bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic improvement and liver regeneration by inhibiting CXXC5 function for non-alcoholic steatohepatitis treatment
Authors: Seo Seol Hwa , Kim Eunhwan , Yoon Minguen , Lee Soung-Hoon , Park Byung-Hyun , Choi Kang-Yell
Published: September 2022

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease that results from multiple metabolic disorders. Considering the complexity of the pathogenesis, the identification of a factor mediating the multiple pathogenic phenotypes of NASH will be important for treatment. In this study, we found that CXXC5, a negative feedback regulator of the Wnt/β-catenin pathway, was overexpressed with suppression of Wnt/β-catenin signaling and its target genes involved in hepatic metabolism in obese-NASH patients. Cxxc5−/− mice were found to be resistant to NASH pathogenesis with metabolic improvements. KY19334, a small molecule that activates the Wnt/β-catenin pathway via interference of the CXXC5-Dvl interaction, reversed the overall pathogenic features of NASH as Cxxc5−/− mice. The improvement in NASH by KY19334 is attributed to its regenerative effects through restorative activation of the suppressed Wnt/β-catenin signaling. Overall, the pronounced metabolic improvements with the stimulation of liver regeneration by interfering with the CXXC5-Dvl interaction provide a therapeutic approach for NASH.
Leveraging interindividual variability of regulatory activity for refining genetic regulation of gene expression in schizophrenia
Authors: Alver Maris , Lykoskoufis Nikolaos , Ramisch Anna , Dermitzakis Emmanouil T. , Ongen Halit
Published: September 2022

Schizophrenia is a polygenic psychiatric disorder with limited understanding about the mechanistic changes in gene expression regulation. To elucidate on this, we integrate interindividual variability of regulatory activity (ChIP-sequencing for H3K27ac histone mark) with gene expression and genotype data captured from the prefrontal cortex of 272 cases and controls. By measuring interindividual correlation among proximal chromatin peaks, we show that regulatory element activity is structured into 10,936 and 10,376 cis-regulatory domains in cases and controls, respectively. The schizophrenia-specific cis-regulatory domains are enriched for fetal-specific (p = 0.0014, OR = 1.52) and depleted of adult-specific regulatory activity (p = 3.04 × 10−50, OR = 0.57) and are enriched for SCZ heritability (p = 0.001). By studying the interplay among genetic variants, gene expression, and cis-regulatory domains, we ascertain that changes in coordinated regulatory activity tag alterations in gene expression levels (p = 3.43 × 10−5, OR = 1.65), unveil case-specific QTL effects, and identify regulatory machinery changes for genes affecting synaptic function and dendritic spine morphology in schizophrenia. Altogether, we show that accounting for coordinated regulatory activity provides a novel mechanistic approach to reduce the search space for unveiling genetically perturbed regulation of gene expression in schizophrenia.
Difficulties capturing co-occurring traumatic brain injury among people with traumatic spinal cord injury: a population-based study
Authors: Snell Deborah L. , Johns Julianne , Dunn Jennifer A. , Nunnerley Joanne L. , Singhal Balraj
Published: September 2022

Abstract

Study design

This is a population-based prospective cohort study.

Objectives

Traumatic brain injury (TBI) is common among people with traumatic spinal cord injury (TSCI), but rates vary across studies associated with variable approaches to diagnosis. We aimed to determine if a published diagnostic algorithm could be consistently applied to capture co-occurring TBI among persons sustaining TSCI.

Setting

One of two spinal centres in New Zealand (NZ), the Burwood Spinal Unit (BSU) captures approximately 45% of NZ TSCI admissions.

Methods

Adults (age 16+) with TSCI admitted to the BSU between 1 January 2021 and 31 August 2021 (n = 51) were included. Clinical notes were audited prospectively to identify co-occurring TBI.

Results

We identified co-occurring TBI in 39% of TSCI cases with a small number of additional suspected TBI cases where TBI could not be confidently ruled in or out. Including all TBI cases, suspected or otherwise resulted in up to 55% of the sample having sustained co-occurring TBI. There were difficulties applying the published algorithm, associated with inconsistent documentation of TBI indicators from acute to rehabilitation contexts.

Conclusions

In this study, the feasibility of a TBI diagnostic algorithm for the TSCI population was low. Alternative approaches to screening for TBI among people sustaining TSCI are needed. Greater consistency in documenting TBI across the continuum of care will ensure TBI if present, is included in treatment planning.
Knock-out of 5-lipoxygenase in overexpressing tumor cells—consequences on gene expression and cellular function
Authors: Weisser Hannah , Göbel Tamara , Melissa Krishnathas G. , Kreiß Marius , Angioni Carlo , Sürün Duran , Thomas Dominique , Schmid Tobias , Häfner Ann-Kathrin , Kahnt Astrid S.
Published: September 2022

5-Lipoxygenase (5-LO), the central enzyme in the biosynthesis of leukotrienes, is frequently expressed in human solid malignancies even though the enzyme is not present in the corresponding healthy tissues. There is little knowledge on the consequences of this expression for the tumor cells regarding gene expression and cellular function. We established a knockout (KO) of 5-LO in different cancer cell lines (HCT-116, HT-29, U-2 OS) and studied the consequences on global gene expression using next generation sequencing. Furthermore, cell viability, proliferation, migration and multicellular tumor spheroid (MCTS) formation were studied in these cells. Our results show that 5-LO influences the gene expression and cancer cell function in a cell type-dependent manner. The enzyme affected genes involved in cell adhesion, extracellular matrix formation, G protein signaling and cytoskeleton organization. Furthermore, absence of 5-LO elevated TGFβ2expression in HCT-116 cells while MCP-1, fractalkine and platelet-derived growth factor expression was attenuated in U-2 OS cells suggesting that tumor cell-derived 5-LO shapes the tumor microenvironment. In line with the gene expression data, KO of 5-LO had an impact on cell proliferation, motility and MCTS formation. Interestingly, pharmacological inhibition of 5-LO only partly mimicked the KO suggesting that also noncanonical functions are involved.
Structural impact of arrested foveal development in children born extremely preterm without ROP at 6.5 years of age
Authors: Venkataraman Abinaya Priya , Popovic Zoran , Hellgren Kerstin , Sjöstrand Johan , Nilsson Maria
Published: September 2022

Objectives

To characterize changes of foveal topography and microstructure of persisting foveal immaturity at 6.5 years of age in children born extremely preterm without retinopathy of prematurity (EPT-NoROP).

Methods

Images from previous optical coherence tomography examinations of 37 EPT-NoROP and 92 control eyes were selected from a regional cohort of the EXPRESS (Extremely Preterm Infants in Sweden) study. Thickness of ganglion cell + inner plexiform layer (GCL+), outer nuclear layer (ONL), retinal thickness (RT) at the foveal centre (FC), foveal depth (FD) and RT at the foveal rim were evaluated.

Results

Layer thickness of GCL+, ONL and RT was increased at FC in the EPT-NoROP group. More than two-thirds had thickness values above the control limit (control mean +2 SD) at FC (GCL + 68%, ONL 76%, and RT 68%), and 50% had reduced FD compared to controls. All parameters showed a high correlation within the EPT-NoROP group, whereas no or weaker correlation was seen in control eyes. The EPT-NoROP sub-groups, divided based on the control limit, did not differ in terms of associated factors such as gestational age, birth weight, visual acuity, and refraction.

Conclusions

Extreme prematurity without impact of ROP is associated with increased GCL + , ONL, and RT thickness at FC as well as reduced FD compared to full-term controls at age 6.5. This indicates that prematurity per se may have a profound effect on foveal anatomical maturation during the first months after birth. Our results suggest RT at FC to be a simple and useful measure of foveal anatomical immaturity.
Electrostatic and steric effects underlie acetylation-induced changes in ubiquitin structure and function
Authors: Kienle Simon Maria , Schneider Tobias , Stuber Katrin , Globisch Christoph , Jansen Jasmin , Stengel Florian , Peter Christine , Marx Andreas , Kovermann Michael , Scheffner Martin
Published: September 2022

Covalent attachment of ubiquitin (Ub) to proteins is a highly versatile posttranslational modification. Moreover, Ub is not only a modifier but itself is modified by phosphorylation and lysine acetylation. However, the functional consequences of Ub acetylation are poorly understood. By generation and comprehensive characterization of all seven possible mono-acetylated Ub variants, we show that each acetylation site has a particular impact on Ub structure. This is reflected in selective usage of the acetylated variants by different E3 ligases and overlapping but distinct interactomes, linking different acetylated variants to different cellular pathways. Notably, not only electrostatic but also steric effects contribute to acetylation-induced changes in Ub structure and, thus, function. Finally, we provide evidence that p300 acts as a position-specific Ub acetyltransferase and HDAC6 as a general Ub deacetylase. Our findings provide intimate insights into the structural and functional consequences of Ub acetylation and highlight the general importance of Ub acetylation.
Conserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer
Authors: Barger Carter J. , Suwala Abigail K. , Soczek Katarzyna M. , Wang Albert S. , Kim Min Y. , Hong Chibo , Doudna Jennifer A. , Chang Susan M. , Phillips Joanna J. , Solomon David A. , Costello Joseph F.
Published: September 2022

Mutations in the TERT promoter represent the genetic underpinnings of tumor cell immortality. Beyond the two most common point mutations, which selectively recruit the ETS factor GABP to activate TERT, the significance of other variants is unknown. In seven cancer types, we identify duplications of wildtype sequence within the core promoter region of TERT that have strikingly similar features including an ETS motif, the duplication length and insertion site. The duplications recruit a GABP tetramer by virtue of the native ETS motif and its precisely spaced duplicated counterpart, activate the promoter and are clonal in a TERT expressing multifocal glioblastoma. We conclude that recurrent TERT promoter duplications are functionally and mechanistically equivalent to the hotspot mutations that confer tumor cell immortality. The shared mechanism of these divergent somatic genetic alterations suggests a strong selective pressure for recruitment of the GABP tetramer to activate TERT.
A multi-adenylate cyclase regulator at the flagellar tip controls African trypanosome transmission
Authors: Bachmaier Sabine , Giacomelli Giacomo , Calvo-Alvarez Estefanía , Vieira Larissa Rezende , Van Den Abbeele Jan , Aristodemou Aris , Lorentzen Esben , Gould Matt K. , Brennand Ana , Dupuy Jean-William , Forné Ignasi , Imhof Axel , Bramkamp Marc , Salmon Didier , Rotureau Brice , Boshart Michael
Published: September 2022

Signaling from ciliary microdomains controls developmental processes in metazoans. Trypanosome transmission requires development and migration in the tsetse vector alimentary tract. Flagellar cAMP signaling has been linked to parasite social motility (SoMo) in vitro, yet uncovering control of directed migration in fly organs is challenging. Here we show that the composition of an adenylate cyclase (AC) complex in the flagellar tip microdomain is essential for tsetse salivary gland (SG) colonization and SoMo. Cyclic AMP response protein 3 (CARP3) binds and regulates multiple AC isoforms. CARP3 tip localization depends on the cytoskeletal protein FLAM8. Re-localization of CARP3 away from the tip microdomain is sufficient to abolish SoMo and fly SG colonization. Since intrinsic development is normal incarp3andflam8knock-out parasites, AC complex-mediated tip signaling specifically controls parasite migration and thereby transmission. Participation of several developmentally regulated receptor-type AC isoforms may indicate the complexity of the in vivo signals perceived.
Structures reveal a key mechanism of WAVE regulatory complex activation by Rac1 GTPase
Authors: Ding Bojian , Yang Sheng , Schaks Matthias , Liu Yijun , Brown Abbigale J. , Rottner Klemens , Chowdhury Saikat , Chen Baoyu
Published: September 2022

The Rho-family GTPase Rac1 activates the WAVE regulatory complex (WRC) to drive Arp2/3 complex-mediated actin polymerization in many essential processes. Rac1 binds to WRC at two distinct sites—the A and D sites. Precisely how Rac1 binds and how the binding triggers WRC activation remain unknown. Here we report WRC structures by itself, and when bound to single or double Rac1 molecules, at ~3 Å resolutions by cryogenic-electron microscopy. The structures reveal that Rac1 binds to the two sites by distinct mechanisms, and binding to the A site, but not the D site, drives WRC activation. Activation involves a series of unique conformational changes leading to the release of sequestered WCA (WH2-central-acidic) polypeptide, which stimulates the Arp2/3 complex to polymerize actin. Together with biochemical and cellular analyses, the structures provide a novel mechanistic understanding of how the Rac1-WRC-Arp2/3-actin signaling axis is regulated in diverse biological processes and diseases.
Interactions between the cortical midline structures and sensorimotor network track maladaptive self-beliefs in clinical high risk for psychosis
Authors: Cowan Henry R. , Damme Katherine S. F. , Mittal Vijay A.
Published: September 2022

Individuals at clinical high risk for psychosis (CHR) report a maladaptive self-concept—with more negative and less positive self-beliefs—linked to clinical symptoms and functional impairment. Alterations have also been reported in brain networks associated with intrinsic (cortical midline structures, CMS) and extrinsic (sensorimotor network, SMN) self-processing. Theoretical accounts of multiple levels of self-experience in schizophrenia suggest that interactions between these networks would be relevant for self-beliefs. This study tested whether self-beliefs related to resting-state functional connectivity within and between the CMS and SMN. Participants were 56 individuals meeting CHR criteria and 59 matched healthy community participants (HC). Pearson correlations examined potential mediators and outcomes. The CHR group reported more negative and less positive self-beliefs. Greater resting-state functional connectivity between the posterior CMS (posterior cingulate cortex) and the SMN was associated with less positive self-beliefs in CHR, but more positive self-beliefs in HC. Attenuated negative symptoms and poorer social functioning were associated with CMS-SMN connectivity (trend level after FDR-correction) and self-beliefs. Reduced connectivity between the left and right PCC was associated with lower positive self-beliefs in CHR, although this effect was specific to very low levels of positive self-beliefs. Left-right PCC connectivity did not correlate with outcomes. Dynamic interactions between intrinsic and extrinsic self-processing supported positive self-beliefs in typically developing youth while undermining positive self-beliefs in CHR youth. Implications are discussed for basic self-fragmentation, narrative self-related metacognition, and global belief updating. Interventions for self-processing may be beneficial in the CHR syndrome.
Incidence of and risk factors for severe neutropenia during treatment with the modified FOLFIRINOX therapy in patients with advanced pancreatic cancer
Authors: Irisawa Ai , Takeno Misaki , Watanabe Kazuo , Takahashi Hideaki , Mitsunaga Shuichi , Ikeda Masafumi
Published: September 2022

Although FOLFIRINOX (l-Leucovorin/5-FU/Irinotecan/Oxaliplatin) is established as one of the standard therapies for patients with metastatic pancreatic cancer, the modified FOLFIRINOX (mFOLFIRINOX) is often used in clinical practice to reduce the incidence of toxicities. Febrile neutropenia (FN) and severe neutropenia during FOLFIRINOX are especially frequently observed in Japanese patients. In this study, we evaluated the incidence of FN and severe neutropenia, and explored the risk factors for severe neutropenia in patients receiving treatment with mFOLFIRINOX. The data of patients who had received mFOLFIRINOX between December 2013 and December 2014 at the National Cancer Center Hospital East were reviewed retrospectively. We graded the neutropenia severity and defined ≥ Grade 3 neutropenia as severe neutropenia. Univariate and multivariate analysis were undertaken to evaluate the associations with risk of development of severe neutropenia. A total of 122 patients were enrolled in this study. Sixty two patients (51%) and 10 patients (8%) developed severe neutropenia and FN, respectively. Multivariate analysis identified a low baseline white blood cell count (odds ratio [OR], 14.50; 95% confidence interval (CI), 3.27–111.14; p = 0.002) and presence of heterozygosity for UGT1A1*28 or UGT1A1*6 polymorphism (OR, 2.84; 95% CI, 1.18–7.17; p = 0.023) as independent risk factors for severe neutropenia. The incidences of severe neutropenia and FN in patients receiving mFOLFIRINOX in our clinical practice were comparable to previous reports. The risk factors for severe neutropenia in patients receiving mFOLFIRINOX were a low baseline white blood cell count and presence of heterozygosity for UGT1A1*28 or UGT1A1*6 polymorphism.
Neurofilament light as a predictive biomarker of unresolved chemotherapy-induced peripheral neuropathy in subjects receiving paclitaxel and carboplatin
Authors: Burgess B. L. , Cho E. , Honigberg L.
Published: September 2022

Management of chemotherapy-induced peripheral neuropathy (CIPN) remains a significant challenge in the treatment of cancer. Risk mitigation for CIPN involves preemptive reduction of cumulative dose or reduction of dose intensity upon emergence of symptoms, despite the risk of reduced tumor efficacy. A predictive biomarker for dose-limiting CIPN could improve treatment outcomes by allowing providers to make informed decisions that balance both safety and efficacy. To identify a predictive biomarker of CIPN, markers of neurodegeneration neurofilament-light (NfL), glial fibrillary acidic protein (GFAP), tau and ubiquitin c-terminal hydrolase L1 (UCHL1) were assessed in serum of up to 88 subjects drawn 21 days following the first of 6 treatments with chemotherapeutics paclitaxel and carboplatin. Serum NfL and GFAP were increased with chemotherapy. Further, NfL change predicted subsequent onset of grade 2–3 CIPN during the remainder of the trial (mean treatment duration = 200 days) and trended toward stronger prediction of CIPN that remained unresolved at the end of the study. These results confirm previous reports that serum NfL is increased in CIPN and provide the first evidence that NfL can be used to identify subjects susceptible to dose-limiting paclitaxel and carboplatin induced CIPN prior to onset of symptoms.
Insight into the heat transfer of third-grade micropolar fluid over an exponentially stretched surface
Authors: Guedri Kamel , Ameer Ahammad N. , Nadeem Sohail , Tag-ElDin ElSayed M. , Awan Aziz Ullah , Yassen Mansour F.
Published: September 2022

Due to their unique microstructures, micropolar fluids have attracted enormous attention for their industrial applications, including convective heat and mass transfer polymer production and rigid and random cooling particles of metallic sheets. The thermodynamical demonstration is an integral asset for anticipating the ideal softening of heat transfer. This is because there is a decent connection between mathematical and scientific heat transfers through thermodynamic anticipated outcomes. A model is developed under the micropolar stream of a non-Newtonian (3rd grade) liquid in light of specific presumptions. Such a model is dealt with by summoning likeness answers for administering conditions. The acquired arrangement of nonlinear conditions is mathematically settled using the fourth-fifth order Runge-Kutta-Fehlberg strategy. The outcomes of recognized boundaries on liquid streams are investigated in subtleties through the sketched realistic images. Actual amounts like Nusselt number, Sherwood number, and skin-part coefficient are explored mathematically by tables. It is observed that the velocity distribution boosts for larger values of any of $$\alpha _1$$

α
1

, $$\beta$$
β
, and declines for larger $$\alpha _2$$

α
2

and Hartmann numbers. Furthermore, the temperature distribution $$\theta (\eta )$$

θ
(
η
)

shows direct behavior with the radiation parameter and Eckert number, while, opposite behavior with Pr, and K. Moreover, the concentration distribution shows diminishing behavior as we put the higher value of the Brownian motion number.
A machine learning COVID-19 mass screening based on symptoms and a simple olfactory test
Authors: Azeli Youcef , Fernández Alberto , Capriles Federico , Rojewski Wojciech , Lopez-Madrid Vanesa , Sabaté-Lissner David , Serrano Rosa Maria , Rey-Reñones Cristina , Civit Marta , Casellas Josefina , El Ouahabi-El Ouahabi Abdelghani , Foglia-Fernández Maria , Sarrá Salvador , Llobet Eduard
Published: September 2022

The early detection of symptoms and rapid testing are the basis of an efficient screening strategy to control COVID-19 transmission. The olfactory dysfunction is one of the most prevalent symptom and in many cases is the first symptom. This study aims to develop a machine learning COVID-19 predictive tool based on symptoms and a simple olfactory test, which consists of identifying the smell of an aromatized hydroalcoholic gel. A multi-centre population-based prospective study was carried out in the city of Reus (Catalonia, Spain). The study included consecutive patients undergoing a reverse transcriptase polymerase chain reaction test for presenting symptoms suggestive of COVID-19 or for being close contacts of a confirmed COVID-19 case. A total of 519 patients were included, 386 (74.4%) had at least one symptom and 133 (25.6%) were asymptomatic. A classification tree model including sex, age, relevant symptoms and the olfactory test results obtained a sensitivity of 0.97 (95% CI 0.91–0.99), a specificity of 0.39 (95% CI 0.34–0.44) and an AUC of 0.87 (95% CI 0.83–0.92). This shows that this machine learning predictive model is a promising mass screening for COVID-19.
Quantitative analysis of CRISPR/Cas9-mediated provirus deletion in blue egg layer chicken PGCs by digital PCR
Authors: Altgilbers Stefanie , Dierks Claudia , Klein Sabine , Weigend Steffen , Kues Wilfried A.
Published: September 2022

Primordial germ cells (PGCs), the precursors of sperm and oocytes, pass on the genetic material to the next generation. The previously established culture system of chicken PGCs holds many possibilities for functional genomics studies and the rapid introduction of desired traits. Here, we established a CRISPR/Cas9-mediated genome editing protocol for the genetic modification of PGCs derived from chickens with blue eggshell color. The sequence targeted in the present report is a provirus (EAV-HP) insertion in the 5’-flanking region of the SLCO1B3 gene on chromosome 1 in Araucana chickens, which is supposedly responsible for the blue eggshell color. We designed pairs of guide RNAs (gRNAs) targeting the entire 4.2 kb provirus region. Following transfection of PGCs with the gRNA, genomic DNA was isolated and analyzed by mismatch cleavage assay (T7EI). For absolute quantification of the targeting efficiencies in homozygous blue-allele bearing PGCs a digital PCR was established, which revealed deletion efficiencies of 29% when the wildtype Cas9 was used, and 69% when a high-fidelity Cas9 variant was employed. Subsequent single cell dilutions of edited PGCs yielded 14 cell clones with homozygous deletion of the provirus. A digital PCR assay proved the complete absence of this provirus in cell clones. Thus, we demonstrated the high efficiency of the CRISPR/Cas9 system in introducing a large provirus deletion in chicken PGCs. Our presented workflow is a cost-effective and rapid solution for screening the editing success in transfected PGCs.
Autoprocessing and oxyanion loop reorganization upon GC373 and nirmatrelvir binding of monomeric SARS-CoV-2 main protease catalytic domain
Authors: Nashed Nashaat T. , Kneller Daniel W. , Coates Leighton , Ghirlando Rodolfo , Aniana Annie , Kovalevsky Andrey , Louis John M.
Published: September 2022

The monomeric catalytic domain (residues 1–199) of SARS-CoV-2 main protease (MPro1-199) fused to 25 amino acids of its flanking nsp4 region mediates its autoprocessing at the nsp4-MPro1-199 junction. We report the catalytic activity and the dissociation constants of MPro1-199 and its analogs with the covalent inhibitors GC373 and nirmatrelvir (NMV), and the estimated monomer-dimer equilibrium constants of these complexes. Mass spectrometry indicates the presence of the accumulated adduct of NMV bound to MProWT and MPro1-199 and not of GC373. A room temperature crystal structure reveals a native-like fold of the catalytic domain with an unwound oxyanion loop (E state). In contrast, the structure of a covalent complex of the catalytic domain-GC373 or NMV shows an oxyanion loop conformation (E* state) resembling the full-length mature dimer. These results suggest that the E-E* equilibrium modulates autoprocessing of the main protease when converting from a monomeric polyprotein precursor to the mature dimer.
Mechanism of action of non-camptothecin inhibitor Genz-644282 in topoisomerase I inhibition
Authors: Nishida Masahiro , Terabayashi Takeshi , Matsuoka Shigeru , Okuma Tomoko , Adachi Sawako , Tomo Tadashi , Kawano Masanori , Tanaka Kazuhiro , Tsumura Hiroshi , Anai Hirofumi , Ishizaki Toshimasa , Nishida Yoshihiro , Hanada Katsuhiro
Published: September 2022

Topoisomerase I (TOP1) controls the topological state of DNA during DNA replication, and its dysfunction due to treatment with an inhibitor, such as camptothecin (CPT), causes replication arrest and cell death. Although CPT has excellent cytotoxicity, it has the disadvantage of instability under physiological conditions. Therefore, new types of TOP1 inhibitor have attracted particular attention. Here, we characterised the effect of a non-camptothecin inhibitor, Genz-644282 (Genz). First, we found that treatment with Genz showed cytotoxicity by introducing double-strand breaks (DSBs), which was suppressed by co-treatment with aphidicolin. Genz-induced DSB formation required the functions of TOP1. Next, we explored the advantages of Genz over CPT and found it was effective against CPT-resistant TOP1 carrying either N722S or N722A mutation. The effect of Genz was also confirmed at the cellular level using a CPT-resistant cell line carrying N722S mutation in theTOP1gene. Moreover, we found arginine residue 364 plays a crucial role for the binding of Genz. Because tyrosine residue 723 is the active centre for DNA cleavage and re-ligation by TOP1, asparagine residue 722 plays crucial roles in the accessibility of the drug. Here, we discuss the mechanism of action of Genz on TOP1 inhibition.
Differences between gridded population data impact measures of geographic access to healthcare in sub-Saharan Africa
Authors: Hierink Fleur , Boo Gianluca , Macharia Peter M. , Ouma Paul O. , Timoner Pablo , Levy Marc , Tschirhart Kevin , Leyk Stefan , Oliphant Nicholas , Tatem Andrew J. , Ray Nicolas
Published: September 2022

Background

Access to healthcare is imperative to health equity and well-being. Geographic access to healthcare can be modeled using spatial datasets on local context, together with the distribution of existing health facilities and populations. Several population datasets are currently available, but their impact on accessibility analyses is unknown. In this study, we model the geographic accessibility of public health facilities at 100-meter resolution in sub-Saharan Africa and evaluate six of the most popular gridded population datasets for their impact on coverage statistics at different administrative levels.

Methods

Travel time to nearest health facilities was calculated by overlaying health facility coordinates on top of a friction raster accounting for roads, landcover, and physical barriers. We then intersected six different gridded population datasets with our travel time estimates to determine accessibility coverages within various travel time thresholds (i.e., 30, 60, 90, 120, 150, and 180-min).

Results

Here we show that differences in accessibility coverage can exceed 70% at the sub-national level, based on a one-hour travel time threshold. The differences are most notable in large and sparsely populated administrative units and dramatically shape patterns of healthcare accessibility at national and sub-national levels.

Conclusions

The results of this study show how valuable and critical a comparative analysis between population datasets is for the derivation of coverage statistics that inform local policies and monitor global targets. Large differences exist between the datasets and the results underscore an essential source of uncertainty in accessibility analyses that should be systematically assessed.
Integrated multi-material portable 3D-printed platform for electrochemical detection of dopamine and glucose
Authors: Domingo-Roca Roger , Macdonald Alexander R. , Hannah Stuart , Corrigan Damion K.
Published: September 2022

Design and production of a one-step 3D-printed functional electrochemical biosensor for efficient detection of dopamine and glucose in low-volume samples (100 μL). Glucose detection via ruthenium-mediated amperometry provides results in 60 seconds.
Tetrad-binding ligands do not bind specifically to left-handed G-quadruplexes
Authors: Das Poulomi , Phan Anh Tuân
Published: September 2022

The characteristic T-capping feature of left-handed G-quadruplexes prevents specific binding of G4 ligands on the tetrads.
Visible light-assisted organocatalytic α-acyloxylation of ketones using carboxylic acids and N-halosuccinimides
Authors: Sakkani Nagaraju , Jha Dhiraj K. , Whatley Emily , Zhao John C.-G.
Published: September 2022

The α-acyloxylketone motif can be found in many important pharmaceuticals and biologically active natural products and their derivatives. Now we have realized a direct synthesis of α-acyloxylketones from ketones and readily available carboxylic acids using a photo-assisted organocatalytic reaction.
Low-voltage-hysteresis aluminum–sulfur battery with covalently functionalized mesoporous graphene
Authors: Chu Weiqin , He Shiman , Liu Shiqi , Zhang Xu , Li Shuaixia , Yu Haijun
Published: September 2022

A pyridyl-functionalized mesoporous graphene is developed to accommodate sulfur for Al-S batteries, which contributed to the lowest voltage hysteresis (∼0.43 V) and fast reaction kinetics of Al–S battery without catalyst.
Nitroisobenzofuranone, a small molecule inhibitor of multidrug-resistant Staphylococcus aureus, targets peptidoglycan biosynthesis
Authors: Rawat Viral , Tiwari Sona , Khanna Shweta , Gupta Umang , S. N. C. Sridhar , Yadav Dharmendra K. , Kaul Grace , Akhir Abdul , Saxena Deepanshi , Matheshwaran Saravanan , Chopra Sidharth , Allimuthu Dharmaraja
Published: September 2022

To target antimicrobial resistance, 4-nitroisobenzofuran-1(3H)-one (IITK2020), is presented as an exclusive inhibitor of S. aureus including drug-resistant S. aureus clinical strains, that prevents peptidoglycan biosynthesis.
Cobalt-catalyzed cross-coupling of Umpolung carbonyls with alkyl halides under mild conditions
Authors: Cheng Ruofei , de Ruiter Graham , Li Chao-Jun
Published: September 2022

A novel cobalt-catalyzed alkyl–alkyl cross-coupling reaction of hydrazone with alkyl halides under mild reaction conditions has been developed, where the use of a PNP-type pincer ligand is essential for catalysis. Both aldehyde and ketone hydrazones are compatible with this reaction.
Azide modification forming luminescent sp2 defects on single-walled carbon nanotubes for near-infrared defect photoluminescence
Authors: Hayashi Keita , Niidome Yoshiaki , Shiga Tamehito , Yu Boda , Nakagawa Yasuto , Janas Dawid , Fujigaya Tsuyohiko , Shiraki Tomohiro
Published: September 2022

Luminescent defects are successfully created by chemical modification of single-walled carbon nanotubes using azide compounds. The sp2 carbon type defect formation allows unique exciton and photoluminescence property generation.
Pressure and guest-mediated pore shape modification in a small pore MOF to 1200 bar
Authors: McMonagle Charles J. , Turner Gemma F. , Jones Isabelle , Allan David R. , Warren Mark R. , Kamenev Konstantin V. , Parsons Simon , Wright Paul A. , Moggach Stephen A.
Published: September 2022

Guest-mediated flexibility in the metal–organic framework, Sc2BDC3, is examined under moderate pressure in a sapphire capillary cell, revealing pore-shapes changes at much lower pressures than previously reported.
Design and assembly of AIE-active fluorescent organic nanoparticles for anti-counterfeiting fluorescent hydrogels and inks
Authors: Li Xia-fen , Zhou Wei , Liu Yi-chen , Hou Min , Feng Gai-li , Ji Yan-ming , Zhang Yuan , Xing Guo-wen
Published: September 2022

The preparation and applications of AIE-active nanoparticles based on self-assembly and nanoprecipitation strategies as hydrogels and an erasable fluorescent ink were successfully explored due to their unique amphiphilicity and photo-responsiveness.
A sulfur-containing two-dimensional covalent organic framework with electrocatalytic hydrogen evolution in alkaline medium
Authors: Ma Yunchao , Fu Yue , Han Yuhang , Li Jingyang , Jiang Wei , Lu Yang , Liu Chunbo , Che Guangbo , Hu Bo
Published: September 2022

In this work, we successfully synthesized metal-free 2D COF electrocatalysts with high hydrogen evolution performance in alkaline solution. The overpotential is 290 mV at 10 mA cm−2 with small Tafel slopes.
In-site coupling of NiFe layered double hydroxides with N-doped carbon nanosheets on carbon cloth as integrated cathode for rechargeable Zn–air batteries
Authors: Song Zhaohai , Li Zheng , Liu Yanqi , Chen Linlin , Zhang Jianmin , Zheng Zongmin
Published: September 2022

Exploring low-cost, high catalytic activity and high durability dual-function catalysts is critical for rechargeable Zn–air batteries to promote the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) processes.
Co-sintering process of LiCoO2 cathodes and NASICON-type LATP solid electrolytes studied by X-ray diffraction and X-ray absorption near edge structure
Authors: Ichihara Fumihiko , Miyoshi Shogo , Masuda Takuya
Published: September 2022

The composites of a high-capacity cathode material in lithium-ion batteries, LiCoO2 and an oxide-based solid electrolyte, Li1.3Al0.3Ti1.7(PO4)3 were sintered at various temperature and their reaction products were identified by XRD and XANES.
Strain-induced thermoelectricity in pentacene
Authors: Mondal Kallol , Ganguly Sudin , Maiti Santanu K.
Published: September 2022

The present work discusses a non-synthetic strategy to achieve a favorable thermoelectric response in pentacene via strain.
Triplet and singlet exciton diffusion in disordered rubrene films: implications for photon upconversion
Authors: Radiunas Edvinas , Dapkevičius Manvydas , Raišys Steponas , Kazlauskas Karolis
Published: September 2022

Triplet and singlet exciton diffusion plays a decisive role in triplet–triplet annihilation (TTA) and singlet fission processes of rubrene films at low excitation power, and thus has an important implication for TTA-mediated photon upconversion.
Cation–π aggregation-induced white emission of moisture-resistant carbon quantum dots: a comprehensive spectroscopic study
Authors: Ghasedi Arman , Koushki Ehsan , Baedi Javad
Published: September 2022

Controlling mechanisms involved in the aggregation of carbon quantum dots (CQDs) can lead to new application developments for these quantum dot materials.
Spin-hedgehog-derived electromagnetic effects in itinerant magnets
Authors: Paradezhenko G. V. , Pervishko A. A. , Swain N. , Sengupta P. , Yudin D.
Published: September 2022

We explore the effective spin model of a three-dimensional itinerant magnet with bilinear–biquadratic exchange interactions that supports a spin hedgehog lattice, highlighting its magneto-transport and magneto-optic properties.
Reinforced gel-state polybenzimidazole hydrogen separators for alkaline water electrolysis
Authors: Trisno Muhammad Luthfi Akbar , Dayan Asridin , Lee Su Ji , Egert Franz , Gerle Martina , Kraglund Mikkel Rykær , Jensen Jens Oluf , Aili David , Roznowska Aleksandra , Michalak Artur , Park Hyun S. , Razmjooei Fatemeh , Ansar Syed-Asif , Henkensmeier Dirk
Published: September 2022

Cheap, efficient water electrolysis with non-platinum catalysts is the key to a fossil fuel-free future. Highly conductive, mechanically strong separators are essential components.
Stable perovskite solar cells with 25.17% efficiency enabled by improving crystallization and passivating defects synergistically
Authors: Wu Yihui , Wang Qi , Chen Yuting , Qiu Wuke , Peng Qiang
Published: September 2022

Both improving crystallization and passivating the defects of a perovskite film have been realized by introducing 2-amidinopyrimidine hydrochloride, which resulted in an efficiency of 25.17% along with long-term operational stability.
CO2-responsive surfactants for switchable Pickering emulsions with a recyclable aqueous phase
Authors: Li Huaixin , Liu Yunshan , Jiang Jianzhong
Published: September 2022

CO2-responsive Pickering emulsions were prepared with a CO2-switchable surfactant (NCOONa) and alumina particles, in which the surfactant and alumina particles could be fully recycled and reused from aqueous phase after demulsification.
Microwave-assisted green synthesis ofDesmodium triquetrum-mediated silver nanoparticles: enhanced antibacterial, antibiofilm, and cytotoxicity activities against human breast cancer cell lines
Authors: Maryani Faiza , Septama Abdi Wira
Published: September 2022

A schematic illustration of green synthesis of silver nanoparticles usingDesmodium triquetrumextract, characterization, and their potential as antibacterial, antibiofilm, and cytotoxicity agent.
A novel type-II NiCo-LDH/CeO2 heterojunction for highly efficient photocatalytic H2 production
Authors: Xu Jing , Liu Xinyu , Hu LinYing , Li Zezhong , Ma Yue
Published: September 2022

The study of environmentally friendly semiconductor photocatalysts has important practical significance for efficient photocatalytic hydrogen evolution.
Mechanochemical synthesis of an AIE-TICT-ESIPT active orange-emissive chemodosimeter for selective detection of hydrogen peroxide in aqueous media and living cells, and solid-phase quantitation using a smartphone
Authors: Bhosle Akhil A. , Banerjee Mainak , Gupta Varsha , Ghosh Surajit , Bhasikuttan Achikanath C. , Chatterjee Amrita
Published: September 2022

We report herein the design and mechanochemical synthesis of a chemodosimeter, benzothiazole-derived unsymmetrical azine protected by 4-bromomethylphenylboronic acid (BTPAB), an orange aggregation-induced emission (AIE), for the selective detection of H2O2 in a turn-on manner.
High catalytic performance of nano-flowered Mg-doped NiCo layered double hydroxides for the oxygen evolution reaction
Authors: Hu Xiabing , Zhang Lidong , Li Shuyu , Chen Jiayan , Zhang Baoying , Zheng Zhiyuan , He Hongyu , Luo Shiping , Xie Aijuan
Published: September 2022

Layered double hydroxides (LDHs) are one of the ideal functional materials for the oxygen evolution reaction (OER) because of their special configuration and good electrochemical activity.
New antimicrobial materials with cerium ions in the composition of salts, solutions, and composite systems based on Ce3+(NO3)3 × 6H2O
Authors: Gainanova Asiya A. , Kuz’micheva Galina M. , Terekhova Raisa P. , Pashkin Igor I. , Trigub Alexander L. , Malysheva Natal’ya E. , Svetogorov Roman D. , Alimguzina Aliya R. , Koroleva Alexandra V.
Published: September 2022

The antimicrobial property against different bacteria with cerium oxide formation mainly depends on the content of Ce3+ ions.
Anomalous dewetting growth of Si on Ag(111)
Authors: Kawakami Naoya , Arafune Ryuichi , Minamitani Emi , Kawahara Kazuaki , Takagi Noriaki , Lin Chun-Liang
Published: September 2022

We demonstrate the novel growth of silicene grown on Ag(111) using STM and reveal the mechanism with KMC simulation.
Melt polycondensation of 2,5-tetrahydrofurandimethanol with various dicarboxylic acids towards a variety of biobased polyesters
Authors: Jin Chenhao , Liu Lipeng , Tu Zhu , Wang Bo , Wang Pei , Wei Zhiyong
Published: September 2022

The effects of THFDM's structure on its reactivity, polymer molecular chain energy and properties were systematically studied.
Visible-light-induced indole synthesis via intramolecular C–N bond formation: desulfonylative C(sp2)–H functionalization
Authors: Li Quanzhe , Gu Xintao , Wei Yin , Shi Min
Published: September 2022

LED visible-light-induced redox neutral desulfonylative C(sp2)–H functionalization for the synthesis of N-substituted indoles in the absence of any additional additive has been established on the basis of KIE, Hammett plotting and DFT calculations.
Emerging properties from mechanical tethering within a post-synthetically functionalised catenane scaffold
Authors: Hoyas Pérez Nadia , Sherin Peter S. , Posligua Victor , Greenfield Jake L. , Fuchter Matthew J. , Jelfs Kim E. , Kuimova Marina K. , Lewis James E. M.
Published: September 2022

Using a post-synthetic modification strategy we have prepared a series of functionalised [2]catenanes to study the impact of mechanically-enforced proximity on functional group properties, including emission, electrochemistry and photoreactivity.
Peimine ameliorates pulmonary fibrosis via the inhibition of M2-type macrophage polarization through the suppression of P38/Akt/STAT6 signals
Authors: Cai Ze-hui , Tian Yan-ge , Li Jun-zi , Zhao Peng , Li Jian-sheng , Mei Xue , Bai Yun-ping
Published: September 2022

Peimine, a bioactive substance isolated from Chinese medicine Fritillaria, can potentially suppress pulmonary fibrosis (PF); however, its therapeutic mechanism remains unclear. Recent evidence suggests the participation of M2-type macrophages in the pathogenesis of PF. The present study aimed to investigate the effect of peimine on a bleomycin (BLM)-induced PF rat model and the underlying mechanism of this effect. After BLM administration, peimine was administered to rats from day 29 to day 42, with pirfenidone (PFD) as a positive control. H&E and Masson’s trichrome stain were used to analyze histological changes. Q-PCR and western blotting were used to measure mRNA levels and protein levels, respectively. High-throughput RNA sequencing (RNA-seq) technology detected the differentially expressed genes (DEGs) regulated by peimine. Our results revealed that peimine treatment significantly ameliorated BLM-induced PF by suppressing histological changes and collagen deposition. In addition, peimine decreased the number of M2 macrophages and the expression of profibrotic factors. RNA-seq results showed that DEGs regulated by peimine in IL-4-induced macrophages were mainly associated with immune system processes, the PI3K/Akt pathway, and the MAPKs pathway. Then, immunofluorescence assay and western blot results demonstrated that peimine treatment suppressed the expression of p-p38 MAPK and p-Akt (s473) and also inhibited the nuclear translocation of p-STAT6. In conclusion, the present study demonstrated that peimine has a protective effect on PF through the suppression of M2 polarization of macrophages by inhibiting the STAT6, p38 MAPK, and Akt signals.
Redefining the catalytic HECT domain boundaries for the HECT E3 ubiquitin ligase family
Authors: Kane Emma I. , Beasley Steven A. , Schafer Johanna M. , Bohl Justine E. , Lee Young Sun , Rich Kayla J. , Bosia Elizabeth F. , Spratt Donald E.
Published: September 2022

There are 28 unique human members of the homologous to E6AP C-terminus (HECT) E3 ubiquitin ligase family. Each member of the HECT E3 ubiquitin ligases contains a conserved bilobal HECT domain of approximately 350 residues found near their C-termini that is responsible for their respective ubiquitylation activities. Recent studies have begun to elucidate specific roles that each HECT E3 ubiquitin ligase has in various cancers, age-induced neurodegeneration, and neurological disorders. New structural models have been recently released for some of the HECT E3 ubiquitin ligases, but many HECT domain structures have yet to be examined due to chronic insolubility and/or protein folding issues. Building on these recently published structural studies coupled with our in-house experiments discussed in the present study, we suggest that the addition of ∼50 conserved residues preceding the N-terminal to the current UniProt defined boundaries of the HECT domain are required for isolating soluble, stable, and active HECT domains. We show using in silico bioinformatic analyses coupled with secondary structural prediction software that this predicted N-terminal α-helix found in all 28 human HECT E3 ubiquitin ligases forms an obligate amphipathic α-helix that binds to a hydrophobic pocket found within the HECT N-terminal lobe. The present study brings forth the proposal to redefine the residue boundaries of the HECT domain to include this N-terminal extension that will likely be critical for future biochemical, structural, and therapeutic studies on the HECT E3 ubiquitin ligase family.
Propagation of Parkinson's disease by extracellular vesicle production and secretion
Authors: Shippey Laura E. , Campbell Susan G. , Hill Andrew F. , Smith David P.
Published: September 2022

Parkinson's disease (PD) is a common neurodegenerative condition affecting a significant number of individuals globally, resulting in the presentation of debilitating motor and non-motor symptoms, including bradykinesia, resting tremor, as well as mood and sleep disorders. The pathology of PD has been observed to spread through the central nervous system resulting in progressive brain degeneration and a poor prognosis. Aggregated forms of the protein α-synuclein, particularly intermediary aggregates, referred to as oligomers, or preformed fibrils, have been implicated as the causative agent in the degeneration of neuronal processes, including the dysfunction of axonal transport, mitochondrial activity, and ultimately cellular death. Extracellular vesicles (EVs) have been strongly implicated in the propagation of PD pathology. Current observations suggest that aggregated α-synuclein is transported between neurons via small EVs in a series of exocytosis and endocytosis cellular processes leading to the observed spread of neurotoxicity and cellular death. Despite some understanding of the role of EVs in neurodegeneration, the exact mechanism by which these lipidic particles participate in the progression of Parkinson's pathology is not entirely understood. Here we review the current understanding of the role of EVs in the propagation of PD and explore their potential as a therapeutic target.