bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene Therapy Reforms Photoreceptor Structure and Restores Vision in NPHP5-associated Leber Congenital Amaurosis
Authors: Aguirre Gustavo D. , Cideciyan Artur V. , Dufour Valérie L. , García Ana Ripolles , Sudharsan Raghavi , Swider Malgorzata , Nikonov Roman , Iwabe Simone , Boye Sanford L. , Hauswirth William W. , Jacobson Samuel G. , Beltran William A.
Published: October 2020

The inherited childhood blindness caused by mutations in NPHP5, a form of Leber congenital amaurosis, results in abnormal development, dysfunction and degeneration of photoreceptors. A naturally occurring NPHP5 mutation in dogs results in a phenotype that very nearly duplicates the human retinopathy in terms of the photoreceptors involved, spatial distribution of degeneration and the natural history of vision loss. We show that AAV-mediated NPHP5 gene augmentation of mutant canine retinas at the time of active degeneration and peak cell death stably restores photoreceptor structure, function, and vision with either the canine or human NPHP5 transgenes. Mutant cone photoreceptors, which failed to form outer segments during development, reform this structure after treatment. Degenerating rod photoreceptor outer segments are stabilized and develop normal structure. This process begins within 8 weeks following treatment, and remains stable throughout the 6 month post treatment period. In both photoreceptor cell classes, mislocalization of rod and cone opsins is minimized or reversed. Retinal function and functional vision are restored. Efficacy of gene therapy in this large animal ciliopathy model of Leber congenital amaurosis provides a path for translation to human treatment.
Constraint-based modelling revealed changes in metabolic flux modes associated with the Kok effect
Authors: Ong Wei Qiang , Cheung C. Y. Maurice
Published: October 2020

Constraint-based modelling was applied to provide a mechanistic understanding of the possible metabolic origins of the ‘Kok effect’ – the change in quantum yield of net photosynthesis at low light intensity. The well-known change in quantum yield near the light-compensation point (LCP) was predicted as an emergent behaviour from a purely stoichiometric model. From our modelling results, we discovered another subtle change in quantum yield at a light intensity lower than the LCP. Our model predicted a series of changes in metabolic flux modes in central carbon metabolism associated with the changes in quantum yields. We demonstrated that the Kok effect can be explained by changes in metabolic flux modes between catabolism and photorespiration. Changes in RuBisCO carboxylation to oxygenation ratio resulted in a change in quantum yield at light intensities above the LCP, but not below the LCP, indicating the role of photorespiration in producing the Kok effect. Cellular energy demand was predicted to have no impact on the quantum yield. Our model showed that the Kok method vastly overestimates day respiration – the CO2released by non-photorespiratory processes in illuminated leaves. The theoretical maximum quantum yield at low light intensity was higher than typical measured values, suggesting that leaf metabolism at low light may not be regulated to optimise for energetic efficiency. Our model predictions gave insights into the set of energetically optimal changes in flux modes in low light as light intensity increases from darkness.

One sentence summary

The Kok effect can be explained by the changes in flux modes between catabolism and photorespiration.
Tumor-responsive, multifunctional CAR-NK cells cooperate with impaired autophagy to infiltrate and target glioblastoma
Authors: Wang Jiao , Toregrosa-Allen Sandra , Elzey Bennett D. , Utturkar Sagar , Lanman Nadia Atallah , Bernal-Crespo Victor , Behymer Matthew M. , Knipp Gregory T. , Yun Yeonhee , Veronesi Michael C. , Sinn Anthony L. , Pollok Karen E. , Brutkiewicz Randy R. , Nevel Kathryn S. , Matosevic Sandro
Published: October 2020

Tumor antigen heterogeneity, a severely immunosuppressive tumor microenvironment (TME) and lymphopenia resulting in inadequate immune intratumoral trafficking have rendered glioblastoma (GBM) highly resistant to therapy. As a result, GBM immunotherapies have failed to demonstrate sustained clinical improvements in patient overall survival (OS). To overcome these obstacles, here we describe a novel, sophisticated combinatorial platform for GBM: the first multifunctional immunotherapy based on genetically-engineered, human NK cells bearing multiple anti-tumor functions, including local tumor responsiveness, that addresses key drivers of GBM resistance to therapy: antigen escape, poor immune cell homing, and immunometabolic reprogramming of immune responses. We engineered dual-specific CAR-NK cells to bear a third functional moiety that is activated in the GBM TME and addresses immunometabolic suppression of NK cell function: a tumor-specific, locally-released antibody fragment which can inhibit the activity of CD73 independently of CAR signaling and decrease the local concentration of adenosine. The multifunctional human NK cells targeted patient-derived GBM xenografts, demonstrated local tumor site specific activity in the tissue and potently suppressed adenosine production. We also unveil a complex reorganization of the immunological profile of GBM induced by inhibiting autophagy. Pharmacologic impairment of the autophagic process not only sensitized GBM to antigenic targeting by NK cells, but promoted a chemotactic profile favorable to NK infiltration. Taken together, our study demonstrates a promising new NK cell-based combinatorial strategy that can target multiple clinically-recognized mechanisms of GBM progression simultaneously.
Action potential-coupled Rho GTPase signaling drives presynaptic plasticity
Authors: Dube Shataakshi , Rácz Bence , Brown Walter E. , Gao Yudong , Soderblom Erik J. , Yasuda Ryohei , Soderling Scott H.
Published: October 2020

In contrast to their postsynaptic counterparts, the contributions of activity-dependent cytoskeletal signaling to presynaptic plasticity remain controversial and poorly understood. To identify and evaluate these signaling pathways, we conducted a proteomic analysis of the presynaptic cytomatrix usingin vivobiotin identification (iBioID). The resultant proteome was heavily enriched for actin cytoskeleton regulators, including Rac1, a Rho GTPase that activates the Arp2/3 complex to nucleate branched actin filaments. Strikingly, we find Rac1 and Arp2/3 are closely associated with presynaptic vesicle membranes and negatively regulate synaptic vesicle replenishment at both excitatory and inhibitory synapses. Using optogenetics and fluorescence lifetime imaging, we show this pathway bidirectionally sculpts short-term synaptic depression and that its presynaptic activation is coupled to action potentials by voltage-gated calcium influx. Thus, this study provides a new proteomic framework for understanding presynaptic physiology and uncovers a previously unrecognized mechanism of actin-regulated short-term presynaptic plasticity that is conserved across cell types.
FARCI: Fast and Robust Connectome Inference
Authors: Meamardoost Saber , Bhattacharya Mahasweta , Hwang EunJung , Komiyama Takaki , Mewes Claudia , Wang Linbing , Zhang Ying , Gunawan Rudiyanto
Published: October 2020

The inference of neuronal connectome from large-scale neuronal activity recordings, such as two-photon Calcium imaging, represents an active area of research in computational neuroscience. In this work, we developed FARCI (Fast and Robust Connectome Inference), a MATLAB package for neuronal connectome inference from high-dimensional two-photon Calcium fluorescence data. We employed partial correlations as a measure of the functional association strength between pairs of neurons to reconstruct a neuronal connectome. We demonstrated using gold standard datasets from the Neural Connectomics Challenge (NCC) that FARCI provides an accurate connectome and its performance is robust to network sizes, missing neurons, and noise levels. Moreover, FARCI is computationally efficient and highly scalable to large networks. In comparison to the best performing algorithm in the NCC, FARCI produces more accurate networks over different network sizes and subsampling, while providing over two orders of magnitude faster computational speed.
EFFECT OF CONVALESCENT PLASMA ON MORTALITY IN PATIENTS WITH COVID-19 PNEUMONIA
Authors: Salazar Martín R. , González Soledad E. , Regairaz Lorena , Ferrando Noelia S. , González Martínez Veronica V. , Carrera Ramos Patricia M. , Muñoz Laura , Pesci Santiago A. , Vidal Juan M. , Kreplak Nicolas , Estenssoro Elisa
Published: October 2020

Background

Convalescent plasma, widely utilized in viral infections that induce neutralizing antibodies, has been proposed for COVID-19, and preliminary evidence shows that it might have beneficial effect. Our objective was to compare epidemiological characteristics and outcomes between patients who received convalescent plasma for COVID-19 and those who did not, admitted to hospitals in Buenos Aires Province, Argentina, throughout the pandemic.

Methods

This is a multicenter, retrospective cohort study of 2-month duration beginning on June 1, 2020, including unselected, consecutive adult patients with diagnosed COVID-19, admitted to 215 hospitals with pneumonia. Epidemiological and clinical variables were registered in the Provincial Hospital Bed Management System. Convalescent plasma was supplied as part of a centralized, expanded access program.

Results

We analyzed 3,529 patients with pneumonia, predominantly male, aged 62±17, with arterial hypertension and diabetes as main comorbidities; 51.4% were admitted to the ward, 27.1% to the Intensive Care Unit (ICU), and 21.7% to the ICU with mechanical ventilation requirement (ICU-MV). 28-day mortality was 34.9%; and was 26.3%, 30.1% and 61.4% for ward, ICU and ICU-MV patients. Convalescent plasma was administered to 868 patients (24.6%); their 28-day mortality was significantly lower (25.5% vs. 38.0%, p<0.001). No major adverse effects occurred.

Logistic regression analysis identified age, ICU admission with and without MV requirement, diabetes and preexistent cardiovascular disease as independent predictors of 28-day mortality, whereas convalescent plasma administration acted as a protective factor.

Conclusions

Our study suggests that the administration of convalescent plasma in COVID-19 pneumonia admitted to the hospital might be associated with decreased mortality.

Key Points

Preliminary evidence showed that convalescent plasma might be beneficial in COVID-19.

In a cohort of 3,529 patients with pneumonia due to COVID-19, convalescent plasma was administered to 868 patients, without major adverse effects.

Convalescent plasma was independently associated with decreased mortality.
Phosphoproteomics identifies PI3K inhibitor-selective adaptive responses in pancreatic cancer cell therapy and resistance
Authors: Cintas C , Douche T , Dantes Z , Mouton-Barbosa E , Bousquet MP , Cayron C , Therville N , Pont F , Ramos-Delgado F , Guyon C , Garmy-Susini B , Cappello P , Burlet-Schiltz O , Hirsch E , Gomez-Brouchet A , Thibault B , Reichert M , Guillermet-Guibert J
Published: October 2020

The PI3K pathway is highly active in human cancers. The four class I isoforms of PI3K are activated by distinct mechanisms leading to a common downstream signaling. Their downstream redundancy is thought to be responsible for treatment failures of PI3K inhibitors. We challenged this concept, by mapping the differential phosphoproteome evolution in response to PI3K inhibitors with different isoform selectivity patterns in pancreatic cancer, a disease currently without effective therapy. In this cancer, the PI3K signal was shown to control cell proliferation. We compared the effects of LY294002 that inhibit with equal potency all class I isoenzymes and downstream mTOR with the action of inhibitors with higher isoform-selectivity towards PI3Kα, PI3Kβ or PI3Kγ (namely A66, TGX-221 and AS-252424). A bioinformatics global pathway analysis of phosphoproteomics data allowed us to identify common and specific signals activated by PI3K inhibitors supported by the biological data. AS-252424 was the most effective treatment and induced apoptotic pathway activation as well as the highest changes in global phosphorylation-regulated cell signal. However, AS-252424 treatment induced re-activation of Akt, therefore decreasing the treatment outcome on cell survival. Reversely, AS-252424 and A66 combination treatment prevented p-Akt reactivation and led to synergistic action in cell lines and patient organoids. The combination of clinically approved α-selective BYL-719 with γ-selective IPI-549 was more efficient than single molecule treatment on xenograft growth. Mapping unique adaptive signaling responses to isoform-selective PI3K inhibition will help to design better combinative treatments that prevent the induction of selective compensatory signals.

Graphical abstract

Significance

Half of all human cancers show increased PI3K activity but the mutational pattern of the PI3K pathway is not sufficient to predict sensitivity to PI3K inhibitors. By identifying for the first time specific signaling induced by PI3K inhibitors with different isoform-selectivity patterns, we provide insight in how to handle heterogeneity of PI3K expression in tumor samples for the choice of available PI3K-targetting drugs. Our work provides a roadmap to target the PI3K pathway, balancing the use of isoform-selective PI3K inhibitors with personalized information extending beyond the specific mutational status.
Statistical validation verifies that enantiomorphic states of cell chirality are determinant dictating the left- or right-handed direction of the hindgut rotation inDrosophila
Authors: Ishibashi Tomoki , Inaki Mikiko , Matsuno Kenji
Published: October 2020

In the left-right (LR) asymmetric development of invertebrates, chirality of cells (cell chirality) plays crucial roles. Left- or right-handed structure of cells consequently directs the morphogenesis with corresponding LR asymmetry. InDrosophila, it has been suggested that cell chirality drives the LR-asymmetric development of various organs including the embryonic hindgut. However, this hypothesis is supported only by apparent concordance between these two events and by computer simulations connecting them[1–5]. Therefore, here, we mathematically evaluated the causal relationship between the cell chirality of the hindgut epithelial cells and the LR-directional rotation of the hindgut, which was previously postulated. Our logistic model obtained from various genetic backgrounds significantly explained the correlation between the enantiomorphic states of cell chirality and the LR directionality of hindgut rotation. This model also significantly explained the correlation between cell chirality stochastically formed in advance in each living embryo and the LR-directionality of the following rotation, suggesting the irrelevance of modes how cell chirality is formed. This analysis also showed that the cell chirality is not only sufficient but also required for the rotation. Considering the chronological order of these events, our study validated that cell chirality causally defines the LR asymmetry of the hindgut rotation.
DNAJB chaperones inhibit aggregation of destabilised proteins via a C-terminal region distinct from that used to prevent amyloid formation
Authors: McMahon Shannon , Bergink Steven , Kampinga Harm H. , Ecroyd Heath
Published: October 2020

Disturbances to protein homeostasis (proteostasis) can lead to protein aggregation and inclusion formation, processes associated with a variety of neurodegenerative disorders. DNAJBs are molecular chaperones previously identified as potent suppressors of disease-related protein aggregation. In this work, we over-expressed a destabilised isoform of firefly luciferase (R188Q/R261Q Fluc; FlucDM) in cells to assess the capacity of DNAJBs to inhibit inclusion formation. Co-expression of all DNAJBs tested significantly inhibited the intracellular aggregation of FlucDM. Moreover, we show that DNAJBs suppress aggregation by supporting the Hsp70-dependent degradation of FlucDMvia the proteasome. The serine-rich stretch in DNAJB6 and DNAJB8, essential for preventing fibrillar aggregation, is not involved in the suppression of FlucDMinclusion formation. Conversely, deletion of the C-terminal TTK-LKS region in DNAJB8, a region not required to suppress polyQ aggregation, abolished its ability to inhibit inclusion formation by FlucDM. Thus, our data suggest that DNAJB6 and DNAJB8 possess two distinct domains involved in the inhibition of protein aggregation, one responsible for binding to β-hairpins that form during amyloid formation and another that mediates the degradation of destabilised client proteins via the proteasome.

Summary statement

Specialised DNAJB molecular chaperones are potent suppressors of protein aggregation and interact with different types of client proteins via distinct C-terminal regions
CD73 maintains hepatocyte metabolic integrity and mouse liver homeostasis in a sex-dependent manner
Authors: Alcedo Karel P. , Rouse Morgan A. , Jung Gloria S. , Fu Dong , Minor Marquet , Willcockson Helen H. , Greene Kevin G. , Snider Natasha T.
Published: October 2020

Background & Aims

Metabolic imbalance and inflammation are common features of chronic liver diseases. Molecular factors controlling these mechanisms represent potential therapeutic targets. One promising target is CD73, the major enzyme that dephosphorylates extracellular adenosine monophosphate (AMP) to form the anti-inflammatory adenosine. In normal liver, CD73 is expressed on pericentral hepatocytes, which are important for long-term liver homeostasis. The aim of this study was to determine if CD73 has non-redundant hepatoprotective functions.

Approach & Results

We generated mice with a targeted deletion of the CD73-encoding gene (Nt5e) in hepatocytes (CD73-LKO). Deletion of hepatocyteNt5eresulted in approximately 70% reduction in total liver CD73 protein (p<0.0001). Male and female CD73-LKO mice developed normally during the first 21 weeks, without significant liver phenotypes. Between 21-42 weeks, the CD73-LKO mice developed spontaneous onset liver disease with significant severity in male mice. Notably, middle-aged male CD73-LKO mice displayed hepatocyte swelling and ballooning (p<0.05), inflammation (p<0.01) and variable steatosis. Female CD73-LKO mice had lower serum albumin (p<0.05) and elevated inflammatory markers (p<0.01), but did not exhibit the spectrum of histopathologic changes characteristic of the male mice, potentially due to compensatory induction of adenosine receptors. Serum analysis and proteomic profiling of hepatocytes from male CD73-LKO mice revealed significant metabolic imbalance, with elevated blood urea nitrogen (p<0.0001) and impairments in major metabolic pathways, including oxidative phosphorylation and AMP-activated protein kinase (AMPK) signaling. There was significant hypo-phosphorylation in AMPK substrate in CD73-LKO livers (p<0.0001), while in isolated hepatocytes treated with AMP, soluble CD73 induced AMPK activation (p<0.001).

Conclusions

Hepatocyte CD73 supports long-term metabolic liver homeostasis through AMPK in a sex-dependent manner. These findings have implications for human liver diseases marked by CD73 dysregulation.
Raptor: A fast and space-efficient pre-filter for querying very large collections of nucleotide sequences
Authors: Seiler Enrico , Mehringer Svenja , Darvish Mitra , Turc Etienne , Reinert Knut
Published: October 2020

We present Raptor, a tool for approximately searching many queries in large collections of nucleotide sequences. In comparison with similar tools like Mantis and COBS, Raptor is 12-144 times faster and uses up to 30 times less memory. Raptor uses winnowing minimizers to define a set of representativek-mers, an extension of the Interleaved Bloom Filters (IBF) as a set membership data structure, and probabilistic thresholding for minimizers. Our approach allows compression and a partitioning of the IBF to enable the effective use of secondary memory.
Isolation and characterization of lumpy skin disease virus from cattle in India
Authors: Kumar Naveen , Chander Yogesh , Kumar Ram , Khandelwal Nitin , Riyesh Thachamvally , Chaudhary Khushboo , Shanmugasundaram Karuppusamy , Kumar Sanjit , Kumar Anand , Gupta Madhurendu K. , Pal Yash , Barua Sanjay , Tripathi Bhupendra N.
Published: October 2020

Lumpy skin disease (LSD) has devastating economic impact. During the last decade, LSD had spread to climatically new and previously disease-free countries, which also includes its recent emergence in the Indian subcontinent (2019). This study deals with the LSD outbreak(s) from cattle in Ranchi (India). Virus was isolated from the scabs (skin lesions) in the primary goat kidney cells. Phylogenetic analysis based on nucleotide sequencing of LSD virus (LSDV) ORF011, ORF012 and ORF036 suggested that the isolated virus (LSDV/Bos taurus-tc/India/2019/Ranchi) is closely related to Kenyan LSDV strains. Further, we adapted the isolated virus in Vero cells, an alternative cell line that was found suitable for LSDV propagation. In addition, kinetics of viral DNA synthesis and one-step growth curve analysis suggested that LSDV initiates synthesizing its genome at ∼24 hours post-infection (hpi) with a peak level at ∼96 hpi whereas evidence of progeny virus particles was observed at 36-48 hours (h) with a peak titre at ∼120 h. This study reports the first successful isolation of LSDV in India, besides describing alternative cells for virus isolation (primary goat kidney cells) andin vitropropagation (Vero cells) as well as providing some insights on LSDV life cycle.

Author Summary

This study describes the first successful isolation of LSDV in India. Nucleotide sequencing of LSDV ORF011, ORF012 and ORF036 suggested that the isolated virus is closely related to Kenyan LSDV strains. This is in accordance with the previous (only) study, thereby suggesting that a single LSDV strain is circulating in India. For the first time, we employed primary goat kidney (PGK) cells for the isolation of LSDV, where PGK cells were found more sensitive for LSDV isolation as compared to the primary lamb testicle (PLT) and primary goat testicle (PGT) cells. We also adapted the isolated virus in Vero cells and demonstrated that Vero cells are also suitable forin vitropropagation of LSDV. Besides, we also provide some insights on the LSDV life cycle.
Whole-genome SNP analysis elucidates the genetic population structure and diversity of Acrocomia species
Authors: Díaz Brenda G. , Zucchi Maria I. , Alves-Pereira Alessandro. , de Almeida Caléo P. , Moraes Aline C. L. , Vianna Suelen A. , Azevedo-Filho Joaquim A. , Colombo Carlos A
Published: October 2020

Acrocomia (Arecaceae) is a genus widely distributed in tropical and subtropical America that has been achieving economic interest due to the great potential of oil production of some of its species. In particularA. aculeata, due to its vocation to supply oil with the same productive capacity as the oil palm even in areas with water deficit. Although eight species are recognized in the genus, the taxonomic classification based on morphology and geographic distribution is still controversial. Knowledge about the genetic diversity and population structure of the species is limited, which has limited the understanding of the genetic relationships and the orientation of management, conservation, and genetic improvement activities of species of the genus. In the present study, we analyzed the genomic diversity and population structure of seven species of Acrocomia including 117 samples ofA. aculeatacovering a wide geographical area of occurrence, using single nucleotide Polymorphism (SNP) markers originated from Genotyping By Sequencing (GBS). The genetic structure of the Acrocomia species were partially congruent with the current taxonomic classification based on morphological characters, recovering the separation of the speciesA. aculeata, A. totai, A. crispaandA. intumescensas distinct taxonomic groups. However, the species A. media was attributed to the cluster ofA. aculeatawhileA. hassleriandA. glauscescenswere grouped together withA. totai. The species that showed the highest and lowest genetic diversity were A. totai and A. media, respectively. When analyzed separately, the species A.aculeatashowed a strong genetic structure, forming two genetic groups, the first represented mainly by genotypes from Brazil and the second by accessions from Central and North American countries. Greater genetic diversity was found in Brazil when compared to the other countries. Our results on the genetic diversity of the genus are unprecedented, as is also establishes new insights on the genomic relationships between Acrocomia species. It is also the first study to provide a more global view of the genomic diversity ofA. aculeata. We also highlight the applicability of genomic data as a reference for future studies on genetic diversity, taxonomy, evolution and phylogeny of the Acrocomia genus, as well as to support strategies for the conservation, exploration and breeding of Acrocomia species and in particularA. aculeata.
Biting and resting preferences of malaria vectors in The Gambia
Authors: Hamid-Adiamoh Majidah , Nwakanma Davis , Assogba Benoit Sessinou , Ndiath Mamadou Ousmane , D’Alessandro Umberto , Afrane Yaw A. , Amambua-Ngwa Alfred
Published: October 2020

Background

The scale-up of indoor residual spraying and long-lasting insecticidal nets, together with other interventions have considerably reduced the malaria burden in The Gambia. This study examined the biting and resting preferences of the local insecticide-resistant vector populations few years following scale-up of anti-vector interventions.

Method

Indoor and outdoor-restingAnopheles gambiaemosquitoes were collected between July and October 2019 from ten villages in five regions in The Gambia using pyrethrum spray collection (indoor) and prokopack aspirator from pit traps (outdoor). Polymerase chain reaction assays were performed to identify molecular species, insecticide resistance mutations,Plasmodiuminfection rate and host blood meal.

Results

A total of 844 mosquitoes were collected both indoors (421, 49.9%) and outdoors (423, 50.1%). Four main vector species were identified, includingAn. arabiensis(indoor: 15%, outdoor: 26%);An. coluzzii(indoor: 19%, outdoor: 6%),An. gambiae s.s. (indoor: 11%, outdoor: 16%),An. melas(indoor: 2%, outdoor: 0.1%) and hybrids ofAn. coluzzii-An. gambiae(indoors: 3%, outdoors: 2%). A significant preference for outdoor resting was observed inAn. arabiensis(PearsonX2=22.7, df=4, P<0.001) and for indoor resting inAn. coluzzii(PearsonX2=55.0, df=4, P<0.001). Prevalence of the voltage-gated sodium channel (Vgsc)-1014Swas higher in the indoor-resting (allele freq. = 0.96, 95%CI: 0.78–1) than outdoor-resting (allele freq. = 0.82, 95%CI: 0.76–0.87)An. arabiensispopulation. ForAn. coluzzii, the prevalence of most mutation markers were higher in the outdoor (allele freq. = 0.92, 95%CI: 0.81–0.98) than indoor-resting (allele freq. = 0.78, 95%CI: 0.56–0.86) mosquitoes. Sporozoite positivity rate was 1.3% (95% CI: 0.5–2%). Indoor-restingAn. coluzziihad mainly fed on human blood while indoor-restingAn. arabiensis, animal blood.

Conclusion

The indoor-resting behavior ofAn. arabiensisthat preferred animal blood and had low sporozoite rates, may be determined by theVgsc-1014Smutation. Control interventions may include complementary vector control approaches such as zooprophylaxis.
Hsp90 and its co-chaperone Sti1 control TDP-43 misfolding and toxicity
Authors: Lin Lilian Tsai-Wei , Razzaq Abdul , Di Gregorio Sonja E. , Hong Soojie , Charles Brendan , Lopes Marilene H. , Beraldo Flavio , Prado Vania F. , Prado Marco A.M. , Duennwald Martin L.
Published: October 2020

Protein misfolding is a central feature of most neurodegenerative diseases. Molecular chaperones can modulate the toxicity associated with protein misfolding, but it remains elusive which molecular chaperones and co-chaperones interact with specific misfolded proteins. TDP-43 misfolding and inclusion formation is a hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. Using yeast and mammalian neuronal cells we find that Hsp90 and its co-chaperones have a strong capacity to alter TDP-43 misfolding, inclusion formation, aggregation, and cellular toxicity. Our data also demonstrate that impaired Hsp90 function sensitizes cells to TDP-43 toxicity. We further show that the co-chaperone Sti1 specifically interacts with and modulates TDP-43 toxicity in a dose-dependent manner. Our study thus uncovers a previously unrecognized tie between Hsp90, Sti1, TDP-43 misfolding, and its cellular toxicity.
Synonymous mutations reveal genome-wide driver mutation rates in healthy tissues
Authors: Poon Gladys , Watson Caroline J. , Fisher Daniel S. , Blundell Jamie R.
Published: October 2020

Genetic alterations that drive clonal expansions in ostensibly healthy tissues have implications for cancer risk. However, the total rate at which clonal expansions occur in healthy tissues remains unknown. Synonymous passenger mutations that hitchhike to high variant allele frequency due to a linked driver mutation can be used to estimate the total rate of positive selection across the genome. Because these synonymous hitchhikers are influenced byallmutations under selection, regardless of type or location, they can be used to estimate how many driver mutations are missed by narrow gene-focused sequencing panels. Here we analyse the variant allele frequency spectrum of synonymous passenger mutations to estimate the total rate at which mutations driving clonal expansions occur in healthy tissues. By applying our framework to data from physiologically healthy blood, we find that a large fraction of mutations driving clonal expansions occur outside of canonical cancer driver genes. In contrast, analysis of data from healthy oesophagus reveals little evidence for many driver mutations outside of those inNOTCH1andTP53. Our framework, which generalizes to other tissues, sheds light on the fraction of drivers mutations that remain undiscovered and has implications for cancer risk prediction.
The transcriptome of regenerating zebrafish scales identifies genes involved in human bone disease
Authors: Bergen Dylan J.M. , Tong Qiao , Shukla Ankit , Newman Elis , Zethof Jan , Lundberg Mischa , Ryan Rebecca , Youlten Scott E. , Zeggini Eleftheria , Croucher Peter I. , Flik Gert , Richardson Rebecca J. , Kemp John P. , Hammond Chrissy L. , Metz Juriaan R.
Published: October 2020

Zebrafish scales are mineralised plates that can regenerate involvingde novobone formation. This presents an opportunity to uncover genes and pathways relevant to human musculoskeletal disease relevant to impaired bone formation. To investigate this hypothesis, we defined transcriptomic profiles of ontogenetic and regenerating scales, and identified 604 differentially expressed genes (DEGs) that were enriched for extracellular matrix, ossification, and cell adhesion pathways. Next, we showed that human orthologues of DEGs were 2.8 times more likely to cause human monogenic skeletal diseases (P<8×10−11), and they showed enrichment for human orthologues associated with polygenetic disease traits including stature, bone density and osteoarthritis (P<0.005). Finally, zebrafish mutants of two human orthologues that were robustly associated with height and osteoarthritis (COL11A2) or bone density only (SPP1) developed skeletal abnormalities consistent with our genetic association studies.Col11a2Y228X/Y228Xmutants showed endoskeletal features consistent with abnormal growth and osteoarthritis, whereasspp1P160X/P160Xmutants had elevated bone density (P<0.05). In summary, we show that transcriptomic studies of regenerating zebrafish scales have potential to identify new genes and pathways relevant to human skeletal disease.
SARS-CoV-2 elicits robust adaptive immune responses regardless of disease severity
Authors: Nielsen Stine SF , Vibholm Line K , Monrad Ida , Olesen Rikke , Frattari Giacomo S , Pahus Marie H , Højen Jesper F , Gunst Jesper D , Erikstrup Christian , Holleufer Andreas , Hartmann Rune , Østergaard Lars , Søgaard Ole S , Schleimann Mariane H , Tolstrup Martin
Published: October 2020

The SARS-CoV-2 pandemic currently prevails worldwide. To understand the immunological signature of SARS-CoV-2 infections and aid the search for treatments and vaccines, comprehensive characterization of adaptive immune responses towards SARS-CoV-2 is needed. We investigated the breadth and potency of antibody-, and T-cell immune responses, in 203 recovered SARS-CoV-2 infected patients who presented with asymptomatic to severe infections. We report very broad serological profiles with cross-reactivity to other human coronaviruses. Further, >99% had SARS-CoV-2 epitope specific antibodies, with SARS-CoV-2 neutralization and spike-ACE2 receptor interaction blocking observed in 95% of individuals. A significant positive correlation between spike-ACE2 blocking antibody titers and neutralization potency was observed. SARS-CoV-2 specific CD8+T-cell responses were clear and quantifiable in 90% of HLA-A2+individuals. The viral surface spike protein was identified as the dominant target for both neutralizing antibodies and CD8+T cell responses. Overall, the majority of patients had robust adaptive immune responses, regardless of disease severity.

Author summary

SARS-CoV-2 can cause severe and deadly infections. However, the immunological understanding of this viral infection is limited. Currently, several vaccines are being developed to help limit transmission and prevent the current pandemic. However, basic understanding of the adaptive immune response developed during SARS-CoV-2 infections is needed to inform further vaccine development and to understand the protective properties of the developed immune response. We investigated, the adaptive immune response developed during SARS-CoV-2 infections in recovered patients experiencing a full spectrum of disease severity, from asymptomatic infections to severe cases requiring hospitalization. We used a novel multiplex serological platform, cell-based neutralization assays and dextramer flow cytometry assays to characterize a broad and robust humoral and cellular immune response towards SARS-CoV-2. We found that the vast majority of recovered individuals have clear detectable and functional SARS-CoV-2 spike specific adaptive immune responses, despite diverse disease severities. The detection of both a humoral and cellular functional spike specific immune response in the vast majority of the individuals, irrespective of asymptomatic manifestations, supports vaccine designs currently underway, and encourages further exploration of whether primary infections provide protection to reinfection.
A deep learning framework for elucidating whole-genome chemical interaction space
Authors: Cai Tian , Lim Hansaim , Abbu Kyra Alyssa , Qiu Yue , Nussinov Ruth , Xie Lei
Published: October 2020

Molecular interaction is the foundation of biological process. Elucidation of genome-wide binding partners of a biomolecule will address many questions in biomedicine. However, ligands of a vast number of proteins remain elusive. Existing methods mostly fail when the protein of interest is dissimilar from those with known functions or structures. We develop a new deep learning framework DISAE that incorporates biological knowledge into self-supervised learning techniques for predicting ligands of novel unannotated proteins on a genome-scale. In the rigorous benchmark studies, DISAE outperforms state-of-the-art methods by a significant margin. The interpretability analysis of DISAE suggests that it learns biologically meaningful information. We further use DISAE to assign ligands to human orphan G-Protein Coupled Receptors (GPCRs) and to cluster the human GPCRome by integrating their phylogenetic and ligand relationships. The promising results of DISAE open an avenue for exploring the chemical landscape of entire sequenced genomes.
Platinum(II) complex with 4-nitro-N-(pyridin-2-ylmethylidene)aniline: synthesis, characterization, crystal structure and antioxidant activity
Authors: Khalaj Mehdi , Olyaei Abolfazl , Sadeghpour Mahdieh , Lalegani Arash , Lipkowski Janusz , Lough Alan J.
Published: October 2020

A novel complex has been prepared using the (E)-4-nitro-N-(pyridin-2-ylmethylidene)aniline bidentate Schiff base ligand and PtCl2, namely, dichlorido[(E)-4-nitro-N-(pyridin-2-ylmethylidene)aniline-κ2N,N′]platinum(II) acetonitrile hemisolvate, [PtCl2(C12H9N3O2)]·0.5CH3CN,1. According to the X-ray measurements of the crystal structure, the PtIIion adopts a PtCl2N2square-planar coordination. The coordination of the Schiff base ligand to the PtIIion occurs in a cyclic bidentate fashion, as a result of which a five-membered metallacycle is formed. Furthermore, in the structure of1, the neutral molecules form a one-dimensional chain structure through C—H...Cl and C—H...O hydrogen bonds. The characterization of the complex was performedviasingle-crystal X-ray diffraction, IR spectroscopy and elemental analysis, and the antioxidant activity of the complex was evaluated using spectrophotometry by the 1,1-diphenyl-2-picrylhydrazyl (DPPH) method.
Nickel(II) carbonyl, ammonia, and acetonitrile complexes supported by a pyridine dipyrrolide pincer ligand
Authors: Dias H. V. Rasika , Pramanik Abhijit
Published: October 2020

The synthesis, isolation and crystal structures of nickel(II) carbonyl, acetonitrile and ammonia complexes supported by a dianionic, pyridine dipyrrolide pincer ligand [pyrr2py]2−, namely, carbonyl[2,2′-(pyridine-2,6-diyl)bis(3,5-di-p-tolylpyrrolido-κN)]nickel(II), [Ni(C41H33N3)(CO)], ammine[2,2′-(pyridine-2,6-diyl)bis(3,5-di-p-tolylpyrrolido-κN)]nickel(II), [Ni(C41H33N3)(NH3)], and (acetonitrile-κN)[2,2′-(pyridine-2,6-diyl)bis(3,5-di-p-tolylpyrrolido-κN)]nickel(II), [Ni(C41H33N3)(CH3CN)], as well as the free ligand 2,6-bis(3,5-di-p-tolylpyrrol-2-yl)pyridine, C41H35N3 or [pyrr2py]H2 are reported. The nickel complexes are four-coordinate and adopt a square-planar geometry. The CO stretch of the nickel-bound carbon monoxide ligand of [pyrr2py]Ni(CO) has been observed at 2101 cm−1. The ammonia and acetonitrile complexes, [pyrr2py]Ni(NH3) and [pyrr2py]Ni(NCMe) feature all-nitrogen coordination spheres around nickel consisting of different N-donor ligand types.
Development and training for the dealers' community in Macau casinos
Authors: Zhou Jinquan
Published: October 2020

Purpose

The purpose of this paper is to discuss characteristics of dealers training and development in Macau gambling industry by investigating and analyzing the current dealers training and development status of Macau gambling casinos. Training and development prepare and enhance dealer's knowledge and skills to enable them to adapt to the working environment and create a career opportunity in their organization.

Design/methodology/approach

In-depth interviews were conducted with Macau casino human recourse manger, and questionnaire survey was used to investigate the views of dealers in training and development provided by their organization.

Findings

This paper revealed that the development and training of Macao's dealers are mainly in individual professional skills, including executive ability, professional attitude and communication skills training. According to the current situation of dealer's training and development, a human resource investment policy is that the government requires undertaking a part of the work in the dealers' community.

Research limitations/implications

This paper examined the current demand for talents in Macau gambling casinos focusing on dealers' survey of the casino's training concepts, including training perception, organization arrangement and training information, etc. It is the least published official information, and training and development program in Macau gambling industry wreaked the questionnaire design.

Practical implications

This survey first time revealed a characteristic of dealer's human resources training and development in the Macau gambling industry. The authors got comprehensive and profound understanding of dealers' job skills and career development needs through the professional position and job characteristics investigation and analysis.

Social implications

The investigation reveals the inadequately training offered for dealers pre-employment. At least, it cannot meet the gambling industry's basic needs for dealer occupation in many ways. The school's training of dealers and the training provided by the casino has a huge gap, which the school's training is a short-term, compared to the gambling enterprises on the professional skills requirements of recruit dealers. But the school in long-term provide a wider range of knowledge for dealers career development.

Originality/value

This research conducted by the author in 2017 showed that dealer training and development views could be used to in the gambling industry in human resource practical management.
A novel PV array interconnection scheme to extract maximum power based on global shade dispersion using grey wolf optimization algorithm under partial shading conditions
Authors: R. Balraj , Stonier Albert Alexander
Published: October 2020

Purpose

Partial shading causes significant power decreases in the PV systems. The purpose of this paper is to address this problem, connectivity regulation is designed to reduce partial shading problems.

Design/methodology/approach

In this approach, the partial shading was estimated and dispersed evenly on the whole array by global shade dispersion technique (GSD). The grey wolf algorithm was implemented for the interconnection of arrays by an efficient switching matrix.

Findings

After the implementation of the GSD technique using a grey wolf algorithm, the performance under different shading conditions was analyzed using the MatLab simulation tool. The results were compared with total cross-tied (TCT), Su Do Ku and the proposed method of reconfiguration, where the proposed method improves the maximum power of the PV system appropriately.

Research limitations/implications

This methodology uses any size of PV systems.

Social implications

Replacement of conventional energy systems with renewable energy systems such as solar helps the environment clean and green.

Originality/value

The GSD interconnection scheme using the grey wolf optimization algorithm has proved an improved output performance compared with the existing TCT and Sudoku based reconfiguration techniques. By comparing with existing techniques in literature, the proposed method is more advantageous for reducing mismatch losses between the modules of any size of the PV array with less operating time.
The unwitting corruption of broadening of marketing into neoliberalism: a beast unleashed?
Authors: Dholakia Nikhilesh , Ozgun Aras , Atik Deniz
Published: October 2020

Purpose

This paper aims to uncover links, overlaps and influence flows across two seemingly unrelated historical processes – the broadening of the marketing concept and the rapid rise of neoliberal ideology, and associated economic and social policies.

Design/methodology/approach

Historical examination of the pivotal points in marketing thought, especially since 1960s and 1970s, is juxtaposed with the historical rise of neoliberalism to uncover linkages between marketing and neoliberalism, with a particular reference to Foucault’s analysis of the neoliberal transgression of classical liberalism.

Findings

While noble intentions were behind the broadening of the concept of marketing, the implicit assumptions reinforced neoliberal ideology and policies that led to rapid rise in inequality and to disastrous financial and economic crises.

Research limitations/implications

This study, relying on extensive interdisciplinary theorizing, could benefit from empirical and practical extensions.

Practical implications

Globally pervasive marketing practices – based on the broadening of the marketing concept – have become imbricated in contemporary spiraling crises. To escape such spirals, radical rethinking of marketing theories and practices is required.

Social implications

To reorient away from serving only the interests of centralized capital and to serve the needs of people the world over, marketing thought and practice need to reorient to innovative ideas that transcend the broadened and generic marketing concepts.

Originality/value

The paper develops the linkages between marketing theory and practices since the late 1960s and the neoliberal ideology politics and policies, with roots in the 1920s, that rose to prominence in the 1970s. A key contribution is an exploration of, in a marketing context, Foucault’s analysis of the neoliberal eclipsing of classical liberalism.
Empirical relationship between workers' remittances and financial development (an ARDL cointegration approach for Sri Lanka)
Authors: Mohamed Aslam Ahamed Lebbe , Sivarajasingham Selliah
Published: October 2020

Purpose

The purpose of this study aims to investigate the nature of the relationship between workers' remittances and financial development (FD) in Sri Lanka for the period from 1975 to 2017.

Design/methodology/approach

This study used both the exploratory data analysis and inferential data analysis (IDA) techniques to test the objective of this study. The IDA technique consisted of the augmented Dickey–Fuller (ADF) and Phillips–Perron unit root tests, the autoregressive distributed lag (ARDL) bounds cointegration technique, the Granger causality test and impulse response function analysis.

Findings

The unit root test results show that the variables are in mixed order. The empirical results of cointegration confirm that workers' remittances have a beneficial long-run relationship with FD in Sri Lanka. The Granger causality test result indicates that there is a bidirectional relationship between workers' remittances and FD. The impulse response analysis indicates that a positive shock to workers' remittance has an immediate significant positive impact on the FD of up to 10 years.

Practical implications

The analytical techniques used in this study explain how workers' remittances induce FD in Sri Lanka.

Originality/value

This study fills an important gap in the academic literature by using newly developed ARDL bounds cointegration techniques in Sri Lanka, by using impulse response function analysis, and by studying the dynamic relationship between workers' remittances and FD using time series data.
What is the effect of banking concentration and competition on financial development? An international assessment
Authors: De Moraes Claudio Oliveira , Antunes José Americo Pereira , Coutinho Márcio Silva
Published: October 2020

Purpose

This paper analyzes the effect of the banking market (concentration and competition) on financial development.

Design/methodology/approach

In order to estimate the effects of banking concentration and competition on financial development, we conducted an empirical analysis using the System Generalized Method of Moments (S-GMM) through a dynamic panel data model.

Findings

The main results suggest that concentration and competition affect financial development. In particular, an increase in bank concentration may inhibit the country's financial development, due to the lack of competition. Our results do not confirm the controversy between concentration and competition, suggesting that concerning financial development, concentration is the reverse of competition.

Practical implications

The results of this study add a new perspective on banking market power: a financial system concentrated or uncompetitive constrains financial development.

Originality/value

The literature that combines the investigation of the effects of banking market structure (concentration) and banking market conduct (competition) on financial development is scarce. Although a concentrated banking sector can reduce competition through barriers to new entrants (which could expand financial services offer), it is also true that a concentrated banking sector can be competitive. In order to avoid the controversy, our paper chooses to look into a comprehensive approach considering independent measures of bank concentration and bank competition, which together refer to the banking framework.