bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep learning-based Drug discovery of Mac domain of SARS-CoV-2 (WT) Spike inhibitors: using experimental ACE2 Inhibition TR-FRET Assay Screening and Molecular Dynamic Simulations
Authors: Iqbal Saleem , Sheng-Xiang-Lin
Published: October 2022

SARS-CoV-2 exploits the homotrimer transmembrane Spike glycoproteins (S protein) during host cell invasion. Omicron, delta, and prototype SARS-CoV-2 receptor-binding domain show similar binding strength to hACE2 (Angiotensin-Converting Enzyme 2). Here we utilized multi-ligand virtual screening to identify small molecule inhibitors for their efficacy against SARS-CoV-2 virus using quantum Docking, pseudovirus ACE2 Inhibition TR-FRET Assay Screening, and Molecular Dynamic simulations (MDS). 350-thousand compounds were screened against the macrodomain of non-structural protein 3 of SARS-CoV-2. Using TR-FRET Assay, we filtered out two of 10 compounds that had no reported activity inin-vitroscreen against Spike S1: ACE2 binding assay. Percentage Inhibition at 30 µM was found to be 79% for “Compound F1877-0839” and 69% for “Compound F0470-0003”. This first of its kind study identified “FILLY” pocket in macrodomains. Our 200 ns MDS revealed stable binding poses of both leads. They can be used for further development of preclinical candidates.

Abstract Image

In Brief

Iqbal et al., described a deep learning guided drug discovery, efficacy against SARS-CoV-2 Spike inhibitors: using experimental pseudovirus ACE2 Inhibition TR-FRET Assay. Our molecular dynamic simulation results were next validated a posteriori against the corresponding experimental data of identified leads with 80 percent inhibition. Moreover, this study is first of kind to identify “FILLY” pocket in macrodomains.

Highlights

Experimental pseudovirus ACE2 Inhibition TR-FRET Assay and HTS lead to identification of two potential clinical leads.

Conformational Dynamics analysis reveal the structural stability of complexes throughout 200 ns molecular dynamic simulations.

Unveiling of the impact surface charge on the Variant of Concerns

Detection of conformational changes within ACE2/RBD complex

We identified the FILLY pocket in the SARS viruses.
Application of a multispecies probiotic reduces gastro-intestinal discomfort and induces microbial changes after colonoscopy
Authors: Labenz J. , Borkenstein D. P. , Heil F. J. , Madisch A. , Tappe U. , Schmidt H. , Terjung B. , Klymiuk I. , Horvath A. , Gross M. , Stadlbauer V.
Published: October 2022

Even after decades of research and pharmaceutical development, cancer is still one of the most common causes of death in the western population and the management of cancer will remain a major challenge of medical research. One of the most common types of cancer is colorectal cancer (CRC). Prevention by detection of early-stage precursors is the most reliable method to prevent CRC development. In dependence of age, familial predisposition, and other risk factors the preventative routine screening for CRC by colonoscopy should be performed at least twice in intervals of about ten years. Although colonoscopy is a life-saving clinical examination reducing both incidence and mortality of CRC significantly, it has still a bad reputation in the population as an uncomfortable procedure with unpleasant side effects lasting sometimes over days to weeks. These effects are most likely caused by the bowel preparation before colonoscopy, which is crucial for a successful colonoscopy with high quality. Beside pain, bleeding and other rare but severe complications of colonoscopy, cleaning of the intestinal mucosa alters the gut microbiome significantly and consistently. Abdominal pain, cramps, diarrhea, nausea, bloating, and constipation are common adverse events which can continue to affect patients for days or even weeks after the procedure. In this multicenter, placebo controlled, double blind clinical trial, we investigated the effect of an intervention with a multispecies probiotic formulation for 30 days on the adverse events due to bowel preparation. We show that the treatment of participants with the multispecies probiotic formulation decreases the number of days with constipation significantly, and reduced pain, bloating, diarrhea, and general discomfort. 16S based amplicon analyses reveal recovery of administered probiotic strains from stool samples and differences in alpha diversity dynamics with higher variability in the probiotic group compared to the placebo group. In conclusion, the probiotic ameliorates the side effects after colonoscopy and might be an important supplement to increase acceptance of this life-saving preventative examination. Further, we present here for the first time that probiotic intervention of only 30 days affects alpha diversity parameters in stool samples.
Isolation and characterization of a neoxanthin synthase gene functioning in fucoxanthin biosynthesis ofPhaeodactyum tricornutum
Authors: Sui J.K. , Zhang Z.Y. , Han J.C. , Yang G.P. , Liu T.Z. , Wang H.
Published: October 2022

Golden-brown xanthophyll fucoxanthin in marine organisms, especially in diatoms, has attracted widespread attention because of its diverse biological activities. However, the biosynthetic pathway of fucoxanthin remains unclear in diatoms. Fucoxanthin may derive from either neoxanthin or diadinoxanthin pathway. However, the key point is whether neoxanthin and its synthesizing genes exist or not. In this study, we successfully identified a few xanthophylls in trace amounts in the concentrated fraction of carotenoids of diatomPhaeodactylum tricornutumcultured at different light intensities with the co-chromatography method, and cloned the neoxanthin synthase (NXS) gene which was not annotated in diatom genome. TheNXSknockdown and knockout experiment show a positive correlation in the accumulation of neoxanthin and zeaxanthin while a negative correlation in violaxanthin and fucoxanthin with the expression ofNXS. In vitroassay evidenced that neoxanthin is the precursor for fucoxanthin biosynthesis, indicating that other molecules intermediate the conversion between violaxanthin and fucoxanthin. Overall, we cloned a novel gene functioning in neoxanthin biosynthesis, which should aid to clarifying the fucoxanthin biosynthetic pathway in diatom.
Role of Caveolin 1 in metabolic programming of fetal brain
Authors: Islam Maliha , Behura Susanta K
Published: October 2022

Caveolin-1 (Cav1) encodes a major protein of the lipid rafts, called caveolae, which are plasma membrane invaginations found in most cells of mammals.Cav1-null mice, at an early adult age, exhibit symptoms that are hallmarks of Alzheimer’s disease, and show brain aging similar to that of one and half year old wildtype mice. In the present study, integrative analysis of metabolomics, transcriptomics, epigenetics and single cell data was performed to test the hypothesis that metabolic deregulation of fetal brain due to lack ofCav1influenced brain aging in these mice. The results of this study show that lack ofCav1deregulated lipid and amino acid metabolism in the fetal brain. Genes associated with the deregulated metabolites were significantly altered in specific glial cells of the fetal brain, and epigenetically altered in a coordinated manner with specific genes of mouse epigenetic clock. The interaction between metabolic and epigenetic changes in the fetal brain altered gene expression of the brain at old age. Together, these results suggested that metabolic deregulation in the fetal life elicited an epigenetic memory that altered brain programming for aging inCav1-null mice.
Single Cell RNA Sequencing of the AdultDrosophilaEye Reveals Distinct Clusters and Novel Marker Genes for All Major Cell Types
Authors: Yeung Kelvin , Raja Komal Kumar Bollepogu , Shim Yoon-Kyung , Li Yumei , Chen Rui , Mardon Graeme
Published: October 2022

The adultDrosophilaeye is a powerful model system for phototransduction and neurodegeneration research. However, single cell resolution transcriptomic data are lacking for this tissue. We present single cell RNA-seq data on 1-day male and female, 3-day and 7-day old male adult eyes, covering early to mature adult eyes. All major cell types, including photoreceptors, cone and pigment cells in the adult eye were captured and identified. Our data sets identified novel cell type specific marker genes, some of which were validatedin vivo. R7 and R8 photoreceptors form clusters that reflect their specificRhodopsinexpression and the specificRhodopsinexpression by each R7 and R8 cluster is the major determinant to their clustering. The transcriptomic data presented in this report will facilitate a deeper mechanistic understanding of the adult fly eye as a model system.
Identifying cell culturing parameters that improve endocytic uptake of the HIV-TAT cell penetrating peptide
Authors: Diaz Joshua , Pellois Jean-Philippe
Published: October 2022

Delivery tools, including cell-penetrating peptides (CPPs) are often inefficient due to a combination of poor endocytosis and endosomal escape. Herein, the impact of cell culturing techniques on the endocytic uptake of a typical CPP, the TAT peptide (derived from HIV1-TAT), was quantified. Parameters previously found to generally modulate endocytosis such as cell density, washing steps, and cell aging did not affect TAT endocytosis. In contrast, cell dissociation methods, media, temperature, serum starvation, and media composition all contributed to changes in uptake. The combination of these parameters in worst versus best-uptake protocols, led to changes in uptake of more than 13-fold and indicated that small variations in cell culturing techniques have a cumulative effect on CPP uptake. More specifically, modulating cell culture protocols does not result in an increased amount of peptide inside endosomes, rather the number of TMR-TAT containing endosomes increases. Taken together this study highlights how technical aspects of cell culture protocols can be used to improve experimental reproducibility, as well as parameters that can be potentially exploited to improve CPP accumulation in endosomes, and hence increase the possibility of endosomal escape and cytosolic access.
Data-Dependent Acquisition with Precursor Coisolation Improves Proteome Coverage and Measurement Throughput for Label-Free Single-Cell Proteomics
Authors: Truong Thy , Johnston S. Madisyn , Webber Kei , Boekweg Hannah , Lindgren Caleb M , Liang Yiran , Nydeggar Alissia , Xie Xiaofeng , Payne Samuel H. , Kelly Ryan T.
Published: October 2022

The sensitivity of single-cell proteomics (SCP) has increased dramatically in recent years due to advances in experimental design, sample preparation, separations and mass spectrometry instrumentation. Further increasing the sensitivity of SCP methods and instrumentation will enable the study of proteins within single cells that are expressed at copy numbers too small to be measured by current methods. Here we combine efficient nanoPOTS sample preparation and ultra-low-flow liquid chromatography with a newly developed data acquisition and analysis scheme termed wide window acquisition (WWA) to quantify >3,000 proteins from single cells in fast label-free analyses. WWA is based on data-dependent acquisition (DDA) but employs larger precursor isolation windows to intentionally co-isolate and co-fragment additional precursors along with the selected precursor. The resulting chimeric MS2 spectra are then resolved using the CHIMERYS search engine within Proteome Discoverer 3.0. Compared to standard DDA workflows, WWA employing isolation windows of 8-12 Th increases peptide and proteome coverage by ~28% and ~39%, respectively. For a 40-min LC gradient operated at ~15 nL/min, we identified an average of 2,150 proteins per single-cell-sized aliquots of protein digest directly from MS2 spectra, which increased to an average of 3,524 proteins including proteins identified with MS1-level feature matching. Reducing the active gradient to 20 min resulted in a modest 10% decrease in proteome coverage. We also compared the performance of WWA with DIA. DIA underperformed WWA in terms of proteome coverage, especially with faster separations. Average proteome coverage for single HeLa and K562 cells was respectively 1,758 and 1,642 based on MS2 identifications with 1% false discovery rate and 3042 and 2891 with MS1 feature matching. As such, WWA combined with efficient sample preparation and rapid separations extends the depths of the proteome that can be studied at the single-cell level.
Long-term, super-resolution HIDE imaging of the inner mitochondrial membrane in live cells with a cell-permeant lipid probe
Authors: Zheng Shuai , Dadina Neville , Mozumdar Deepto , Lesiak Lauren , Martinez Kayli , Miller Evan W. , Schepartz Alanna
Published: October 2022

The densely packed inner mitochondrial membrane (IMM) is vital for bioenergy generation and its dynamics control mitochondrial health and cellular homeostasis. IMM structure is complex, however, and imaging its dynamics with high temporal and spatial resolution is complicated by the photosensitivity of IMM-resident enzymes. Here we describe the cell-permeant, lipid-like acridine orange derivative MAO-N3and use it to assemble high-density, environmentally sensitive (HIDE) probes that selectively label and image the IMM in live cells. MAO-N3pairs with multiple SPAAC-reactive fluorophores to support HIDE imagingviaconfocal, Structured Illumination, Single Molecule Localization, and Stimulated Emission Depletion microscopy, all with significantly improved resistance against photobleaching. The HIDE probes generated using MAO-N3require no genetic manipulations, are non-toxic in model cell lines and primary cardiomyocytes, even under conditions that amplify the effects of mitochondrial toxins, and visualize the IMM for up to 12.5 hours with unprecedented spatial and temporal resolution.
A new high temperature, high heating rate, low axial gradient capillary heater
Authors: Marshall Kenneth P. , Emerich Hermann , McMonagle Charles J. , Fuller Chloe A. , Dyadkin Vadim , Chernyshov Dmitry , van Beek Wouter
Published: October 2022

A new heater design, capable of fast heating and cooling to and from >1000°C, has been developed at the Swiss–Norwegian Beamlines, European Synchrotron Radiation Facility, France. The design uses a SiC head to distribute heat, and resistive Si3N4 heat cartridges to provide heat.
Does the presence of three or more female directors associate with corporate recognition?
Authors: Neuberger Madeline N. , Bernardi Richard A. , Bosco Susan M. , Landry Erynne E.
Published: October 2022

Purpose

The purpose of this study is to extend Landry et al.’s (2016) work and examines the possible association between corporations having three or more female directors and these companies being features on corporate recognition lists.

Design/methodology/approach

This study examines a sample of 335 corporations ranked as Fortune 500 corporations in the period 2013–2019. The authors test for the association between the percent of corporations that had three or more female directors and the percent of these corporations on external recognition lists.

Findings

The data indicate that the percent of corporations with three or more female directors more than doubled between 2013 and 2019; this change was accompanied by an increase in the percent of presence of these companies in corporate recognition lists. The percent of corporations that had three or more female directors was significantly associated with the percent of these corporations on external recognition lists.

Research limitations/implications

The first is the sample selection process; this study used only publicly traded corporations that were included in the Fortune 500 between 2013 through 2019. The second limitation is that this study did not include data on board members considered minorities.

Practical implications

The findings imply that there is a strong link between gender diversity on boards and being featured on corporate recognition lists, which means that firms who care about corporate social responsibility-related works, and more instrumentally, care about being on such lists should reconsider the gender balance on their boards.

Originality/value

This study extends this work for a time period in which the number of corporations with three or more female directors has significantly increased.
Two-step flash sintering of (Mg1/3Ta2/3)0.01Ti0.99O2 giant dielectric ceramics
Authors: Wang Zhentao , Peng Pai , Zhong Sujuan , Cheng Yafang , Xu Dong
Published: October 2022

Purpose

The purpose of this paper on the one hand is to reduce the sintering temperature, shorten the sintering time and improve the electrical properties of the sample through the two-step flash sintering method and on the other hand is to study the effect of electric field on the phase structure, microstructure and electrical properties of the flash sintering sample.

Design/methodology/approach

In this paper, (Mg1/3Ta2/3)0.01Ti0.99O2 giant dielectric ceramics were prepared by conventional sintering and two-step flash sintering, respectively. Further, the effect of electric field (600–750 V/cm) on the electrical properties of (Mg1/3Ta2/3)0.01Ti0.99O2 giant dielectric ceramics was studied.

Findings

The results show that compared with the conventional sintering, the sintering temperature of the two-step flash sintering can be reduced by 200°C and the sintering time can be shortened by 12 times. All sintered samples were single rutile TiO2 structure. Compared with conventional sintering, two-step flash sintering samples have finer grain size. The two-step flash sintered sample has similar dielectric properties to the conventional sintered sample. The dielectric constant of flash sintered samples decreases with the increase of electric field. When the electric field is 700 V/cm, the ceramic sample has the optimal dielectric properties, where the dielectric constant is approximately 5.5 × 103 and the dielectric loss is about 0.18 at 1 kHz. Impedance spectroscopy analysis shows that the excellent dielectric properties are attributed to the internal barrier layer capacitance model.

Originality/value

This paper not only provides a new method for the preparation of co-doped TiO2 giant dielectric ceramics but also has great potential in greatly improving efficiency and saving energy.
Demonstration of bacterium‐free very rapid reverse genetics system using mumps virus
Authors: Bae Chaewon , Katoh Hiroshi , Wakata Aika , Sakata Masafumi , Kato Fumihiro , Takeda Makoto
Published: October 2022

The reverse genetics system is a very powerful tool for analyzing the molecular mechanisms of viral propagation and pathogenesis. However, full‐length genome plasmid construction is highly time‐consuming and laborious, and undesired mutations may be introduced by Escherichia coli. This study shows a very rapid E. coli‐free method of full‐genome construction using the mumps virus as an example. This method was able to reduce dramatically the time for full‐genome construction, which was used very efficiently for virus rescue, from several days or more to ~2 days, with a similar accuracy and yield to the conventional method using E. coli/plasmid.
Smoking enhances the expression of angiotensin‐converting enzyme 2 involved in the efficiency of severe acute respiratory syndrome coronavirus 2 infection
Authors: Suzuki Rigel , Ono Yuki , Noshita Koji , Kim Kwang Su , Ito Hayato , Morioka Yuhei , Tamura Tomokazu , Okuzaki Daisuke , Tagawa Tetsuzo , Takenaka Tomoyoshi , Yoshizumi Tomoharu , Shimamura Teppei , Iwami Shingo , Fukuhara Takasuke
Published: October 2022

Smoking is one of the risk factors most closely related to the severity of coronavirus disease 2019 (COVID‐19). However, the relationship between smoking history and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infectivity is unknown. In this study, we evaluated the ACE2 expression level in the lungs of current smokers, ex‐smokers, and nonsmokers. The ACE2 expression level of ex‐smokers who smoked cigarettes until recently (cessation period shorter than 6 months) was higher than that of nonsmokers and ex‐smokers with a long history of nonsmoking (cessation period longer than 6 months). We also showed that the efficiency of SARS‐CoV‐2 infection was enhanced in a manner dependent on the angiotensin‐converting enzyme 2 (ACE2) expression level. Using RNA‐seq analysis on the lungs of smokers, we identified that the expression of inflammatory signaling genes was correlated with ACE2 expression. Notably, with increasing duration of smoking cessation among ex‐smokers, not only ACE2 expression level but also the expression levels of inflammatory signaling genes decreased. These results indicated that smoking enhances the expression levels of ACE2 and inflammatory signaling genes. Our data suggest that the efficiency of SARS‐CoV‐2 infection is enhanced by smoking‐mediated upregulation of ACE2 expression level.
Assessing the value of monitoring to biological inference and expected management performance for a European goose population
Authors: Johnson Fred A. , Madsen Jesper , Clausen Kevin K. , Frederiksen Morten , Jensen Gitte H.
Published: October 2022

Informed conservation and management of wildlife require sufficient monitoring to understand population dynamics and to direct conservation actions. Because resources available for monitoring are limited, conservation practitioners must strive to make monitoring as cost‐effective as possible.

Our focus was on assessing the value of monitoring to the adaptive harvest management (AHM) programme for pink‐footed geeseAnser brachyrhynchus. We conducted a retrospective analysis to assess the costs and benefits of a capture–mark–resight (CMR) programme, a productivity survey and biannual population censuses. Using all available data, we fit an integrated population model (IPM) and assumed that inference derived from it represented the benchmark against which reduced monitoring was to be judged. We then fit IPMs to reduced sets of monitoring data and compared their estimates of demographic parameters and expected management performance against the benchmark IPM.

Costs and the precision and accuracy of key demographic parameters decreased with the elimination of monitoring data. Eliminating the CMR programme, while maintaining other monitoring instruments, resulted in the greatest cost savings, usually with small effects on inferential reliability. Productivity surveys were also expensive and some reduction in survey effort may be warranted. The biannual censuses were inexpensive and generally increased inferential reliability.

The expected performance of AHM strategies was surprisingly robust to a loss of monitoring data. We attribute this result to explicit consideration of parametric uncertainty in harvest‐strategy optimization and the fact that a broad range of population sizes is acceptable to stakeholders.

Synthesis and applications. Our study suggests that existing or potential monitoring instruments for wildlife populations should be scrutinized as to their cost‐effectiveness for improving biological inference and management performance. Using Svalbard pink‐footed geese as a case study, we show that the loss of some existing monitoring instruments may not be as adverse as commonly assumed if data are jointly analysed in an IPM. Finally, regardless of the monitoring data available, we suggest that conservation strategies that explicitly account for uncertainty in demography are more likely to be successful than those that do not.
Endogenous timing, strategic tariff game and bilateral trade in vertical oligopoly
Authors: Chen Tai‐Liang , Kuang Ying
Published: October 2022

This paper builds an observable delay game in endogenous timing to study the possible occurrence of trade wars in a vertical, bilateral trade model. It examines the effects of production cost differences and order of moves on optimal tariffs, market equilibria, dumping margin and social welfare in both fixed timing and endogenous timing games. In a fixed timing game, it shows that price dumping in the intermediate good market arises from differences in country‐specific final good production costs. Different from Bernhofen (1995; Journal of International Economics), trade costs resulting from reciprocal tariffs in upstream markets can reverse the price dumping under certain conditions. In an endogenous timing game, this paper finds that the magnitude of cost differences significantly influences countries’ decisions on the order of moves in a strategic tariff‐making game. Both countries want to be the first movers under a small cost difference and consequently reach a simultaneous equilibrium result. This demonstrates that the second‐best equilibrium proceeds under certain conditions. Under a large cost difference, sequential policy‐making is the subgame perfect Nash equilibrium. If the cost difference is sufficiently large, both countries have an incentive to launch a trade war as a multiple equilibrium game.
The impact of topical NSAID treatment on selective laser trabeculoplasty efficacy
Authors: Dahlgren Tobias , Ayala Marcelo , Zetterberg Madeleine
Published: October 2022

Purpose

Selective laser trabeculoplasty (SLT) is a first‐line intervention for glaucoma, with the aim to reduce the intraocular pressure (IOP). Topical non‐steroidal anti‐inflammatory drugs (NSAIDs) are sometimes prescribed after SLT. However, it has been proposed that such treatment may either increase or reduce SLT efficacy. The purpose of this study was to investigate this further.

Methods

The study was a retrospective chart review, including 192 eyes of 192 patients, half of which received a course of NSAID eyedrops after SLT. Absolute and relative IOP reduction 3–12 weeks after SLT was compared. Furthermore, subgroup analyses, a multiple linear regression analysis, and a Kaplan–Meier survival analysis regarding time to treatment escalation were performed.

Results

The mean absolute IOP reduction was 4.3 ± 3.4 mmHg in the NSAID group and 5.4 ± 4.1 mmHg in the control group (p = 0.049). Relative IOP reduction was 17.5% ± 13.0% and 21.8% ± 14.8% in the NSAID and control groups, respectively (p = 0.033). The same tendency of superior results in control eyes compared with NSAID eyes was seen in an extensive subgroup analysis. A multiple linear regression analysis confirmed NSAID treatment as a negative predictor of IOP reduction after adjustment for covariates (p = 0.023). Survival analysis showed a longer median time to treatment escalation in the control group, though not statistically significant.

Conclusion

Topical NSAID treatment was not associated with an increased SLT efficacy. On the contrary, the present study is the first to demonstrate that SLT effectiveness may even be reduced by NSAIDs.
Real‐world experience among patients with relapsed/refractory mantle cell lymphoma after Bruton tyrosine kinase inhibitor failure in Europe: The SCHOLAR‐2 retrospective chart review study
Authors: Hess Georg , Dreyling Martin , Oberic Lucie , Gine Eva , Zinzani Pier Luigi , Linton Kim , Vilmar Adam , Jerkeman Mats , Chen Jenny M. H. , Ohler Anke , Stilgenbauer Stephan , Thieblemont Catherine , Lambert Jonathan , Zilioli Vittorio Ruggero , Sancho Juan‐Manuel , Jiménez‐Ubieto Ana , Fischer Luca , Eyre Toby A. , Keeping Sam , Park Julie E. , Wu James J. , Siddiqi Rubina , Reitan John , Wade Sally , Salles Gilles
Published: October 2022

Mantle cell lymphoma (MCL) after relapse is associated with poor prognosis. No standard of care exists and available evidence for treatments is limited, particularly in patients who fail Bruton tyrosine kinase inhibitor (BTKi) therapy. This multicentre retrospective chart review study, SCHOLAR‐2, addresses this knowledge gap and reports on data collected from 240 patients with relapsed/refractory MCL in Europe who were treated with BTKi‐based therapy between July 2012 and July 2018, and had experienced disease progression while on BTKi therapy or discontinued BTKi therapy due to intolerance. The median overall survival (OS) from initiation of first BTKi therapy was 14.6 months (95% confidence interval [CI] 11.6–20.0) in the overall cohort, 5.5 months (95% CI 3.9–8.2) in 91 patients without post‐BTKi therapy, and 23.8 months (95% CI 18.9–30.1) in 149 patients who received post‐BTKi therapy (excluding chimeric antigen receptor T‐cell treatment). In the latter group, patients received a median of one (range, one to seven) line of post‐BTKi therapy, with lenalidomide‐containing regimens and bendamustine plus rituximab being the most frequently administered; the median OS from initiation of first post‐BTKi therapy was 9.7 months (95% CI 6.3–12.7). These results provide a benchmark for survival in patients with R/R MCL receiving salvage therapy after BTKi failure.
Thulium fibre laser vs holmium: yttrium‐aluminium‐garnet laser lithotripsy for urolithiasis: meta‐analysis of clinical studies
Authors: Chua Michael E. , Bobrowski Adam , Ahmad Ihtisham , Kim Jin Kyu , Silangcruz Jan Michael , Rickard Mandy , Lorenzo Armando , Lee Jason Y.
Published: October 2022

Objective

To compare and assess the clinical outcomes between thulium fibre laser (TFL) and holmium: yttrium‐aluminium‐garnet (Ho:YAG) laser endoscopic lithotripsy of urolithiasis through a meta‐analysis of comparative clinical studies.

Methods

A systematic literature search was performed in May 2022, grey literature search in July 2022. Comparative clinical studies were evaluated according to Cochrane recommendations. Assessed outcomes include the stone‐free rate (SFR), complication rate, operative time (OT), laser utilisation time (LUT), ablation rate (stone volume/laser time), ablation efficiency (energy use/stone volume), total energy usage, degree of retropulsion, and hospital stay. Risk ratios (RRs) and standardised mean differences (SMDs) were extrapolated. Subgroup analyses, heterogeneity, publication bias, and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) assessment were performed. International Prospective Register of Systematic Reviews (PROSPERO) registration: CRD42022300788.

Results

A total of 15 studies with 1698 cases were included in this review. The outcome of SFR showed no significant between‐group difference (RR 1.09, 95% confidence interval [CI] 0.99–1.20). However, subgroup analysis of TFL vs Ho:YAG with no pulse modulation showed a SFR favouring TFL (RR 1.11, 95% CI 1.01–1.23). The composite postoperative complication rate was comparable between the two intervention groups (RR 0.97, 95% CI 0.66–1.43). OT, LUT and ablation rate were significantly better for TFL than Ho:YAG (SMD −1.19, 95% CI −1.85 to −0.52; SMD −1.67, 95% CI −2.62 to −0.72; SMD 0.59, 95% CI 0.15–1.03; respectively). The degree of retropulsion was significantly lower for TFL than Ho:YAG without pulse modulation (SMD −1.23, 95% CI −1.74 to −0.71). Ablation efficiency, total energy usage, and hospital stay were all comparable. Based on GRADE criteria, the evidence certainty was determined to be very low.

Conclusion

Overall, there was no between‐group difference for the SFR. However, compared to Ho:YAG with no pulse modulation, TFL rendered a better SFR. Shorter OT and LUT, a lesser degree of retropulsion, and a better ablation rate were noted in favour of the TFL. There was no overall between‐group difference for composite postoperative complication rate, ablation efficiency, total energy usage, and hospital stay. Currently, the available clinical evidence was assessed to be of very low certainty.
Do chimpanzees reason logically?
Authors: Engelmann Jan M. , Haux Lou M. , Völter Christoph , Schleihauf Hanna , Call Josep , Rakoczy Hannes , Herrmann Esther
Published: October 2022

Psychologists disagree about the development of logical concepts such as or and not. While some theorists argue that infants reason logically, others maintain that logical inference is contingent on linguistic abilities and emerges around age 4. In this Registered Report, we conducted five experiments on logical reasoning in chimpanzees. Subjects (N = 16; 10 females; M = 24 years) participated in the same setup that has been administered to children: the two‐, three‐, and four‐cup‐task. Chimpanzees performed above chance in the two‐cup‐, but not in the three‐cup‐task. Furthermore, chimpanzees selected the logically correct option more often in the test than the control condition of the four‐cup‐task. We discuss possible interpretations of these findings and conclude that our results are most consistent with non‐deductive accounts.
When phylogenetics met biogeography: Willi Hennig, Lars Brundin and the roots of phylogenetic and cladistic biogeography
Authors: Morrone Juan J.
Published: October 2022

Willi Hennig's (Beitr. Ent. 1960, 10, 15)Die Dipteren‐Fauna von Neuseeland als systematisches und tiergeographisches Problemapplied a phylogenetic approach to examine the distributional patterns exhibited by the Diptera of New Zealand. Hennig showed how phylogenetic trees may be used to infer dispersal, based on the progression and deviation rules, and also discussed the existence of vicariance patterns. The most important author who applied Hennig's phylogenetic biogeography was Lars Brundin, when analysing the phylogenetic relationships of two taxa of Chironomidae (Diptera) and using them to examine the biogeographic relationships of Australia, New Zealand, South America and South Africa. The relevance of Brundin's contribution was noted by several authors, as it began the cladistic or vicariance approach to biogeography, that implies the discovery of vicariance events shared by different monophyletic groups. Both phylogenetic and cladistic biogeography have a place in contemporary biogeography, the former for analysing taxon biogeography and the latter when addressing Earth or biota biogeography. The recent use of the term “phylogenetic biogeography” to refer toa posteriorimethods of cladistic biogeography is erroneous and should be avoided.
Prediction of in‐hospital hypokalemia using machine learning and first hospitalization day records in patients with traumatic brain injury
Authors: Zhou Zhengyu , Huang Chiungwei , Fu Pengfei , Huang Hong , Zhang Qi , Wu Xuehai , Yu Qiong , Sun Yirui
Published: October 2022

Aims

Hypokalemia is a common complication following traumatic brain injury, which may complicate treatment and lead to unfavorable outcomes. Identifying patients at risk of hypokalemia on the first day of admission helps to implement prophylactic treatment, reduce complications, and improve prognosis.

Methods

This multicenter retrospective study was performed between January 2017 and December 2020 using the electronic medical records of patients admitted due to traumatic brain injury. A propensity score matching approach was adopted with a ratio of 1:1 to overcome overfitting and data imbalance during subgroup analyses. Five machine learning algorithms were applied to generate a best‐performed prediction model for in‐hospital hypokalemia. The internal fivefold cross‐validation and external validation were performed to demonstrate the interpretability and generalizability.

Results

A total of 4445 TBI patients were recruited for analysis and model generation. Hypokalemia occurred in 46.55% of recruited patients and the incidences of mild, moderate, and severe hypokalemia were 32.06%, 12.69%, and 1.80%, respectively. Hypokalemia was associated with increased mortality, while severe hypokalemia cast greater impacts. The logistic regression algorithm had the best performance in predicting decreased serum potassium and moderate‐to‐severe hypokalemia, with an AUC of 0.73 ± 0.011 and 0.74 ± 0.019, respectively. The prediction model was further verified using two external datasets, including our previous published data and the open‐assessed Medical Information Mart for Intensive Care database. Linearized calibration curves showed no statistical difference (p > 0.05) with perfect predictions.

Conclusions

The occurrence of hypokalemia following traumatic brain injury can be predicted by first hospitalization day records and machine learning algorithms. The logistic regression algorithm showed an optimal predicting performance verified by both internal and external validation.
Impact of induction therapy on cytomegalovirus infection and post‐transplant outcomes in pediatric heart transplant recipients receiving routine antiviral prophylaxis
Authors: Zang Suhua , Zhang Xin , Niu Jianli , Das Bibhuti B.
Published: October 2022

Objectives

Induction therapy has been increasingly used in pediatric heart transplantation. This study evaluated the impact of anti‐thymocyte globulin (ATG) versus basiliximab as induction therapy on post‐transplant cytomegalovirus (CMV) infection, rejection at 1 year, coronary allograft vasculopathy (CAV), and mortality in pediatric heart transplant recipients receiving antiviral prophylaxis.

Results

Of the 96 patients (age < 18 years) analyzed, 46 (47.9%) patients received basiliximab, and 50 (52.1%) received ATG. Median follow‐up was 3.0 (IQR, 1.7–4.9) years with 32.3% reporting CMV infection. The ATG group, as compared with the basiliximab group, had similar incidences of CMV infection (36% vs. 28.3%, p = .418), CMV viremia (22% vs. 19.6%, p = .769), and CMV‐positive tissue biopsy (30% vs. 22%, p = .486). The ATG group had lower incidences of rejection at 1 year (16% vs. 36.9%, p = .022) and CAV (4% vs. 23.9%, p = .006) with no difference in mortality (8% vs. 15.2%, p = .343), compared with the basiliximab group. Multivariate analysis showed that induction with ATG was associated with a lower risk of rejection at 1 year (OR, .31; 95% CI, .09–.94; p = .039) with no impact on the incidences of CMV infection (HR, 2.06; 95% CI, .54–7.89; p = .292), CAV (HR, .30; 95% CI, .04–2.58; p = .275), and mortality (HR, .39; 95% CI, .09–1.82; p = .233) compared to basiliximab induction.

Discussion and conclusions

In conclusion, induction with ATG was associated with reduction in risk of rejection at 1 year with no effects on CMV infection, CAV, and mortality in pediatric heart transplant recipients with universal antiviral prophylaxis compared with basiliximab induction therapy.
The safety and efficacy of low oral doses of cannabidiol: An evaluation of the evidence
Authors: Arnold Jonathon C. , McCartney Danielle , Suraev Anastasia , McGregor Iain S.
Published: October 2022

Global interest in the non‐intoxicating cannabis constituent, cannabidiol (CBD), is increasing with claims of therapeutic effects across a diversity of health conditions. At present, there is sufficient clinical trial evidence to support the use of high oral doses of CBD (e.g., 10–50 mg/kg) in treating intractable childhood epilepsies. However, a question remains as to whether “low‐dose” CBD products confer any therapeutic benefits. This is an important question to answer, as low‐dose CBD products are widely available in many countries, often as nutraceutical formulations. The present review therefore evaluated the efficacy and safety of low oral doses of CBD. The review includes interventional studies that measured the clinical efficacy in any health condition and/or safety and tolerability of oral CBD dosed at less than or equal to 400 mg per day in adult populations (i.e., ≥18 years of age). Studies were excluded if the product administered had a Δ9‐tetrahydrocannabinol content greater than 2.0%. Therapeutic benefits of CBD became more clearly evident at doses greater than or equal to 300 mg. Increased dosing from 60 to 400 mg/day did not appear to be associated with an increased frequency of adverse effects. At doses of 300–400 mg, there is evidence of efficacy with respect to reduced anxiety, as well as anti‐addiction effects in drug‐dependent individuals. More marginal and less consistent therapeutic effects on insomnia, neurological disorders, and chronic pain were also apparent. Larger more robust clinical trials are needed to confirm the therapeutic potential of lower (i.e., <300 mg/day) oral doses of CBD.
Quantification of changes in human islet G protein‐coupled receptor mRNA expression in obesity
Authors: Lyu Zekun , Zhao Min , Atanes Patricio , Persaud Shanta Jean
Published: October 2022

Background

G protein‐coupled receptors (GPCRs) play crucial roles in regulating islet function, with Gαs‐ and Gαq‐coupled receptors being linked to the stimulation of insulin secretion. We have quantified the mRNA expression of 384 non‐olfactory GPCRs in islets isolated from lean and obese organ donors to determine alterations in islet GPCR mRNA expression in obesity.

Methods

RT‐qPCR was used to quantify GPCR mRNAs relative to five reference genes (ACTB, GAPDH, PPIA, TBP, and TFRC) in human islets isolated from lean (BMI = 22.6 ± 0.5) and obese (BMI = 32.0 ± 0.8) donors.

Results

Overall, 197 and 256 GPCR mRNAs were detected above trace level in islets from lean and obese donors, respectively, with 191 GPCR mRNAs being common to the lean and obese groups. 40.9% (n = 157) and 27.1% (n = 104) of the mRNAs were expressed at trace level whilst 7.8% and 6.3% were absent in islets from lean and obese donors, respectively. Hundred and seventeen GPCR mRNAs were upregulated at least twofold in islets from obese donors, and there was >twofold downregulation of 21 GPCR mRNAs. Of particular interest, several receptors signalling via Gαs or Gαq showed significant mRNA upregulation in islets from obese donors (fold increase: PTH2R: 54.0 ± 14.6; MC2R: 34.3 ± 11.5; RXFP1: 8.5 ± 2.1; HTR2B: 6.0 ± 2.0; GPR110: 3.9 ± 1.2; PROKR2: 3.9 ± 0.7).

Conclusions

Under conditions of obesity, human islets showed significant alterations in mRNAs encoding numerous GPCRs. The increased expression of Gαs‐ and Gαq‐coupled receptors that have not previously been investigated in β‐cells opens up possibilities of novel therapeutic candidates that may lead to the potentiation of insulin secretion and/or β‐cell mass to regulate glucose homeostasis.
Non‐standard Employment and Rent‐sharing
Authors: Fukao Kyoji , Perugini Cristiano , Pompei Fabrizio
Published: October 2022

In this paper, we analyse how non‐standard (or non‐regular) employment affects the capacity of regular workers to appropriate rents. In this context, we first extend the theoretical framework of Estevão and Tevlin to account for the heterogeneity of labour (regular and non‐regular workers). The predictions of the model are then tested with detailed industry‐level data over four decades (1970–2012) for Japan, where, similar to the majority of advanced OECD countries, the role of standard employment has declined significantly. After controlling for worker characteristics (gender, age, education) and using an array of econometric approaches, our results indicate that in contexts characterized by a higher share of non‐regular employment, rent‐sharing by regular workers is lower. This might have contributed to the long‐run wage stagnation observed in Japan in recent decades.
Advanced Technologies and Worker Voice
Authors: Belloc Filippo , Burdin Gabriel , Landini Fabio
Published: October 2022

The interplay between labour institutions and firm‐level adoption of new technologies such as robotics and other advanced digital tools remains poorly understood. Using a cross‐sectional sample of more than 20,000 European establishments, we document a positive association between shop‐floor employee representation (ER) and utilization of emerging technologies. We explore mechanisms driving this correlation by exploiting rich information on the role played by ER in relation to well‐defined decision areas of management, such as work organization, dismissals, training and working time. In addition, we conduct a quantitative case study using a panel of Italian firms and exploiting size‐contingent policy rules governing the operation of ER bodies in the context of a local‐randomization regression discontinuity design. The analysis suggests a positive effect of ER on investments in advanced technologies around the firm size cut‐off, although results are sensitive to type of technology and specification choices. We also document positive effects on training and process innovation, and no evidence of changes in composition of employment. Our findings cast doubt on the idea that ER discourages technology adoption. Rather, ER seems to influence workplace practices that enhance the complementarity between labour and new advanced technologies.
Generic lamotrigine extended‐release tablets are bioequivalent to innovator drug in fully replicated crossover bioequivalence study
Authors: Fang Lanyan , Li Zhichuan , Kinjo Minori , Lomonaco Sara , Zheng Nan , Jiang Wenlei , Zhao Liang
Published: October 2022

Objective

Lamotrigine is a commonly prescribed antiepileptic drug. U.S. Food and Drug Administration (FDA)–funded clinical studies have demonstrated bioequivalence (BE) for generic lamotrigine immediate‐release (IR) products in epilepsy patients with generic substitution. To address the potential concerns about the risk of generic‐brand substitution of lamotrigine extended‐release (ER) products, considering the complexity of controlled release systems and pharmacokinetic variations associated with possible within‐subject variability (WSV), this prospective study assessed (1) BE of generic and brand lamotrigine ER products in a fully replicated BE study design in healthy subjects and (2) whether such fully replicated study design and WSV data can better support the approval of generic lamotrigine ER products.

Methods

This open‐label, single‐dose, two‐treatment, four‐period, two‐sequence, fully replicated crossover BE study compared generic lamotrigine ER tablet to brand Lamictal XR (200 mg) in 30 healthy subjects under fed conditions. Pharmacokinetics (PK) profiles were generated based on intensive blood sampling up to 144 h.

Results

The two products showed comparable peak plasma concentration (Cmax), area under the concentration‐time curve (AUC) from time zero to the last measurable time point (AUC0‐t) and AUC extrapolated to infinity (AUC0‐inf), whereas median time to Cmax(Tmax) values differed, that is, 10 h for generic and 22 h for brand products, respectively. WSVs for PK metrics were small (~8% of Cmaxand ~6% of AUC) and similar between these two products. PK simulation predicted equivalent PK measurements of both products at steady state and after brand‐to‐generic switch, except the first day upon switching. No serious adverse events were reported.

Significance

The generic lamotrigine ER tablet product demonstrates BE to the brand product in a fully replicated BE study design with healthy subjects, supporting the adequacy of the two‐way crossover study design to demonstrate BE and generic‐brand substitution of lamotrigine ER products.
Comparison of behavioural tendencies between “dangerous dogs” and other domestic dog breeds – Evolutionary context and practical implications
Authors: Hammond Alexa , Rowland Thomas , Mills Daniel S. , Pilot Małgorzata
Published: October 2022

Aggressive behaviour by dogs is a considerable social problem, but the ability to predict which individuals may have increased aggressive tendencies is very limited, restricting the development of efficient preventive measures. There is a common perception that certain breeds are more likely to exhibit aggressive behaviour, which has contributed to the introduction of breed‐specific legislation. The rationale for such legislation explicitly assumes high heritability of this trait while also implying relatively little variation within breeds; these assumptions are largely untested. We compared behavioural tendencies between 8 breeds that are subject to legislation in at least one country and 17 breeds that are not subject to legislation using two validated psychometric tools: the Dog Impulsivity Assessment Scale (DIAS), which scores elements of impulsivity, including a tendency for aggressive behaviour, and Positive and Negative Activation Scale (PANAS), which scores sensitivity to positive and negative stimuli (which may trigger aggressive responses). We found that the two groups of breeds do not differ significantly in the specific DIAS factor relating to aggressive behaviour, “Aggression Threshold and Response to Novelty”, or any other DIAS and PANAS factors. We found large variations in all behavioural tendencies measured by both psychometric scales within both groups and within each breed studied. Taken together, our findings indicate that breed alone is not a reliable predictor of individual behavioural tendencies, including those related to aggression, and therefore breed‐specific legislation is unlikely to be an effective instrument for reducing risk.