropic bacteria in UC. Butyrate deficiency in UC may be related to reduced microbial production, rather than inhibition by microbial by-products.
An adaptive optics module for deep tissue multiphoton imaging in vivo
Authors: Ji Na , Rodriguez Cristina , Chen Ichun , Rivera José , Mohr Manuel , Liang Yajie , Sun Wenzhi , Milkie Daniel , Bifano Thomas , Chen Xiaoke 
Published: December 2020

Abstract
Understanding complex biological systems requires visualizing structures and processes deep within living organisms. We developed a compact adaptive optics module and incorporated it into two- and three-photon fluorescence microscopes, to measure and correct tissue-induced aberrations. We resolved synaptic structures in deep cortical and subcortical areas of the mouse brain, and demonstrated high-resolution imaging of neuronal structures and somatosensory-evoked calcium responses in the mouse spinal cord at unprecedented depths in vivo.
Whole Genome Sequence of biosurfactant producing Bacillus tequilensis
Authors: Nayarisseri Anuraj , Singh Sanjeev Kumar 
Published: December 2020

Abstract
We announce the complete genome sequence of Bacillus tequilensis, a biosurfactant producing bacterium isolated from Chilika lake, Odisha, India(latitude and longitude: 19.8450 N 85.4788 E). The genome sequence is 4.47 MB consisting of 4,478,749 base pairs forming a circular chromosome with 528 scaffolds, 4492 protein-encoding genes(ORFs), 81 tRNA genes, and 114 ribosomal RNA transcription units. The total number of raw reads was 4209415 and processed reads were 4058238 with predicted genes of 4492. The whole-genome obtained from the present investigation was used for genome annotation, variant calling, variant annotation and comparative genome analysis with other existing Bacillus species. In this study we constructed a pathway which describe the biosurfactant metabolism of Bacillus tequilensis and identified the genes such as SrfAD, SrfAC, SrfAA which are involved in biosurfactant synthesis. The sequence of the same was deposited in Genbank database with accession MUG02427.1, MUG02428.1, MUG02429.1, MUG03515.1 respectively. The whole-genome sequence was submitted to Genbank with an accession RMVO00000000 and the raw reads can be obtained from SRA, NCBI repository using accession: SRX5023292.
Second-harmonic generation and the conservation of spatiotemporal orbital angular momentum of light
Authors: Gui Guan , Brooks Nathan , Kapteyn Henry , Murnane Margaret , Liao Chen-Ting 
Published: December 2020

Abstract
Light with spatiotemporal orbital angular momentum (ST-OAM) is a recently discovered type of structured electromagnetic field with characteristic space-time spiral phase structure and transverse OAM. In this work, we present the first generation and characterization of the second-harmonic of ST-OAM pulses. By uncovering the conservation of transverse OAM in a second-harmonic generation process, where the space-time topological charge of the fundamental field is doubled along with the optical frequency, we establish a general nonlinear scaling rule— analogous to that describing the spatial topological charges associated with the conventional longitudinal OAM of light. Furthermore, we observe that the topology of a second-harmonic ST-OAM pulse can be modified by complex spatiotemporal astigmatism, giving rise to multiple phase singularities separated in space and time. Our finding thus confirms that a spatiotemporal phase winding, surrounding one or many phase singularities in space and time, can be interpreted as a new class of topological charge. Our study opens a new route for nonlinear conversion and scaling of light carrying ST-OAM with the potential for driving other secondary ST-OAM sources of electromagnetic fields, electron pulses, and beyond.
Malaria Early Detection in a Declining Transmission Setting in the Amhara Region of Ethiopia
Authors: Nekorchuk Dawn , Gebrehiwot Teklehaimanot , Lake Mastewal , Awoke Worku , Mihretie Abere , Wimberly MIchael 
Published: December 2020

Abstract
Background Despite remarkable progress in the reduction of malaria incidence, this disease remains a public health threat to a significant portion of the world’s population. Surveillance, combined with early detection algorithms, can be an effective intervention strategy to inform timely public health responses to potential outbreaks. Our main objective was to compare the potential for detecting malaria outbreaks by selected event detection methods.Methods We used historical surveillance data with weekly counts of confirmed Plasmodium falciparum (including mixed) cases from the Amhara region of Ethiopia, where there was a resurgence of malaria in 2019 following several years of declining cases. We evaluated three early detection methods to detect the 2019 malaria events: 1) the Centers for Disease Prevention and Control (CDC) Early Aberration Reporting System (EARS), 2) methods based on weekly statistical thresholds, including the WHO and Cullen methods, and 3) the Farrington algorithms.Results All of the methods and parameters evaluated performed better than a naïve random alarm generator. We also found distinct trade-offs between the percent of events detected and the percent of true positive alarms. CDC EARS and weekly statistical threshold methods had high event sensitivities (80% − 100% CDC; 57% − 100% weekly statistical) and low to moderate alarm specificities (25% − 40% CDC; 16% − 61% weekly statistical). Farrington variants had a wide range of scores (20% − 100% sensitivities; 16% − 100% specificities) and could achieve various balances between sensitivity and specificity.Conclusions Of the methods tested, we found that the Farrington improved method was most effective at maximizing both the percent of events detected and true positive alarms for our dataset (83% sensitivity, 51% specificity). This method uses statistical models to establish thresholds while controlling for seasonality and multi-year trends, and we suggest that it and other model-based approaches should be considered more broadly for malaria early detection.
Identification of Cutaneous Fungi and Mites in Adult Atopic Dermatitis: Analysis by Targeted 18S rRNA Amplicon Sequencing
Authors: Edslev Sofie , Andersen Paal , Ingham Anna , Johannesen Thor , Lindhardt Ditte , Agner Tove , Clausen Maja-Lisa 
Published: December 2020

Abstract
Background: Atopic dermatitis (AD) patients have a changed skin bacterial community, with high abundance of Staphylococcus aureus associated with flairs, highlighting that microbial organisms may be important for disease exacerbation. Despite strong evidence of association between bacterial skin colonization and AD, very limited knowledge regarding the eukaryotic microbial community, including fungi and ectoparasites, in AD exists. In this study, we compared the skin and nasal eukaryotic microbial community between adult AD patients (n=55) and non-AD healthy controls (n=45) using targeted 18S rRNA amplicon sequencing. Analysis was based on the presence or absence of eukaryotic microorganisms. Results: The cutaneous composition of the eukaryotic microbial community and the alpha-diversity differed significantly between AD patients and non-AD individuals, with increased species richness on AD skin. Alpha-diversity and beta-diversity were similar on lesional and non-lesional skin of patients. The ectoparasite Demodex folliculorum and the yeast Geotrichum candidum were significantly more prevalent on the skin of AD patients. The prevalence of D. folliculorum on lesional skin was greater among patients recently treated with topical corticosteroid. Malassezia was one of the most frequently detected genera at all sites, with M. globosa and M. restricta being the most prevalent. M. restricta was overrepresented in the anterior nares of AD patients as compared to the non-AD control population. Conclusion: Significant differences in the eukaryotic microbial communities were found between AD patients and non-AD individuals, with the most striking finding being the significantly overrepresentation of D. folliculorum on AD skin. Whether D. folliculorum can contribute to skin inflammation in AD needs further investigation.
Oxidative Stress, Lysosome Functioning, and Element Interactions in the Muscles of the Sea Trout Salmo Trutta m. Trutta L. Depending on Its Life Cycle
Authors: Kurhaluk Natalia , Takchenko Halyna 
Published: December 2020

Abstract
The aim of our study was to elucidate the effects of both development stages (parr, smolt, adult, spawner), and kelt as a survival form and sex (male, female) on the functional stability of the lysosomal complex, biomarkers of oxidative stress, and element contents in the muscle tissue of the sea trout (Salmo trutta m. trutta L.) sampled in the Pomerania region (northern Poland). We have evaluated the maximal activities of lysosomal enzymes (alanyl aminopeptidase, leucyl aminopeptidase, β-N-acetylglucosaminidase, and acid phosphatase), lipid peroxidation level, and protein carbonyl derivatives as indices of muscle tissue degradation. The relationship between lysosomal activity and oxidative stress biomarkers estimated by the lipid peroxidation level and protein carbonyl derivatives was also assessed, as well as the relationships between element levels and oxidative stress biomarkers. Trends of the main effects (i.e., the development stages and sex alone, the interaction of the sex and development stage simultaneously) on oxidative stress biomarkers, lysosomal functioning, and element contents in the muscle tissue were evaluated. The study has shown sex-related relationships between the pro- and antioxidant balance and the tissue type in the adult stage as well as modifications in the lysosomal functioning induced by long-term environmental stress associated with changing the habitats from freshwater to seawater and intense migrations. The highest level of toxic products generated in oxidative reactions and oxidative modification of proteins was noted in both the spawner stage and the kelt form. The holistic model of analysis of all parameters of antioxidant defense in all development stages and sex demonstrated the following dependencies for the level of lipid peroxidation, oxidative modification of proteins, lysosomal activities, and element contents: TBARS>OMP KD>OMP AD>TAC, AcP>NAG>LAP>AAP and Cu>Fe>Ca>Mn>Zn>Mg, respectively.