bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient and Graft Survival After A1/A2-incompatible Living Donor Kidney Transplantation
Authors: Bisen Shivani S. , Getsin Samantha N. , Chiang Po-Yu , Herrick-Reynolds Kayleigh , Zeiser Laura B. , Yu Sile , Desai Niraj M. , Al Ammary Fawaz , Jackson Kyle R. , Segev Dorry L. , Massie Allan B. 
Published: February 2023

Background.
ABO type B and O kidney transplant candidates have increased difficulty identifying a compatible donor for living donor kidney transplantation (LDKT) and are harder to match in kidney paired donation registries. A2-incompatible (A2i) LDKT increases access to LDKT for these patients. To better inform living donor selection, we evaluated the association between A2i LDKT and patient and graft survival.

Methods.
We used weighted Cox regression to compare mortality, death-censored graft failure, and all-cause graft loss in A2i versus ABO-compatible (ABOc) recipients.

Results.
Using Scientific Registry of Transplant Recipients data 2000–2019, we identified 345 A2i LDKT recipients. Mortality was comparable among A2i and ABOc recipients; weighted 1-/5-/10-y mortality was 0.9%/6.5%/24.2%, respectively, among A2i LDKT recipients versus 1.4%/7.7%/22.2%, respectively, among ABOc LDKT recipients (weighted hazard ratio [wHR], 0.811.041.33; P = 0.8). However, A2i recipients faced higher risk of death-censored graft failure; weighted 1-/5-/10-y graft failure was 5.7%/11.6%/22.4% for A2i versus 1.7%/7.5%/17.2% for ABOc recipients (wHR in year 1 = 2.243.565.66; through year 5 = 1.251.782.53; through year 10 = 1.151.552.07). By comparison, 1-/5-/10-y wHRs for A1-incompatible recipients were 0.631.966.08/0.390.942.27/0.390.831.74.

Conclusions.
A2i LDKT is generally safe, but A2i donor/recipient pairs should be counseled about the increased risk of graft failure and be monitored as closely as their A1-incompatible counterparts posttransplant.
Development of a mobile laboratory system in hydrogen fuel cell buses and evaluation of the performance for COVID-19
Authors: Okude Miho , Suzuki Kenji , Naito Asami , Ebashi Akio , Kusama Tomoka , Kiyotaki Junichi , Akashi Yusaku , Kiyasu Yoshihiko , Kurihara Yoko , Notake Shigeyuki , Takanashi Masaki , Setoyama Tomokazu , Kawakami Yasushi , Suzuki Hiromichi 
Published: February 2023

AbstractIntroductionWe newly designed and developed two types of hydrogen fuel cell (HFC) buses (motorcoach type and minibus type) with a mobile laboratory system. Feasibility studies have been performed for mobile laboratory testing, especially for the laboratory performance of COVID-19 RT-PCR (PCR).MethodsWe evaluated the driving range capability, PCR sample size capacity, turn-around time (TAT), and analytical performance for the detection of SARS-CoV-2. Saliva samples were used for the current research and the analytical performance was compared with reference PCR.ResultsThe estimated driving range and sample size capacity were 432 km and 3,258 samples, respectively for the HFC motorcoach and 313 km and 2,146 samples for the HFC minibus, respectively. For the TAT, the median time between the sample submission and the completion of PCR were 86 min for the motorcoach and 76 min for the minibus, and the median time between sample submission and the electronic reporting of the result to each visitor were 182 min for the motorcoach and 194 min for the minibus. A secondary analysis of 1,574 HFC mobile laboratory testing samples was conducted and all negative samples were negative by reference PCR. Furthermore, all positive samples were confirmed as positive by reference PCR or other molecular examinations.ConclusionWe confirmed the feasibility of HFC mobile laboratory systems for achieving the rapid reporting of highly accurate PCR results.
Data-driven neuropathological staging and subtyping of TDP-43 proteinopathies
Authors: Young Alexandra L , Vogel Jacob W , Robinson John L , McMillan Corey T , Ossenkoppele Rik , Wolk David A. , Irwin David J. , Elman Lauren , Grossman Murray , Lee Virginia M-Y , Lee Edward B , Hansson Oskar 
Published: February 2023

AbstractTAR DNA-binding protein-43 (TDP-43) accumulation is the primary pathology underlying several neurodegenerative diseases. Charting the progression and heterogeneity of TDP-43 accumulation is necessary to better characterise TDP-43 proteinopathies, but current TDP-43 staging systems are heuristic and assume each syndrome is homogeneous. Here, we use data-driven disease progression modelling to derive a fine-grained empirical staging system for the classification and differentiation of frontotemporal lobar degeneration due to TDP-43 (FTLD-TDP, n=126), amyotrophic lateral sclerosis (ALS, n=141) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) with and without Alzheimer’s disease (n=304). The data-driven staging of ALS and FTLD-TDP complement and extend previously described human-defined staging schema for ALS and behavioural variant frontotemporal dementia. In LATE-NC individuals, progression along data-driven stages was positively associated with age, but negatively associated with age in individuals with FTLD-TDP. Using only regional TDP-43 severity, our data driven model distinguished individuals diagnosed with ALS, FTLD-TDP or LATE-NC with a cross-validated accuracy of 85.9%, with misclassifications associated with mixed pathological diagnosis, age and genetic mutations. Adding age and SuStaIn stage to this model increased accuracy to 92.3%. Our model differentiates LATE-NC from FTLD-TDP, though some overlap was observed between late-stage LATE-NC and early-stage FTLD-TDP. We further tested for the presence of subtypes with distinct regional TDP-43 progression patterns within each diagnostic group, identifying two distinct cortical-predominant and brainstem-predominant subtypes within FTLD-TDP and a further two subcortical-predominant and corticolimbic-predominant subtypes within ALS. The FTLD-TDP subtypes exhibited differing proportions of TDP-43 type, while there was a trend for age differing between ALS subtypes. Interestingly, a negative relationship between age and SuStaIn stage was seen in the brainstem/subcortical-predominant subtype of each proteinopathy. No subtypes were observed for the LATE-NC group, despite aggregating AD+ and AD-individuals and a larger sample size for this group. Overall, we provide an empirical pathological TDP-43 staging system for ALS, FTLD-TDP and LATE-NC, which yielded accurate classification. We further demonstrate that there is substantial heterogeneity amongst ALS and FTLD-TDP progression patterns that warrants further investigation in larger cross-cohort studies.
Mosquito repellent efficacy of Australian Blue CypressCallitris intratropicaessential oil and its topical formulation under laboratory and field conditions
Authors: Koinari Melanie , Amos Brogan , Townsend Michael , Karl Stephan 
Published: February 2023

AbstractMosquito repellents are important for personal protection against nuisance and potentially infectious mosquito bites. Repellent activity of Australian Blue Cypress (ABC) essential oil and a commercially formulated skin lotion containing ABC oil were compared with 20% DEET (N, N-diethyl-3methylbenzamide) and evaluated against mosquitoes under laboratory and field conditions in North Queensland, Australia. Using the arm-in-cage method, the following cumulative doses of ABC oil in ethanol were tested; 0.5%, 1.5%, 3%, 5%, 7.5% and 10.5% against femaleAedes aegypti. In the field, 2.5%, 5% and 10% of diluted ethanolic ABC oil were tested using the human landing catch method. We observed a dose-dependent increase in protection with diluted ABC oil approaching 80% at high concentrations. While some protection was afforded, mosquito landing and probing was still recorded immediately after application (laboratory) for both ABC essential oil and skin lotion. Protection declined from 80 – 70% and 93 – 50% for 20% ABC oil (laboratory) and 10% ABC oil (highest dose, field), respectively. For the formulated product, protection declined from 85 – 75% in the laboratory and from 63 – 50% in the field. To conclude, both ABC essential oil and the formulated skin lotion provided moderate protection against mosquito bites, which decreased soon after application.
Simvastatin therapy in different subtypes of hypercholesterolemia – a physiologically based modelling approach
Authors: Bartsch Florian , Grzegorzewski Jan , Pujol Helena Leal , Tautenhahn Hans-Michael , König Matthias 
Published: February 2023

ABSTRACTHypercholesterolemia is a multifaceted plasma lipid disorder with heterogeneous causes including lifestyle and genetic factors. A key feature of hypercholesterolemia is elevated plasma levels of low-density lipoprotein cholesterol (LDL-C). Several genetic variants have been reported to be associated with hypercholesterolemia, known as familial hypercholesterolemia (FH). Important variants affect the LDL receptor (LDLR), which mediates the uptake of LDL-C from the plasma, apoliporotein B (APOB), which is involved in the binding of LDL-C to the LDLR, and proprotein convertase subtilisin/kexin type 9 (PCSK9), which modulates the degradation of the LDLR. A typical treatment for hypercholesterolemia is statin medication, with simvastatin being one of the most commonly prescribed statins. In this work, the LDL-C lowering therapy with simvastatin in hypercholesterolemia was investigated using a computational modeling approach. A physiologically based pharmacokinetic model of simvastatin integrated with a pharmacodynamic model of plasma LDL-C (PBPK/PD) was developed based on extensive data curation. A key component of the model is LDL-C turnover by the liver, consisting of: hepatic cholesterol synthesis with the key enzymes HMG-CoA reductase and HMG-CoA synthase; cholesterol export from the liver as VLDL-C; de novo synthesis of LDLR; transport of LDLR to the membrane; binding of LDL-C by LDLR via APOB; endocytosis of the LDLR-LDL-C complex; recycling of LDLR from the complex. The model was applied to study the effects of simvastatin therapy in hypercholesterolemia due to different causes in the LDLR pathway corresponding to different subtypes of hypercholesterolemia. Model predictions of LDL-C lowering therapy were validated with independent clinical data sets. Key findings are: (i) hepatic LDLR turnover is highly heterogeneous among FH classes; (ii) despite this heterogeneity, simvastatin therapy results in a consistent reduction in plasma LDL-C regardless of class; and (iii) simvastatin therapy shows a dose-dependent reduction in LDL-C. Our model suggests that the underlying cause of hypercholesterolemia does not influence simvastatin therapy. Furthermore, our model supports the treatment strategy of stepwise dose adjustment to achieve target LDL-C levels. Both the model and the database are freely available for reuse.
Structural basis for guide RNA selection by the RESC1-RESC2 complex
Authors: Dolce Luciano G. , Nesterenko Yevheniia , Walther Leon , Weis Félix , Kowalinski Eva 
Published: February 2023

AbstractKinetoplastid parasites, such as trypanosomes or leishmania, rely on RNA-templated RNA editing to mature mitochondrial cryptic pre-mRNAs into functional protein-coding transcripts. Processive pan-editing of multiple editing blocks within a single transcript is dependent on the 20-subunit RNA editing substrate binding complex (RESC) that serves as a platform to orchestrate the interactions between pre-mRNA, guide RNAs (gRNAs), the catalytic RNA editing complex (RECC), and a set of RNA helicases. Due to the lack of molecular structures and biochemical studies with purified components, neither the spacio-temporal interplay of these factors nor the selection mechanism for the different RNA components is understood. Here we report the cryo-EM structure ofTrypanosoma bruceiRESC1-RESC2, a central hub module of the RESC complex. The structure reveals that RESC1 and RESC2 form an obligatory domain-swapped dimer. Although the tertiary structures of both subunits closely resemble each other, only RESC2 selectively binds 5’-triphosphate-nucleosides, a defining characteristic of gRNAs. We therefore propose RESC2 as the protective 5’-end binding site for gRNAs within the RESC complex. Overall, our structure provides a starting point for the study of the assembly and function of larger RNA-bound kinetoplast RNA editing modules and might aid in the design of anti-parasite drugs.Key findingsThe kinetoplastid mitochondrial RNA editing factors RESC1 and RESC2 resemble a group of capping enzymes that are only found in protozoans, fungi and viruses.RESC1 and RESC2 lack the typical catalytic residues, and only RESC2 can bind a triphosphate-nucleoside.We propose that the RESC1-RESC2 dimer selects guide RNAs based on their 5’-triphosphate and serves as a protective 5’-end binding complex.
Staphylococcus aureusfunctional amyloids catalyze degradation of β-lactam antibiotics
Authors: Arad Elad , Golan Nimrod , Rapaport Hanna , Landau Meytal , Jelinek Raz 
Published: February 2023

ABSTRACTAntibiotic resistance of bacteria is considered one of the most alarming developments in modern medicine. While varied pathways for bacteria acquiring antibiotic resistance have been identified, there still are open questions concerning the mechanisms underlying resistance. Here, we show that alpha phenol-soluble modulins (PSMα’s), functional bacterial amyloids secreted byStaphylococcus aureus, catalyze breakup of β-lactams, a prominent class of antibiotic compounds. Specifically, we show that PSMα2 and, particularly, PSMα3 catalyze hydrolysis of the amide-bond four-member ring of nitrocefin, a widely used β-lactam surrogate. Microscopic and spectroscopic analyses of several PSMα3 variants and correlation with their catalytic activities allowed mapping of the catalytic sites on the amyloid fibrils’ surface, specifically underscoring the key roles of the cross-α fibril organization, and the combined electrostatic and nucleophilic functions of the lysine residue array. This study unveils a previously unknown role of functional bacterial amyloids as catalytic agents for antibiotic compounds, pointing to possible mechanisms for antibiotic resistance of bacteria.ToC Graphical Abstract
Spermidine Is The Main Polyamine Required By Intracellular Parasites For Survival Within Host Erythrocytes
Authors: Singh Pallavi , Mamoun Choukri Ben 
Published: February 2023

AbstractIntracellular eukaryotic pathogens such asBabesiaandPlasmodium, the agents of human babesiosis and malaria, require salvage or de novo synthesis of several nutrients for survival in human erythrocytes. One such nutrient is putrescine, which is either transported from the host or synthesized from ornithine and serves as a precursor for the biosynthesis of two other polyamines: spermidine and spermine. However, the specific polyamines required by these parasites for survival and the molecular process they control remain unknown. We show in bothB. duncaniandP. falciparumthat spermidine is the main product of the polyamine biosynthesis machinery required for parasite survival. Simultaneous inhibition of spermidine synthesis from putrescine and catabolism from spermine results in cell death and parasite survival can only be rescued by spermidine. Finally, we demonstrate that spermidine’s essential function in these parasites is through regulation of protein translation via hypusination of the translation initiation factor eIF5A.
Quantification of gallium cryo-FIB milling damage in biological lamella
Authors: Lucas Bronwyn A. , Grigorieff Nikolaus 
Published: February 2023

AbstractCryogenic electron microscopy (cryo-EM) has the potential to reveal the molecular details of biological processes in their native, cellular environment at atomic resolution. However, few cells are sufficiently thin to permit imaging with cryo-EM. Thinning of frozen cells to <500 nm lamellae by cryogenic focused ion beam (FIB) milling has enabled visualization of cellular structures with cryo-EM. FIB-milling represents a significant advance over prior approaches because of its ease of use, scalability, and lack of large-scale sample distortions. However, the amount of damage caused by FIB-milling to the generated thin cell section has not yet been determined. We recently described a new approach for detecting and identifying single molecules in cryo-EM images of cells using 2D template matching (2DTM). 2DTM is sensitive to small differences between a molecular model (template) and the detected structure (target). Here we use 2DTM to demonstrate that under the standard conditions used for machining lamellae of biological samples, FIB-milling introduces a layer of variable damage that extends to a depth of 60 nm from each lamella surface. This thickness exceeds previous estimates and limits the recovery of information forin situstructural biology. We find that the mechanism of FIB-milling damage is distinct from radiation damage during cryo-EM imaging. By accounting for both electron scattering and FIB-milling damage, we find that FIB-milling damage will negate the potential improvements from lamella thinning beyond 90 nm.SignificanceThe molecular mechanisms of biological macromolecules and their assemblies is often studied using purified material. However, the composition, conformation and function of most macromolecules depend on their cellular context, and therefore, must also be studied inside cells. Focused ion beam (FIB) milling enables cryogenic electron microscopy to visualize macromolecules in cells at close to atomic resolution by generating thin sections of frozen cells. However, the extent of FIB-milling damage to frozen cells is unknown. Here we show that Ga+FIB-milling introduces damage to a depth of ∼60 nm from each lamella surface, leading to a loss of recoverable information of up to 20% in 100 nm samples. FIB-milling with Ga+therefore presents both an opportunity and an obstacle for structural cell biology.
Frequency variation and dose modification of benznidazole administration for the treatment ofTrypanosoma cruziinfection in mice, dogs and non-human primates
Authors: Bustamante Juan M. , White Brooke E. , Wilkerson Gregory K. , Hodo Carolyn L. , Auckland Lisa D. , Wang Wei , McCain Stephanie , Hamer Sarah A. , Saunders Ashley B. , Tarleton Rick L. 
Published: February 2023

AbstractTrypanosoma cruzinaturally infects a broad range of mammalian species and frequently results in the pathology that has been most extensively characterized in human Chagas disease. Currently employed treatment regimens fail to achieve parasitological cure ofT. cruziinfection in the majority of cases. In this study, we have extended our previous investigations of more effective, higher dose, intermittent administration protocols using the FDA-approved drug benznidazole (BNZ), in experimentally infected mice and in naturally infected dogs and non-human primates (NHP). Collectively these studies demonstrate that twice-weekly administration of BNZ for more than 4 months at doses that are ∼2.5-fold that of previously used daily dosing protocols, provided the best chance to obtain parasitological cure. Dosing less frequently or for shorter time periods was less dependable in all species. Prior treatment using an ineffective dosing regimen in NHPs did not prevent the attainment of parasitological cure with an intensified BNZ dosing protocol. Furthermore, parasites isolated after a failed BNZ treatment showed nearly identical susceptibility to BNZ as those obtained prior to treatment, confirming the low risk of induction of drug resistance with BNZ and the ability to adjust the treatment protocol when an initial regimen fails. These results provide guidance for the use of BNZ as an effective treatment forT. cruziinfection and encourage its wider use, minimally in high value dogs and at-risk NHP, but also potentially in humans, until better options are available.
Regulation of Bacterial Two-Component Systems by Cardiolipin
Authors: Yeo Won-Sik , Dyzenhaus Sophie , Torres Victor J , Brinsmade Shaun R , Bae Taeok 
Published: February 2023

AbstractThe composition of phospholipid membranes is critical to regulating the activity of membrane proteins for cellular functions. Cardiolipin is a unique phospholipid present within the bacterial membrane and mitochondria of eukaryotes and plays a role in maintaining the function and stabilization of membrane proteins. Here, we report that, in the human pathogen Staphylococcus aureus, cardiolipin is required for full activity of the SaeRS two-component system (TCS). Deletion of the cardiolipin synthase genes,cls1, andcls2, reduces the basal activity of SaeRS and other TCSs. Cardiolipin is an indispensable requisite for Sae activation mediated by human neutrophil peptides (HNPs) in the stationary growth phase but not mandatory for Sae induction in the exponential growth phase. Ectopic expression withcls2, but not withcls1, in thecls1 cls2double mutant fully restores Sae activity. Elimination of cardiolipin from the membranes results in decreased kinase activity of the sensor protein SaeS. Purified SaeS protein directly binds to cardiolipin as well as phosphatidylglycerol. A strain lackingcls2orcls1cls2rendersS. aureusless cytotoxic to human neutrophils and less virulent in a mouse model of infection. Our findings suggest that cardiolipin enables a pathogen to confer virulence by modulating the kinase activity of SaeS and other sensor kinases upon infection.
Sexually transmitted infection knowledge levels, socio-demographic characteristics and sexual behaviour among men who have sex with men: results from a cross-sectional survey in Nairobi, Kenya
Authors: Nyasani Delvin Kwamboka , Onyambu Meshack , Lunani Laura Lusike , Oino Geoffrey Ombati , Mutua Gaundensia Nzembi , Price Matt , Osero Justus.O. 
Published: February 2023

AbstractBackgroundHigh rates of sexually transmitted infections (STIs) among men who have sex with men (MSM) have been reported, there is little research on their STI knowledge. Our study sought to characterize knowledge and awareness of STIs among MSM in Nairobi, Kenya.MethodsWe mobilized MSM aged ≥18 years from Nairobi into a cross-sectional study. To determine their understanding about STIs, a pre-tested structured questionnaire was administered. Knowledge score was generated by summing up the number of responses answered correctly by a participant. We dichotomized scores as “low” and “high”, by splitting the group at <12 and ≥12 which was the mean.ResultsA total of 404 participants were interviewed between the month of March and August 2020. The mean age was 25.2 (SD=6.4) years. Majority were single (80.4%) and Christians (84.2%). All participants had some formal education ranging from primary to tertiary; the majority (92.3%) had secondary education or more. Most (64.0%) were employed and their monthly income ranged from <50->150 USD. Almost all (98.5%) were Kenyans.Of the 404 (90.6%) self-identified as male and (47.5%) reported to be exclusively top partners. Many (39.9%) reported being both bottom and top, while those reporting to be bottom partners were, (12.6%). The last 12 months, (55.4%) of the participants reported having sex with men only and (88.6%) reported to have had more than one sexual partner.Participants scored an average of 12.2, out of 29 SD 4.5. The multivariable modelling revealed that participants aged ≥25 years were more likely to have a higher knowledge score compared with the participants aged 18-24 years (aOR=0.973, CI: 0.616-1.538). Regarding education and occupation, participants who had tertiary education and those who were employed were more likely to have a higher knowledge score compared with the participants who had primary education and were not employed (aOR=2.627, CI:1.142-6.043) (aOR=0.922, CI:0.401-2.117). Participants who were earning (USD >150) were more likely to have a higher knowledge score compared to the ones who were not earning (aOR=2.520, CI: 0.900-7.055). Further bisexual men were more likely to have a higher knowledge score compared with the participants who were having sex with men only (aOR= 1.550, CI: 1026-2.342)ConclusionParticipant’s knowledge level regarding STIs was low. We recommend health care workers to continue educating patients about STIs.