bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigating Leptospira dynamics in a multi-host community using an agent-based modeling approach
Authors: Belsare Aniruddha V. , Gompper Matthew E. , Mason Meghan , Munoz-Zanzi Claudia
Published: July 2022

Leptospirosis, a neglected bacterial zoonosis, is a global public health issue disproportionately affecting impoverished communities such as urban slums in the developing world. A variety of animal species, including peridomestic rodents and dogs, can be infected with different strains of leptospirosis. Humans contract leptospirosis via exposure to water or soil contaminated with the urine of infected animals. Due to the unavailability of safe and effective vaccines, preventive strategies mainly focus on minimizing human exposure to contaminated environment. In marginalized communities, this approach is ineffective due to infrastructure deficiencies and the difficulties in implementing sanitation and hygiene practices. Moreover, continuing expansion of urban slums worldwide will likely contribute to the increase in outbreaks of leptospirosis. Effective prevention of leptospirosis outbreaks will therefore require a thorough understanding of Leptospira transmission dynamics in impoverished, high-density settings. We developed the agent-based model MHMSLeptoDy to investigate Leptospira dynamics in a realistic, in silico high-density community of rodents, dogs, and human hosts, and two host-adapted Leptospira strains. Virtual explorations using MHMSLeptoDy were undertaken to evaluate alternate interventions and to assess the zoonotic transmission risk of leptospirosis. A key finding from model explorations is that rodents are the main contributors of rodent-adapted as well as dog-adapted strains in the environment, while dogs play an important role in distributing the rodent-adapted strain. Assessment of alternate leptospirosis control strategies using model iterations revealed that dog vaccination and rodent control interventions had the most impact on lowering human outbreak probability. Our open-source, customizable agent-based model provides a sophisticated mechanism to quantitatively evaluate nuanced intervention strategies and inform the design of rational, locally relevant leptospirosis control programs.
Invasive streptococcal infection can lead to the generation of cross-strain opsonic antibodies
Authors: de Neergaard Therese , Bläckberg Anna , Ivarsson Hanna , Thomasson Sofia , Ahnlide Vibha Kumra , Chowdhury Sounak , Khakzad Hamed , Malmström Johan , Rasmussen Magnus , Nordenfelt Pontus
Published: July 2022

Introduction

The human pathogen Streptococcus pyogenes causes substantial morbidity and mortality. It is unclear if antibodies developed after infections with this pathogen are opsonic and if they are strain-specific or more broadly protective. Here, we quantified the opsonic antibody response following invasive S. pyogenes infection.

Materials and Methods

Four patients with S. pyogenes bacteremia between 2018-2020 at Skåne University Hospital in Lund, Sweden, were prospectively enrolled. Acute and convalescent sera were obtained, and the S. pyogenes isolates were genome-sequenced (emm118, emm85, and two emm1). Quantitative antibody binding and phagocytosis assays were used to evaluate isolate-dependent opsonic antibody function in response to infection.

Results

Antibody binding increased modestly against the infecting isolate and across emm types in convalescent compared to acute sera for all patients. For two patients, phagocytosis increased in convalescent serum for both the infecting isolate and across types. The increase was only across types for one patient, and one had no improvement. No correlation to the clinical outcomes was observed.

Conclusion

Invasive S. pyogenes infections result in a modestly increased antibody binding with differential opsonic capacity, both non-functional binding and broadly opsonic binding across types. These findings question the dogma that an invasive infection should lead to a strong type-specific antibody increase rather than a more modest but broadly reactive response, as seen in these patients. Furthermore, our results indicate that an increase in antibody titers might not be indicative of an opsonic response and highlight the importance of evaluating antibody function in S. pyogenes infections.
Thalamocortical contribution to cognitive task activity
Authors: Sorenson Evan , Shine James M. , Cole Michael W. , Hwang Kai
Published: July 2022

Thalamocortical interaction is a ubiquitous functional motif in the mammalian brain. Previously (Hwang et al., 2021), we reported that lesions to network hubs in the human thalamus are associated with multi-domain behavioral impairments in language, memory, and executive functions. Here we show how task-evoked thalamic activity and thalamocortical interactions are organized to support these broad cognitive abilities. To address this question, we analyzed functional MRI data from human subjects that performed 127 tasks encompassing a broad range of cognitive representations. We first investigated the spatial organization of task-evoked activity and found that multi-task thalamic activity converged onto a low-dimensional structure, through which a basis set of activity patterns are evoked to support processing needs of each task. Specifically, the anterior, medial, and posterior-medial thalamus exhibit hub-like activity profiles that are suggestive of broad functional participation. These thalamic task hubs overlapped with network hubs interlinking cortical systems. To further determine the cognitive relevance of thalamocortical interactions, we built a data-driven thalamocortical interaction model to test whether thalamocortical functional connectivity transformed thalamic activity to cortical task activity. The thalamocortical model predicted task-specific cortical activity patterns, and outperformed comparison models built on cortical, hippocampal, and striatal regions. Simulated lesions to low-dimensional, multi-task thalamic hub regions impaired task activity prediction. This simulation result was further supported by profiles of neuropsychological impairments in human patients with focal thalamic lesions. In summary, our results suggest a general organizational principle of how thalamocortical interactions support cognitive task activity.

Impact Statement

Human thalamic activity transformed via thalamocortical functional connectivity to support task representations across functional domains.
Mutations in a set of ancient matrisomal glycoprotein genes across neoplasia predispose to disruption of morphogenetic transduction
Authors: Langthasa Jimpi , Mishra Satyarthi , Monica U , Kalal Ronak , Bhat Ramray
Published: July 2022

Misexpression and remodeling of the extracellular matrix is a canonical hallmark of cancer, although the extent of cancer-associated aberrations in the genes coding for ECM proteins and consequences thereof, are not well understood. In this study, we examined the alterations in core matrisomal genes across a set of nine cancers. These genes, especially the ones encoding for ECM glycoproteins, were observed to be more susceptible to mutations than copy number variations across cancers. We classified the glycoprotein genes based on the ubiquity of their mutations across the nine cancer groups and estimated their evolutionary age using phylostratigraphy. To our surprise, the ECM glycoprotein genes commonly mutated across all cancers were predominantly unicellular in origin, whereas those commonly showing mutations in specific cancers evolved mostly during and after the unicellular-multicellular transition. Pathway annotation for biological interactions revealed that the most pervasively mutated glycoprotein set regulated a larger set of inter-protein interactions and constituted more cohesive interaction networks relative to the cancer-specific mutated set. In addition, ontological prediction revealed the pervasively mutated set to be strongly enriched for basement membrane dynamics. Our results suggest that ancient unicellular-origin ECM glycoproteins were canalized into playing critical tissue morphogenetic roles, and when disrupted through matrisomal gene mutations, associate with neoplastic transformation of a wide set of human tissues.
Circadian regulation of dentate gyrus excitability mediated by G-protein signaling
Authors: Gonzalez Jose Carlos , Lee Haeun , Vincent Angela M , Goode Lacy K , King Gwendalyn D , Gamble Karen L , Wadiche Jacques I , Overstreet-Wadiche Linda
Published: July 2022

The central circadian regulator within the suprachiasmatic nucleus transmits time of day information by a diurnal spiking rhythm that is driven by intrinsic activity of molecular clock genes controlling membrane excitability. Most brain regions, including the hippocampus, harbor similar intrinsic circadian transcriptional machinery but whether these molecular programs generate oscillations of membrane properties is unexplored. Here, we show that intrinsic excitability of mouse dentate granule neurons exhibits a 24-hour oscillation that controls spiking probability. Diurnal changes in excitability are mediated by antiphase G-protein regulation of potassium and sodium conductances to reduce excitability during the light phase. Disruption of the circadian transcriptional machinery by conditional deletion of Bmal1 enhances excitability selectively during the light phase, increasing engram recruitment and spatial discrimination memory. These results reveal that circadian transcriptional machinery regulates intrinsic excitability, highlighting the role of cell-autonomous oscillations in hippocampal function and behavior.

Highlights

Dentate neurons exhibit a 24-hour oscillation of excitability with low excitability during the Light phase

Reduced excitability results from G-protein regulation of passive and active properties

Bmal1 deletion disrupts G-protein regulation to enhance excitability during the Light

Bmal1 deletion enhances the size of memory engrams and spatial discrimination
Host use does not drive genetic structure of mountain pine beetles in western North America
Authors: Boone Celia K. , Thompson Kirsten M. , Henry Philippe , Murray Brent W.
Published: July 2022

The mountain pine beetle (MPB) is one component of an intensively studied co-evolved host-pest system. We investigated the spatial genetic structure of MPB within its historic and recent geographic range expansion as it relates to host use in western North America using 13 pre-selected microsatellite loci. AMOVA shows that genetic structure is not correlated with the host tree species, arguing against the formation of host-race within this species. STRUCTURE analysis shows 4 main clusters in western North America: Northern - Northern British Columbia/Alberta; Central - Southern British Columbia/Alberta/Washington/Idaho/Montana; Southwest - Oregon/California/Nevada and; Southeast - Utah/Wyoming/Arizona/Colorado/South Dakota. Heterozygosity, allelic richness, and number of private alleles is greatest in the Southwest cluster. This cluster correlates with one of the three refugia hypothesized from a recent analysis of neo-Y haplotypes by Dowle and colleagues and represents an important reservoir of MPB genetic diversity.
Pick-up Single-Cell Proteomic Analysis for Quantifying up to 3000 Proteins in a Tumor Cell
Authors: Wang Yu , Guan Zhi-Ying , Shi Shao-Wen , Jiang Yi-Rong , Wu Qiong , Wu Jie , Chen Jian-Bo , Ying Wei-Xin , Xu Qin-Qin , Fan Qian-Xi , Wang Hui-Feng , Zhou Li , Pan Jian-Zhang , Fang Qun
Published: July 2022

The shotgun proteomic analysis is currently the most promising single-cell protein sequencing technology, however its identification level of ∼1000 proteins per cell is still insufficient for practical applications. Here, we develop a pick-up single-cell proteomic analysis (PiSPA) workflow to achieve a deep identification capable of quantifying up to 3000 protein groups in a tumor cell using the label-free quantitative method. The PiSPA workflow is specially established for single-cell samples mainly based on a nanoliter-scale microfluidic liquid handling robot, capable of achieving single-cell capture, pretreatment and injection under the pick-up operation strategy. Using this customized workflow with remarkable improvement in protein identification, 1804-3349, 1778-3049 and 1074-2487 protein groups are quantified in single A549 cells (n= 37), HeLa cells (n= 44) and U2OS cells (n= 27), respectively. Benefiting from the flexible cell picking-up ability, we study tumor cell migration at the single cell proteome level, demonstrating the potential in practical biological research from single-cell insight.
Symbolic regression analysis of interactions between first trimester maternal serum adipokines in pregnancies which develop pre-eclampsia
Authors: Wilstrup Casper , Hedley Paula L. , Rode Line , Placing Sophie , Wøjdemann Karen R. , Shalmi Anne-Cathrine , Sundberg Karin , Christiansen Michael
Published: July 2022

Objectives

Pre-eclampsia (PE) is an important cause of perinatal morbidity and mortality. Despite an elusive pathophysiology, PE has been associated with changes in maternal serum concentrations of adipokines in early pregnancy. We hypothesized, that symbolic regression might identify interactions between adipokines and PE, which may have eluded regression and Bayesian models.

Methods

In this nested case-control sub-study, of the Copenhagen First Trimester Screening Study, data regarding maternal weight and serum concentrations of PAPP-A, leptin (Lp), soluble leptin receptor (sLR), adiponectin, and resistin (Re) was available from 423 first trimester pregnancies (gestational week 10+3– 13+6), 126 of which developed PE. Symbolic regression with QLattice/Feyn 2.1 was used to identify models comprising two-interactions between up-to three markers.

Results

The optimal mathematical model exhibited a non-linear relation between Re and the combined effect of sLR and Lp. The model was dependent, in a Gaussian way, on the level of Re. The receiver operating characteristic (ROC) curve of the model viz. identification of PE cases in first trimester had an AUC of 0.81 and a modelled DR of 40 % for a FPR of 4 %. Symbolic regression outperformed logistic regression of the same parameters with a ROC with AUC = 0.77, and a DR of 7 % for a 3 % FPR.

Conclusions

Symbolic regression identified non-linear interactions between Lp, sLR and Re concentrations in first trimester pregnancy serum of pregnancies which later developed PE. Non-linear interactions suggest new pathophysiological pathways and may help in designing more efficient screening protocols for PE.
IFNA pathway drives the more aggressive phenotype of KRASG12D-mutant pancreatic ductal adenocarcinomas via IFNAR1/STAT3 activation
Authors: Inoue Koetsu , Schanne Daniel H. , Matsui Aya , Lei Pinji , Klein Sebastian , Aoki Shuichi , Taniguchi Hajime , Kikuchi Hiroto , Chen Jiang , Liu Zelong , Tsai Shengdar Q. , Schmidt Tyge CE , Iwasaki Masaaki , Geidel Glenn , Koch Alexander , Huang Peigen , Fukumura Dai , Shioda Toshihiro , Munn Lance L. , Castillo Carlos Fernandez-del , Hong Theodore S. , Jain Rakesh K. , Liss Andrew , Bardeesy Nabeel , Duda Dan G.
Published: July 2022

Activating mutations of KRAS play critical roles in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC). Accumulating evidence indicates that distinct KRAS alleles associate with different prognoses, but the underlying mechanisms are not known. We established isogenic KRAS mutants (KRASG12D, KRASG12V, and KRASWT) using a KRASG12R patient-derived PDAC cell line by CRISPR/Cas9 knock-in. We used these isogenic cell lines, a collection of characterized human PDAC patient-derived cell lines, and murine PDAC models to study the role of these KRAS alleles in vitro and in vivo. We verified that the growth of KRASG12D cells is more aggressive compared to KRASG12V isogenic cells in vitro and in vivo using orthotopic mouse models. Signal transducer and activator of transcription (STAT) activation was the most significant difference between KRASG12D and KRASG12V isogenic PDACs. Furthermore, activation of interferon-alpha (IFNA)/IFNA receptor (IFNAR)1/STAT3 signaling in the cancer cells mediated the more aggressive phenotype of KRASG12D PDACs. Conversely, inhibition of IFNAR1 in patient-derived PDAC cells suppressed tumor growth. Finally, IFNAR1 blockade was also effective in murine PDAC models and induced a significant increase in survival when combined with immune checkpoint blockade therapy. We conclude that the IFNA pathway and IFNAR1/STAT3 axis contribute to a more aggressive tumor progression in human KRASG12D PDACs and that IFNAR1 inhibition is a potential therapeutic target for overcoming resistance to immunotherapy in PDAC.

One Sentence Summary

IFNA pathway drives the more aggressive phenotype of KRASG12D-mutant pancreatic ductal adenocarcinomas via IFNAR1/STAT3 activation.
Exon-intron architecture determines mRNA stability by dictating m6A deposition
Authors: Uzonyi Anna , Slobodin Boris , Schwartz Schraga
Published: July 2022

N6-methyladenosine (m6A), a widespread destabilizing mark on mRNA, is non-uniformly distributed across the transcriptome, yet the basis for its selective deposition is unknown. Here, we uncover that m6A deposition is not selective. Instead, m6A distribution is exclusion-based: m6A-consensus harboring sites are methylated by default, unless they are within a window of up to ∼200 nt from an exon-intron junction. A simple model, relying exclusively on presence of m6A motifs and exon-intron architecture allows high accuracy recapitulation of experimentally-measured m6A profiles and of all m6A hallmarks. We further establish that m6A serves as the long-sought mechanism underlying the strong association between exon-intron architecture and mRNA stability. Our findings establish a mechanism by which the memory of nuclear RNA splicing is covalently etched on an mRNA, in the form of m6A, and determines its cytoplasmic stability, with broad implications on the regulation, function, and evolution of both m6A and mRNA stability.
The spindle orienting machinery requires activation, not just localization
Authors: Neville Kathryn E. , Finegan Tara M. , Lowe Nicholas , Bellomio Philip M. , Na Daxiang , Bergstralh Dan T.
Published: July 2022

The orientation of the mitotic spindle at metaphase determines the placement of the daughter cells. Spindle orientation in animals typically relies on an evolutionarily conserved biological machine comprised of at least four proteins - called Partner of Inscuteable (Pins), Gαi, Mushroom body defective (Mud), and Dynein in flies - that exert a pulling force on astral microtubules and reels the spindle into alignment. The canonical model for spindle orientation holds that the direction of pulling is determined by asymmetric placement of this machinery at the cell cortex. In most cell types, this placement is thought to be mediated by Pins, and a substantial body of literature is therefore devoted to identifying polarized cues that govern localized cortical enrichment of Pins. In Drosophila neuroblasts, for example, this cue is thought to be Inscuteable, which helps recruit Pins to the apical cell surface. In this study we revisit the canonical model. We find that spindle orientation in the follicular epithelium requires not only Pins localization but also activation, which relies on direct interaction between Pins and the multifunctional protein Discs large. This mechanism is distinct from the one mediated by Inscuteable, which we find also has an activating step. Together our results show that the canonical model is incomplete. Local enrichment of Pins is not sufficient to determine spindle orientation; an activation step is also necessary.
Prioritization of semantic over visuo-perceptual aspects in multi-item working memory
Authors: Kerrén Casper , Linde-Domingo Juan , Spitzer Bernhard
Published: July 2022

Working Memory (WM) keeps information temporarily available for upcoming tasks. How the contents of WM are distinguished from perceptual representations on the one hand, and from long-term memories on the other, is still debated. Here, we leveraged recent evidence for a reversal of processing dynamics when retrieving episodic long-term memories as opposed to perceiving visual input. In two experiments (n=75 and n=103), we asked participants to hold one or more items in WM and to report their low-level perceptual and high-level semantic qualities. In both experiments, we found faster responses to the items’ semantic qualities, indicating prioritization over visuo-perceptual aspects, when two or more items were held concurrently in WM. These dynamics of accessing information in multi-item WM were akin to those in retrieving episodic long-term memories and opposite to those in processing visual inputs. Little to no semantic prioritization was evident during single-item maintenance, consistent with a strictly capacity-limited focus of attention within which WM information can be transformed into a prospective action plan.
Pseudomonas aeruginosa promotes persistence of Stenotrophomonas maltophilia via increased adherence to depolarized respiratory epithelium
Authors: McDaniel Melissa S. , Lindgren Natalie R. , Billiot Caitlin E. , Valladares Kristina N. , Sumpter Nicholas A. , Swords W. Edward
Published: July 2022

Stenotrophomonas maltophilia is an emerging opportunistic respiratory pathogen in patients with cystic fibrosis (CF). S. maltophilia is frequently observed in polymicrobial infections, and we have previously shown that Pseudomonas aeruginosa promotes colonization and persistence of S. maltophilia in mouse respiratory infections. In this study, we used host and bacterial RNA sequencing to further define this interaction. To evaluate S. maltophilia transcript profiles we used a recently described method for selective capture of bacterial mRNA transcripts with strain specific RNA probes. We found that factors associated with the type IV pilus, including the histidine kinase subunit of a chemotactic two-component signaling system (chpA), had increased transcript levels during polymicrobial infection. Using immortalized CF respiratory epithelial cells, we found that infection with P. aeruginosa increases adherence of S. maltophilia, at least in part due to disruption of epithelial tight junctions. In contrast, an isogenic S. maltophilia chpA mutant lacked cooperative adherence to CF epithelia and decreased bacterial burden in vivo in polymicrobial infections with P. aeruginosa. Similarly, P. aeruginosa lacking elastase (lasB) did not promote S. maltophilia adherence or bacterial colonization and persistence in vivo. Based on these results, we conclude that disruption of lung tissue integrity by P. aeruginosa promotes adherence of S. maltophilia to the lung epithelia in a type IV pilus-dependent manner. These data provide insight into S. maltophilia colonization and persistence in patients in later stages of CF disease and may have implications for interactions with other bacterial opportunists.

IMPORTANCE

Despite advances in treatment options for patients with cystic fibrosis (CF), complications of bacterial infections remain the greatest driver of morbidity and mortality in this patient population. These infections often involve more than one bacterial pathogen, and our understanding of how inter-species interactions impact disease progression is lacking. Previous work in our lab found that two CF pathogens, Stenotrophomonas maltophilia and Pseudomonas aeruginosa can cooperatively infect the lung to cause more severe infection. In the present study, we found that infection with P. aeruginosa promotes persistence of S. maltophilia by interfering with epithelial barrier integrity. Depolarization of the epithelial cell layer by P. aeruginosa secreted elastase increased S. maltophilia adherence, likely in a type IV pilus-dependent manner. Ultimately, this work sheds light on the molecular mechanisms governing an important polymicrobial interaction seen in pulmonary diseases such as CF.
Identification and Mechanistic Basis of non-ACE2 Blocking Neutralizing Antibodies from COVID-19 Patients with Deep RNA Sequencing and Molecular Dynamics Simulations
Authors: Fredericks Alger M. , East Kyle W. , Shi Yuanjun , Liu Jinchan , Maschietto Federica , Ayala Alfred , Cioffi William G. , Cohen Maya , Fairbrother William G. , Lefort Craig T. , Nau Gerard J. , Levy Mitchell M. , Wang Jimin , Batista Victor S. , Lisi George P. , Monaghan Sean F.
Published: July 2022

Variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continue to cause disease and impair the effectiveness of treatments. The therapeutic potential of convergent neutralizing antibodies (NAbs) from fully recovered patients has been explored in several early stages of novel drugs. Here, we identified initially elicited NAbs (Ig Heavy, Ig lambda, Ig kappa) in response to COVID-19 infection in patients admitted to the intensive care unit at a single center with deep RNA sequencing (>100 million reads) of peripheral blood as a diagnostic tool for predicting the severity of the disease and as a means to pinpoint specific compensatory NAb treatments. Clinical data were prospectively collected at multiple time points during ICU admission, and amino acid sequences for the NAb CDR3 segments were identified. Patients who survived severe COVID-19 had significantly more of a Class 3 antibody (C135) to SARS-CoV-2 compared to non-survivors (16,315 reads vs 1,412 reads, p=0.02). In addition to highlighting the utility of RNA sequencing in revealing unique NAb profiles in COVID-19 patients with different outcomes, we provided a physical basis for our findings via atomistic modeling combined with molecular dynamics simulations. We established the interactions of the Class 3 NAb C135 with the SARS-CoV-2 spike protein, proposing a mechanistic basis for inhibition via multiple conformations that can effectively prevent ACE2 from binding to the spike protein, despite C135 not directly blocking the ACE2 binding motif. Overall, we demonstrate that deep RNA sequencing combined with structural modeling offers the new potential to identify and understand novel therapeutic(s) NAbs in individuals lacking certain immune responses due to their poor endogenous production. Our results suggest a possible window of opportunity for administration of such NAbs when their full sequence becomes available. A method involving rapid deep RNA sequencing of patients infected with SARS-CoV-2 or its variants at the earliest infection time could help to develop personalized treatments using the identified specific NAbs.
The Citation of Retracted COVID-19 Papers is Common and Rarely Critical
Authors: Meyerowitz-Katz Gideon , Sekhar Praba , Besançon Lonni , Turner Tari , McDonald Steve
Published: July 2022

Background

Retraction is the final safeguard against research error/misconduct. In principle, retraction exists to prevent serious issues identified in published research through post-publication review. Our study investigated the citing of clinical research papers retracted during the COVID-19 pandemic.

Methods

We used the Retraction Watch database extracted as of 27/01/2022 to identify retracted COVID-19 papers and the Google Scholar citation function to gather a dataset of citations of retracted clinical research. We reviewed key aspects of the citing research.

Results

In total, the Retraction Watch database included 212 entries for retracted COVID-19 papers. Of these, 53 papers were clinical. There were a total of 1,141 citations of retracted papers, with 105 errors, leaving 1,036 citations to analyze. The majority (86%) of citations were not critical. The majority (80%) of papers citing retracted research were published after the retraction date.

Conclusions

The citation of retracted and withdrawn COVID-19 clinical studies is common, and rarely critical. Most researchers who cite retracted research do not identify that the paper is retracted, even when submitting long after the paper has been withdrawn. This has serious implications for the reliability of published research and the academic literature, which need to be addressed.
Structural insights into the assembly of gp130 family cytokine signaling complexes
Authors: Zhou Yi , Stevis Panayiotis E. , Cao Jing , Saotome Kei , Wu Jiaxi , Zaretsky Arielle Glatman , Haxhinasto Sokol , Yancopoulos George D. , Murphy Andrew J. , Sleeman Mark W. , Olson William C. , Franklin Matthew C.
Published: July 2022

The gp130 family cytokine signaling complexes have limited structural information despite their crucial roles in various cellular processes. We determined cryo-EM structures of several complexes of this family, containing full ectodomains of both signaling receptors bound to their respective ligands CNTF, CLCF1, LIF, IL-27, and IL-6. Our structures reveal that gp130 serves as a central receptor by engaging Site 2 of CNTF, CLCF1, LIF, and IL-6, and Site 3 of IL-27 and IL-6. The acute bends at both signaling receptors in all complexes bring the membrane-proximal domains to a ~30 Å range but with distinct distances and orientations, which might determine biological specificities of these cytokines. We also reveal how CLCF1 engages its secretion chaperone CRLF1. Our data provide valuable insights for therapeutically targeting gp130-mediated signaling.
Rapid, time-resolved proximity labeling by sbp1 identifies a porin domain protein at the malaria parasite periphery
Authors: Anaguano David , Brooks Carrie F. , Cobb David W. , Muralidharan Vasant
Published: July 2022

The deadly human malaria-causing parasite, Plasmodium falciparum relies on its capacity to completely remodel its host red blood cell (RBC) through the export of hundreds of parasite proteins across several membranes to the RBC. Among these exported proteins are numerous membrane proteins that are inserted into the parasite plasma membrane (PPM) during their transport via the secretory pathway. It is not known how these exported membrane proteins are extracted from the PPM for export. To answer this question, we fused the exported membrane protein skeleton binding protein 1 (SBP1) with the rapid, efficient, and promiscuous biotin ligase known as TurboID (SBP1TbID). Our data show that the SBP1TbID fusion protein was exported efficiently to the host RBC and was able to rapidly biotinylate proteins at the host-parasite interface during its export as well as at its final destination in the host RBC. Using time-resolved proximity biotinylation and label-free quantitative proteomics, we identified early (pre-export) interactors and late (post-export) interactors of SBP1TbID. This led to the identification of 24 proteins that were 10-fold or more enriched in the pre-export time point compared to the post-export time point. Among these early interactors were two promising membrane-associated proteins, one of which has a predicted porin domain, that could potentially act as a translocon at the PPM for exported membrane proteins (Plasmodium translocon of exported membrane proteins or PTEM). Both proteins localize to the host-parasite interface during early stages of the intraerythrocytic cycle and conditional knockdown of these candidates show that they play essential roles in the asexual lifecycle of the parasite. Taken together, our data suggest that these two proteins may play a role in extracting membrane proteins from the PPM for export to the host RBC.
AAV Vector Transduction Restriction and Attenuated Toxicity in hESCs via a Rationally Designed Inverted Terminal Repeat
Authors: Song Liujiang , Brown Nolan J. , Bower Jacquelyn J. , Samulski Richard J. , Hirsch Matthew L.
Published: July 2022

Recombinant adeno-associated virus (rAAV) inverted terminal repeats (ITRs) induce p53-dependent apoptosis in human embryonic stem cells (hESCs). To interrogate this phenomenon, a rationally designed ITR (SynITR), deleted for p53 binding sites was evaluated for vector production and gene delivery. While SynITR genomes were decreased for transgenic genome replication compared to wtITRs, similar production titers indicated that replication is not rate-limiting. Packaged in the AAV2 capsid, wtITR and SynITR vectors demonstrated similar transduction efficiencies of human cell lines with no differences in reporter kinetics. Following rAAV2-wtITR infection of hESCs, rapid apoptosis was observed, in contrast, rAAV2-SynITR infection resulted in attenuated hESC toxicity with cells retaining their differentiation potential. While hESC particle entry and double stranded circular episomes was similar for the ITR contexts, reporter expression was significantly inhibited from transduced SynITR genomes. Infection of hESCs induced γH2AX in an ITR-independent manner, however, canonical activation of p53α was uncoupled using rAAV-SynITR. Further hESC investigations revealed 2 additional novel findings: i) p53β is uniquely and constitutively active, and ii) rAAV infection, independent of the ITR sequence, induces activation of p53ψ. The data herein reveal an ITR-dependent rAAV transduction restriction specific to hESCs and manipulation of the DNA damage response via ITR engineering.
Impact of late larval nutritional stress on adult metabolic, gut and locomotor phenotypes in Drosophila melanogaster
Authors: Patil Shri Gouri , Sekhar Sushmitha , Agarwal Aman , Oviya TS , Rout Debashis , Megha
Published: July 2022

Dietary quantity and quality are key determinants for insect development from egg to adult. When nutritional deficiency is sub-optimal, development is completed, albeit resulting in an adult insect that is smaller than normal in size. If now fed a normal diet, would the smaller adults be similar to normally developed flies? To begin to answer this question, we characterised a few physiological and musculoskeletal readouts. Larvae were subject to acute starvation in late stages of development, and the resulting adults (Early Life Starved; ELS) maintained on a normal diet, were tested for biochemistry, gut physiology and locomotor activity. In females, no significant difference was observed in biochemical readouts for the whole-body or hemolymph, between control and ELS flies. In males, whole-body glucose and hemolymph trehalose were significantly reduced in ELS flies. Interestingly, ELS flies of both sexes respond with a disproportionally higher accumulation of triacylglycerides (TAGs) when on a high-fat diet. Age-related changes in the adult gut were compared between control and ELS flies: these revealed an increased proportion of ELS flies with loss of gut barrier integrity, deviant number of intestinal stem cells and no difference in enteroendocrine cells. The rate of antimicrobial peptide gene expression to an enteric infection challenge was also slower in ELS flies. For musculoskeletal readouts, climbing and flight behaviour were measured. In population assays, both male and female ELS flies showed climbing deficits. In a fine-scale climbing assay on individual flies, female but not male ELS flies showed higher climbing speed, while males but not females, showed lower geotactic index. This collection of phenotypic assessments show that firstly, larval undernutrition, even when not lethal, continues to impact adult functioning. Secondly, for some phenotypes, a normal diet in adults exposed to early life malnutrition is insufficient to restore optimal functioning. Thirdly, larval dietary loss affects adult insects in a sex-dependent manner. This study lays the framework to uncover the molecular, cellular and hormonal mechanisms that are altered by early life malnutrition. Furthermore, these readouts may be used to develop Drosophila as a high-throughput model for interrogating the efficacy of diet therapies to address malnutrition.
Symbiosis between innovation and tradition applied in the northwestern Mexico food market: an exploratory analysis
Authors: Salgado Lizbeth , Camarena Dena Maria
Published: July 2022

Purpose

The main objective of this paper is to analyse the relationship between innovation and traditional concepts to explain the phenomenon of traditional food with innovation from a market and consumer behaviour perspective in the Mexican context.

Design/methodology/approach

The research is carried out in two phases: (1) analysis of the offer in distribution and (2) consumer research. First, a mixed observation technique in the offer of traditional foods with innovation was carried out. The data were recollected from 24 companies' websites and was complemented with information from main distribution chains of the city of Hermosillo (Mexico). Second, a survey was carried out with 310 Mexican consumers. The data obtained were analysed using bi-variable and multivariable techniques.

Findings

The findings from the websites showed that there are 19 traditional products with innovation that are marketed through this medium, while 39 traditional products with innovation are offered in distribution chains. Of all foods, 61% showed innovations in ingredients and materials. Also, the consumer evaluations identified three segments: the consumers orientated towards innovations, convenience and health (42.2%), those orientated towards sensory innovations (39%), and those more inclined towards innovations in marketing and availability (18.7%).

Research limitations/implications

The research considers a partial perspective of the agri-food chain and not an integral vision, it is limited to a specific area and to certain traditional foods.

Practical implications

The symbiosis between innovation and tradition is identified from the perspective of supply and demand. The trend that exists in the market regarding the types of innovations and the gaps that exist regarding environmental elements are recognized.

Social implications

The data obtained in the research generate information for business decision-making and entrepreneurship; in addition indicates new dietary and consumption patterns. It also provides knowledge about innovation and tradition, and highlights the relevance of traditional food.

Originality/value

This study tries to fill a gap in the literature by focusing on the market and consumer behaviour perspective for traditional food with innovation.
From customer readiness to customer retention: the mediating role of customer psychological and behavioral engagement
Authors: Torkzadeh Samaneh , Zolfagharian Mohammadali , Yazdanparast Atefeh , Gremler Dwayne D.
Published: July 2022

Purpose

Customer engagement (CE) literature features divergent definitions and conceptualizations. To clarify its meaning, antecedents and outcomes, this paper aims to propose that psychological customer engagement (PCE) is the mechanism by which customers’ readiness to engage influences behavioral customer engagement (BCE) in the form of in-role and extra-role behaviors, which then affect customers’ goal attainment, satisfaction and retention.

Design/methodology/approach

Set in the fitness center industry, this study combines perceptual data (from customers) and behavioral data (from the fitness center) to reveal a hierarchy of effects: customer readiness to PCE to BCE to customer goal attainment, satisfaction and retention.

Findings

Customer readiness variables (role clarity, ability, motivation) influence in-role and extra-role BCE directly and indirectly through PCE. Extra-role BCE is associated with goal attainment and satisfaction, and the latter is linked to customer retention. In-role BCE is associated with goal attainment only.

Research limitations/implications

The proposed integrative model bridges the psychological–behavioral divide in CE literature and encourages the adoption of a broader nomological network that accounts for the effects of customers’ characteristics and actions on their goal attainment, satisfaction and retention.

Practical implications

Managers can enhance CE by improving customer role clarity, ability and motivation. Relative to in-role BCE, extra-role BCE appears more critical because it affects both goal attainment and satisfaction directly and retention indirectly.

Originality/value

The novel integrative approach, combining BCE and PCE in a single model, also provides a consumer-oriented view on CE, which establishes a more comprehensive perspective, as summarized in the proposed model of consumer engagement.
Creating private and semi public open spaces to achieve social sustainability in residential complexes
Authors: Bahador Amin , Bavar Cyrus
Published: July 2022

Purpose

The rapid change in the context of urban housing and the spatial organization of contemporary houses caused the alteration and elimination of spaces that met the social needs of residents for centuries. With the advent of multistorey flats, houses became denser and interactive areas became more limited and were gradually eliminated. Therefore, these changes caused the loss of interaction among occupants and social stability in today's residential complexes. Accordingly, the purpose of this paper is to improve interactions between residents and raise the level of social sustainability in residential complexes by reviving the lost interactive spaces and meeting the social needs of inhabitants.

Design/methodology/approach

In this paper, that is, applied research, the library method and a questionnaire have been used to conduct the study. The questionnaire consists of 13 questions categorized based on five hypotheses.

Findings

Existing public open spaces between the blocks of residential complexes are not efficient enough to raise the interaction between residents because of some problems such as difficult access for middle and upper floors, lack of separate territories and spaces, lack of proper control and supervision and lack of privacy and security.

Practical implications

This paper can be helpful for researchers, designers and mass builders in the field of housing to pay attention to the social needs of occupants, as the basic needs of humans, and improve the quality of interactive spaces by realizing their problems and shortcomings.

Originality/value

This paper tries to improve the quality of interactive spaces based on the social needs of residents to increase the level of interaction between dwellers and creates social sustainability in the residential complexes.
Advances in mobile financial services: a review of the literature and future research directions
Authors: Shaikh Aijaz A. , Alamoudi Hawazen , Alharthi Majed , Glavee-Geo Richard
Published: July 2022

Purpose

Using the theory, construct, method, moderator (TCMM) format, this framework-based review critically analyses the mobile financial services (MFSs) field through a detailed synthesis and analysis of a sample of mainstream empirical research published in various scientific journals within the period 2009–2020.

Design/methodology/approach

The authors followed a three-step structured approach suggested by Webster and Watson (2002) to search for the literature to synthesise the global perspectives on MFSs and their associated applications and systems. The literature research resulted in the identification of 115 most relevant articles.

Findings

The authors identified three major categories or domains within the MFSs comprising the entire spectrum of digital financial services. To facilitate the literature analysis, TCMM is developed and proposed as an organising framework. Moreover, the authors also developed and presented the comprehensive framework of MFS domains and explicitly identified 14 different research themes for future research in MFSs.

Originality/value

Prior attempts to synthesise and analyse mainstream academic research in MFSs have been scant and limited to a specific MFS domain: mobile banking or mobile payment. The authors synthesised a more extensive body of knowledge and provided a global perspective on the MFS field. Unlike the past literature reviews which followed traditional frameworks such as antecedents, decisions and outcome (ADO); TCCM; and 6 W Framework (who, when, where, how, what and why), the authors developed and proposed TCMM as organising framework.
Export behaviour of firms in India: does gender of the firm owner matter?
Authors: Garg Kanika , Shastri Shruti
Published: July 2022

Purpose

The purpose of this study is to investigate the impact of the gender of the firm owner on the export behaviour of firms in the Indian context.

Design/methodology/approach

The present study utilizes the data from World Bank’s Enterprise Survey. The survey provides information on 9,281 firms located in different regions in India. Binomial logistic regression is employed to examine if the owner’s gender matters for the firm’s export-related decisions (export propensity, export mode, export intensity and export market diversification) as a direct or moderating factor controlling for other possible determinants of export activity.

Findings

The findings of the study reveal that firms with a majority of female ownership are less likely to export. However, once the firms indulge in exports, their choice of export mode and export intensity is not affected by the owner’s gender. The gender of the firm owner plays an important role in export market diversification as it is observed that the firms owned by the majority of women have concentrated export markets.

Practical implications

The findings advocate the integration of gender perspective into export promotion policies in India. In light of the findings that the gender of the firm owner entails a heterogeneous impact on different dimensions of export, the key areas requiring policy interventions are female entrepreneur’s export participation and export market diversification.

Originality/value

This study augments the previous scholarship by focusing on the intersection of the gender of firm owner and export propensity along with other unexplored dimensions of export behaviour in female entrepreneurship literature viz. mode of export, export intensity and export market diversification.
The effect of economic factors on suicide: an analysis of a developing country
Authors: Akyuz Mert , Karul Cagin
Published: July 2022

Purpose

This study aims to examine the effects of industrial production (IP), inflation and investment on suicide mortality in Turkey as a developing country over the 1988–2018 period.

Design/methodology/approach

Fourier cointegration test and dynamic ordinary least square regression were used in this study.

Findings

IP and investment have a statistically significant and negative impact on suicide mortality, whereas inflation has a statistically significant and positive effect on suicide mortality.

Research limitations/implications

The results of this study have important implications for policymakers and potentially the creation and implementation of suicide prevention policies. Not only do investment promotion, IP and disinflation policies in developing countries have a significant effect on economic growth but they also have a substantial impact on mental health.

Originality/value

Although previous studies have investigated the impact of economic growth and unemployment on suicide deaths in Turkey, no research has probed the effect of economic factors, except for unemployment and gross domestic product, on suicide. Thus, given the hidden unemployment and informal sector in developing economies, it is vital to examine the impact of IP, inflation and investment on mental health.