bluuebunny/crossref_metadata_2025 huggingface dataset:
SARS-CoV-2 attack rate and population immunity in southern New England, March 2020 - May 2021
Authors: Tran Thu Nguyen-Anh , Wikle Nathan B , Yang Fuhan , Inam Haider , Leighow Scott , Gentilesco Bethany , Chan Philip , Albert Emmy , Strong Emily R , Pritchard Justin R , Hanage William P , Hanks Ephraim M , Crawford Forrest W. , Boni Maciej F
Published: December 2021

Estimating an infectious disease attack rate requires inference on the number of reported symptomatic cases of a disease, the number of unreported symptomatic cases, and the number of asymptomatic infections. Population-level immunity can then be estimated as the attack rate plus the number of vaccine recipients who had not been previously infected; this requires an estimate of the fraction of vaccines that were distributed to seropositive individuals. To estimate attack rates and population immunity in southern New England, we fit a validated dynamic epidemiological model to case, clinical, and death data streams reported by Rhode Island, Massachusetts, and Connecticut for the first 15 months of the COVID-19 pandemic, from March 1 2020 to May 31 2021. This period includes the initial spring 2020 wave, the major winter wave of 2020-2021, and the lagging wave of lineage B.1.1.7(Alpha) infections during March-April 2021. In autumn 2020, SARS-CoV-2 population immunity (equal to the attack rate at that point) in southern New England was still below 15%, setting the stage for a large winter wave. After the roll-out of vaccines in early 2021, population immunity in many states was expected to approach 70% by spring 2021, with more than half of this immune population coming from vaccinations. Our population immunity estimates for May 31 2021 are 73.4% (95% CrI: 72.9% - 74.1%) for Rhode Island, 64.1% (95% CrI: 64.0% - 64.4%) for Connecticut, and 66.3% (95% CrI: 65.9% - 66.9%) for Massachusetts, indicating that >33% of southern Englanders were still susceptible to infection when the Delta variant began spreading in July 2021. Despite high vaccine coverage in these states, population immunity in summer 2021 was lower than planned due to 34% (Rhode Island), 25% (Connecticut), and 28% (Massachusetts) of vaccine distribution going to seropositive individuals. Future emergency-setting vaccination planning will likely have to consider over-vaccination as a strategy to ensure that high levels of population immunity are reached during the course of an ongoing epidemic.
Vertical transmission of tissue microbiota in Caenorhabditis elegans
Authors: Zheng Jun , Meng Xin , Fan Jiahao , Yang Dong
Published: December 2021

The past forty-five years has witnessed Caenorhabditis elegans as the most significant model animal in life science since its discovery seventy years ago1,2, as it introduced principles of gene regulated organ development, and RNA interference into biology3-5. Meanwhile, it has become one of the lab animals in gut microbiota studies as these symbionts contribute significantly to many aspects in host biology6,7. Meanwhile, the origin of gut microbiota remains debatable in human8- 11, and has not been investigated in other model animals. Here we show that the symbiont bacteria in C. elegans not only vertically transmit from the parent generation to the next, but also distributes in the worm tissues parallel with its development. We found that bacteria can enter into the embryos of C. elegans, a step associated with vitellogenin, and passed to the next generation. These vertically transmitted bacteria share global similarity, and bacterial distribution in worm tissues changes as they grow at different life stages. Antibiotic treatment of worms increased their vulnerability against pathogenic bacteria, and replenishment of tissue microbiota restored their immunity. These results not only offered a molecular basis of vertical transmission of bacteria in C. elegans, but also signal a new era for the mixed tissue cell-bacteria multi-species organism study.
Revised International Staging System (R-ISS) stage-dependent analysis uncovers oncogenes and potential immunotherapeutic targets in multiple myeloma
Authors: Zhong Ling , Yuan Xinwei , Zhang Qian , Jiang Tao , Li Huan , Xiao Jialing , Li Chenglong , Luo Lan , Shuai Ping , Wang Liang , Liu Yuping , Yu Man , Shi Yi , Zhang Wei , Zhang Yunbin , Gong Bo
Published: December 2021

Multiple myeloma (MM), characterized by high intratumour heterogeneity, accounts for ∼10% of all haematologic malignancies. Stratified by the Revised International Staging System (R-ISS), little is known about R-ISS-related plasma cell (PC) heterogeneity, gene expression modules in cytotoxic T/NK cells and immunoregulatory ligands and receptors. Herein, we constructed a single-cell transcriptome atlas of bone marrow in normal and R-ISS-staged MM patients. Focusing on PCs, we identified and validated a subset of GZMA+ cytotoxic PCs. In addition, a malignant PC population with high proliferation capability (proliferating PCs) was associated with unfavourable prognosis and EBV infection in our collected samples. Ribonucleotide Reductase Regulatory Subunit M2 (RRM2), a specific marker of proliferating PCs, was shown to induce MM cell line proliferation and serve as a detrimental marker in MM. Subsequently, three R-ISS-dependent gene modules in cytotoxic CD8+ T and NKT cells were identified and functionally analysed. Finally, cell-cell communication between neutrophils and proliferating PCs with cytotoxic CD8+ T and NKT cells was investigated, which identified intercellular ligand receptors and potential immunotargets such as SIRPA-CD47 and TIGIT-NECTIN3. Collectively, this study provides an R-ISS-related single-cell MM atlas and reveals the clinical significance of two PC clusters, as well as potential immunotargets in MM progression.
Loss of Neutralizing Antibody Response to mRNA Vaccination against SARS-CoV-2 Variants: Differing Kinetics and Strong Boosting by Breakthrough Infection
Authors: Evans John P. , Zeng Cong , Carlin Claire , Lozanski Gerard , Saif Linda J. , Oltz Eugene M. , Gumina Richard J. , Liu Shan-Lu
Published: December 2021

The waning efficacy of SARS-CoV-2 vaccines combined with the continued emergence of variants resistant to vaccine-induced immunity has reignited debate over the need for booster vaccines. To address this, we examined the neutralizing antibody (nAb) response against four major SARS-CoV-2 variants—D614G, Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2)—in health care workers (HCWs) at pre-vaccination, post-first and post-second mRNA vaccine dose, and six months post-second mRNA vaccine dose. Neutralizing antibody titers against all variants, especially the Delta variant, declined dramatically from four weeks to six months post-second mRNA vaccine dose. Notably, SARS-CoV-2 infection enhanced vaccine durability, and mRNA-1273 vaccinated HCWs also exhibited ~2-fold higher nAb titers than BNT162b2 vaccinated HCWs. Together these results demonstrate possible waning of protection from infection against SARS-CoV-2 Delta variant based on decreased nAb titers, dependent on COVID-19 status and the mRNA vaccine received.
Quantitative and temporal measurement of dynamic autophagy rates
Authors: Beesabathuni Nitin Sai , Shah Priya S.
Published: December 2021

Autophagy is a multistep degradative process that is essential for maintaining cellular homeostasis. Systematically quantifying flux through this pathway is critical for gaining fundamental insights and effectively modulating this process that is dysregulated during many diseases. Established methods to quantify flux use steady state measurements, which provide limited information about the perturbation and the cellular response. We present a theoretical and experimental framework to measure autophagic steps in the form of rates under non-steady state conditions. We use this approach to measure temporal responses to rapamycin and wortmannin treatments, two commonly used autophagy modulators. We quantified changes in autophagy rates in as little as 10 minutes, which can establish direct mechanisms for autophagy perturbation before feedback begins. We identified concentration-dependent effects of rapamycin on the initial and temporal progression of autophagy rates. We also found variable recovery time from wortmannin’s inhibition of autophagy, which is further accelerated by rapamycin. In summary, this new approach enables the quantification of autophagy flux with high sensitivity and temporal resolution and facilitates a comprehensive understanding of this process.
Validating EEG, MEG and combined MEG and EEG beamforming for an estimation of the epileptogenic zone in focal cortical dysplasia
Authors: Neugebauer Frank , Antonakakis Marios , Unnwongse Kanjana , Parpaley Yaroslav , Wellmer Jörg , Rampp Stefan , Wolters Carsten H.
Published: December 2021

MEG and EEG source analysis is frequently used for the presurgical evaluation of pharma-coresistant epilepsy patients. The source localization of the epileptogenic zone depends, among other aspects, on the selected inverse and forward approaches and their respective parameter choices. In this validation study, we compare for the inverse problem the standard dipole scanning method with two beamformer approaches and we investigate the influence of the covariance estimation method and the strength of regularization on the localization performance for EEG, MEG and combined EEG and MEG. For forward modeling, we investigate the difference between calibrated six-compartment and standard three-compartment head modeling. In a retrospective study of two patients with focal epilepsy due to focal cortical dysplasia type IIb and seizure-freedom following lesionectomy or radiofrequency-guided thermocoagulation, we used the distance of the localization of interictal epileptic spikes to the resection cavity resp. rediofrequency lesion as reference for good localization. We found that beamformer localization can be sensitive to the choice of the regularization parameter, which has to be individually optimized. Estimation of the covariance matrix with averaged spike data yielded more robust results across the modalities. MEG was the dominant modality and provided a good localization in one case, while it was EEG for the other. When combining the modalities, the good results of the dominant modality were mostly not spoiled by the weaker modality. For appropriate regularization parameter choices, the beamformer localized better than the standard dipole scan. Compared to the importance of an appropriate regularization, the sensitivity of the localization to the head modeling was smaller, due to similar skull conductivity modeling and the fixed source space without orientation constraint.
In-hospital mortality due to breakthrough COVID-19 among recipients of COVISHIELD (ChAdOx nCoV-19) and COVAXIN (BBV152)
Authors: Suri Tejas M , Ghosh Tamoghna , Arunachalam M , Vadala Rohit , Vig Saurabh , Bhatnagar Sushma , Mohan Anant
Published: December 2021

Background

Multiple vaccines have received emergency-use authorization in different countries in the fight against the COVID-19 pandemic. India had started its vaccination campaign using the COVISHIELD (ChAdOx nCoV-19) and the COVAXIN (BBV152) vaccines. However, there is a lack of head-to-head comparisons of the different vaccines.

Methods

We performed a retrospective cohort study during the second wave of the pandemic in India with predominant circulation of the delta strain of SARS-CoV-2. We enrolled adult patients who were hospitalized with breakthrough COVID-19 infection after vaccination. We compared in-hospital outcomes between patients who had received the COVISHIELD (n=181) or COVAXIN vaccines.

Results

Between April and June 2021, a total of 353 patients were enrolled, among whom 181 (51.3%) received COVAXIN (156 partially vaccinated and 25 fully vaccinated) and 172 (48.7%) received COVISHIELD (155 partially vaccinated and 17 fully vaccinated). The in-hospital mortality did not differ between the recipients of COVISHIELD or COVAXIN in either the fully vaccinated [2 deaths (11.8%) vs 0 deaths (0%), respectively p=0.08] or the partially vaccinated cohorts [31 deaths (20%) vs 28 deaths (17.9%), respectively, p=0.65].

Conclusions

Patients who are hospitalized with breakthrough COVID-19 had similar in-hospital outcome irrespective of whether they received COVISHIELD or COVAXIN.
Impaired LAIR-1-mediated immune control due to collagen degradation in fibrosis
Authors: Carvalheiro Tiago , Marut Wioleta , Pascoal Ramos M. Inês , García Samuel , Fleury Devan , Affandi Alsya J. , Meijers Aniek S. , Giovannone Barbara , Tieland Ralph G. , Elshof Eline , Ottria Andrea , Cossu Marta , Meizlish Matthew L. , Veenendaal Tineke , Ramanujam Meera , Moreno-García Miguel E. , Klumperman Judith , Liv Nalan , Radstake Timothy R.D.J. , Meyaard Linde
Published: December 2021

Tissue repair is disturbed in fibrotic diseases like systemic sclerosis (SSc), where the deposition of large amounts of extracellular matrix components such as collagen interferes with organ function. LAIR-1 is an inhibitory collagen receptor highly expressed on tissue immune cells. We questioned whether in SSc, impaired LAIR-1-collagen interaction is contributing to the ongoing inflammation and fibrosis.

We found that SSc patients do not have an intrinsic defect in LAIR-1 expression or function. Instead, fibroblasts from SSc patients deposit disorganized collagen productsin vitro, which are dysfunctional LAIR-1 ligands. This can be mimicked in healthy fibroblasts stimulated by soluble factors that drive inflammation and fibrosis in SSc and is dependent of matrix metalloproteinases and platelet-derived growth factor receptor signaling.

In support of a non-redundant role of LAIR-1 in the control of fibrosis, we found that LAIR-1-deficient mice have increased skin fibrosis in response to repeated injury and in the bleomycin mouse model for SSc. Thus, LAIR-1 represents an essential control mechanism for tissue repair. In fibrotic disease, excessive collagen degradation may lead to a disturbed feedback loop. The presence of functional LAIR-1 in patients provides a therapeutic opportunity to reactivate this intrinsic negative feedback mechanism in fibrotic diseases.
Decoupling growth and production by removing the origin of replication from a bacterial chromosome
Authors: Kasari Marje , Kasari Villu , Kärmas Mirjam , Jõers Arvi
Published: December 2021

Efficient production of biochemicals and proteins in cell factories frequently benefits from a two-stage bioprocess in which growth and production phases are decoupled. Here we describe a novel growth switch based on the permanent removal of the origin of replication (oriC) from the Escherichia coli chromosome. Without oriC, cells cannot initiate a new round of replication and they stop growing while their metabolism remains active. Our system relies on a serine recombinase from bacteriophage phiC31 whose expression is controlled by the temperature-sensitive cI857 repressor from phage lambda. Reporter protein expression in switched cells continues after cessation of growth, leading to protein levels up to five times higher compared to non-switching cells. Switching induces a unique physiological state that is different from both normal exponential and stationary phases. Switched cells remain in this state even when not growing, retain their protein synthesis capacity, and do not induce proteins associated with the stationary phase. Our switcher technology is potentially useful for a range of products and applicable in many bacterial species for decoupling growth and production.
A single nucleotide variant in the PPARγ-homologEip75Baffects fecundity inDrosophila
Authors: Hoedjes Katja M , Kostic Hristina , Flatt Thomas , Keller Laurent
Published: December 2021

Single nucleotide polymorphisms are the most common type of genetic variation, but how these variants contribute to the evolutionary adaptation of complex phenotypes is largely unknown. Experimental evolution and genome-wide association studies have demonstrated that variation in the PPARg-homologEip75Bis associated with longevity and life-history differences in the fruit flyDrosophila melanogaster. Using RNAi knockdown, we first demonstrate that reduced expression ofEip75Bin adults affects lifespan, egg-laying rate and egg volume. We then tested the effect of a naturally occurring SNP variant within a cis-regulatory domain ofEip75Bby applying two complementary approaches: a Mendelian randomization approach using lines of theDrosophilaGenetic Reference Panel, and allelic replacement using precise CRISPR/Cas9-induced genome editing. Our experiments reveal that this natural polymorphism has a significant pleiotropic effect on fecundity and egg-to-adult viability, but not on longevity or other life-history traits. These results provide a rare functional validation at the nucleotide level and identify a natural allelic variant affecting fitness and life-history adaptation.
Design of aStreptococcus pyogenesM protein immunogen to elicit M type cross-reactivity
Authors: Wang Kuei-Chen , Kuliyev Eziz , Nizet Victor , Ghosh Partho
Published: December 2021

Coiled coil-forming M proteins of the widespread and potentially deadly bacterial pathogenStreptococcus pyogenes(Strep A) are immunodominant targets of opsonizing antibodies. However, antigenic sequence variability into >220 M types, as defined by the M protein hypervariable region (HVR), has been considered to limit its utility as a vaccine immunogen due to type-specificity in the antibody response. Surprisingly, a multi-HVR immunogen in clinical vaccine trials elicited M type cross-reactivity. The basis for this cross-reactivity is unknown but may be due in part to antibody recognition of a three-dimensional (3D) pattern conserved in many M protein HVRs that confers binding to human C4b-binding protein (C4BP). To test this hypothesis, we asked whether a single M protein immunogen carrying the 3D pattern would elicit cross-reactivity against other M types carrying the 3D pattern. We found that a 34-amino acid sequence of M2 protein bearing the 3D pattern retained full C4BP-binding capacity when fused to a coiled coil-stabilizing sequence from GCN4. This immunogen, called M2G, elicited cross-reactive antibodies against a number of M types that carry the 3D pattern but not against those that lack the 3D pattern. The M2G antiserum recognized M proteins as displayed natively on the Strep A surface, and promoted the opsonophagocytic killing of Strep A strains expressing these M proteins. As C4BP-binding is a conserved virulence trait of Strep A, targeting the 3D pattern may prove advantageous in vaccine design.
From STRs to SNPs via ddRAD-seq: geographic assignment of confiscated tortoises at reduced costs
Authors: Biello Roberto , Zampiglia Mauro , Fuselli Silvia , Fabbri Giulia , Bisconti Roberta , Chiocchio Andrea , Trucchi Emiliano , Canestrelli Daniele , Bertorelle Giorgio
Published: December 2021

Assigning individuals to their source populations is crucial for conservation research, especially for endangered species threatened by illegal trade and translocations. Genetic assignment can be achieved with different types of molecular markers, but technical advantages and cost saving are recently promoting the shift from short tandem repeats (STRs) to single nucleotide polymorphisms (SNPs). Here, we designed, developed, and tested a small panel of SNPs for cost-effective geographic assignment of individuals with unknown origin of the endangered Mediterranean tortoise Testudo hermanni. We started by performing a ddRAD-seq experiment on 70 wild individuals of T. hermanni from 38 locations. Results obtained using 3,182 SNPs are comparable to those previously obtained using STR markers in terms of genetic structure and power to identify the macro-area of origin. However, our SNPs revealed further insights into the substructure in Western populations, especially in Southern Italy. A small panel of highly informative SNPs was then selected and tested by genotyping 190 individuals using the KASP genotyping chemistry. All the samples from wild populations of known geographic origin were genetically re-assigned with high accuracy to the original population. This reduced SNPs panel represents an efficient molecular tool that enables individuals to be genotyped at low cost (less than €15 per sample) for geographical assignment and identification of hybrids. This information is crucial for the management in-situ of confiscated animals and their possible re-allocation in the wild. Our methodological pipeline can easily be extended to other species.
Inhibiting Host Protein Deposition on Urinary Catheters Reduces Urinary Tract Infections
Authors: Andersen Marissa Jeme , Fong ChunKi , La Bella Alyssa Ann , Molesan Alex , Champion Matthew M. , Howell Caitlin , Flores-Mireles Ana L.
Published: December 2021

Microbial adhesion to medical devices is common for hospital-acquired infections, particularly for urinary catheters. If not properly treated these infections cause complications and exacerbate antimicrobial resistance. Catheter use elicits bladder inflammation, releasing host serum-proteins, including fibrinogen, into the bladder, which deposit on the urinary catheter. Enterococcus faecalis uses fibrinogen as a scaffold to bind and persist in the bladder despite antibiotic treatments. Inhibition of fibrinogen-pathogen interaction significantly reduces infection. Here, we show deposited fibrinogen is advantageous for uropathogens, suggesting that targeting catheter protein deposition may reduce colonization creating an effective intervention. Hostprotein deposition was reduced, using liquid-infused catheters, resulting in decreased colonization on catheters, in bladders, and dissemination in vivo. Furthermore, proteomics revealed a significant decrease in deposition of host-secreted proteins on liquid-infused catheter surfaces. Our findings suggest targeting microbial binding scaffolds may be an effective antibiotic-sparing intervention for use against catheter-associated urinary tract infections and other medical device infections.
Pre-meiotic pairing of homologous chromosomes during Drosophila male meiosis
Authors: Rubin Thomas , Macaisne Nicolas , Vallés Ana Maria , Guilleman Clara , Gaugué Isabelle , Huynh Jean-René
Published: December 2021

In the early stages of meiosis, maternal and paternal chromosomes pair with their homologous partner and recombine to ensure exchange of genetic information and proper segregation. These events can vary drastically between species and between males and females of the same species. In Drosophila, in contrast to females, males do not form synaptonemal complexes (SCs), do not recombine and have no crossing-over; yet, males are able to segregate their chromosomes properly. Here, we investigated the early steps of homologues pairing in Drosophila males. We found that homologues are not paired in germline stem cells (GSCs) and become paired in the mitotic region before meiotic entry, similarly to females. Surprisingly, male germline cells express SC proteins, which localize to centromeres and promote pairing. We further found that the SUN/KASH (LINC) complex and microtubules are required for homologues pairing as in females. Chromosome movements are however much slower than in females and we demonstrate that this slow dynamic is compensated in males by having longer cell cycles. In agreement, slowing down cell cycles was sufficient to rescue pairing-defective mutants in female meiosis. Our results demonstrate that although meiosis differs significantly between males and females, sex-specific cell cycle kinetics are integrated with similar molecular mechanisms to achieve proper homologues pairing.
Integrin-driven Axon Regeneration in the Spinal Cord Activates a Distinctive CNS Regeneration Program
Authors: Cheah Menghon , Cheng Yuyan , Petrova Veselina , Cimpean Anda , Jendelova Pavla , Swarup Vivek , Woolf Clifford J. , Geschwind Daniel H. , Fawcett James W.
Published: December 2021

The peripheral branch of sensory dorsal root ganglion (DRG) neurons regenerates readily after injury unlike their central branch in the spinal cord. However extensive regeneration and reconnection of sensory axons in the spinal cord can be driven by the expression of α9 integrin and its activator kindlin- 1(α9k1), which enable axons to interact with tenascin-C. To elucidate the mechanisms and downstream pathways affected by activated integrin expression and central regeneration, we conducted transcriptomic analyses of DRG sensory neurons transduced with α9k1, and controls, with and without axotomy of the central branch. Expression of α9k1 without the central axotomy led to upregulation of a known PNS regeneration program, including many genes associated with peripheral nerve regeneration. Coupling α9k1 treatment with dorsal root axotomy led to extensive central axonal regeneration and caused expression of a distinctive CNS regeneration program, including genes associated with ubiquitination, autophagy, endoplasmic reticulum, trafficking, and signalling. Pharmacological inhibition of these processes blocked the regeneration of axons from DRGs and human iPS-derived sensory neurons, validating their causal contributions. This CNS regeneration- associated program showed little correlation with either embryonic development or PNS regeneration programs. Potential transcriptional drivers of this CNS program coupled to regeneration include Mef2a, Runx3, E2f4, Tfeb, Yy1. Signalling from integrins primes sensory neurons for regeneration, but their axon growth in the CNS is associated with a distinctive program that differs from that involved in PNS regeneration.
Zebrafish xenografts to isolate unique human breast cancer metastatic cell populations
Authors: Xiao Jerry , McGill Joseph R. , Nasir Apsra , Lekan Alexander , Johnson Bailey , Wilkins Devan J. , Pearson Gray W. , Tanner Kandice , Goodarzi Hani , Glasgow Eric , Schlegel Richard , Agarwal Seema
Published: December 2021

Cancer metastasis is a critical culprit frequently blamed for treatment failure, drug resistance, poor prognosis, and high mortality rate among all human cancers. Laboratory efforts to isolate metastatic cell populations have typically been confined to mouse models, which are time-consuming and expensive. Here, we present a model system based on xenografting zebrafish embryos to select for cells that are predisposed to progress through the early stages of metastasis. This model requires only 3-5 days to achieve distinct intravasation to the zebrafish circulatory system. The metastatic cells are easily tracked in real-time as they migrate, as well as isolated and propagatedin vitro. Once expanded, molecular characterization of the serially derived invasive cell populations from the tails of the zebrafish accurately predicts genes, signaling pathways, protein-protein interactions, and differential splicing products that are important for an invasive phenotype. This zebrafish model therefore offers a high-throughput and robust method for identifying gene targets critical for cancer metastasis.
Chemical, molecular, and single cell analysis reveal chondroitin sulfate proteoglycan aberrancy in fibrolamellar carcinoma
Authors: Francisco Adam B. , Li Jine , Farghli Alaa R. , Kanke Matt , Shui Bo , Soloway Paul D. , Wang Zhangjie , Reid Lola M. , Liu Jian , Sethupathy Praveen
Published: December 2021

Fibrolamellar carcinoma (FLC) is an aggressive liver cancer with no effective therapeutic options. The extracellular environment of FLC tumors is poorly characterized and may contribute to cancer growth and/or metastasis. To bridge this knowledge gap, we assessed pathways relevant to proteoglycans, a major component of the extracellular matrix. We first analyzed gene expression data from FLC and non-malignant liver tissue (n=27) to identify changes in glycosaminoglycan (GAG) biosynthesis pathways and found that genes associated with production of chondroitin sulfate, but not other GAGs, are significantly increased by 8-fold. We then implemented a novel LC-MS/MS based method to quantify the abundance of different types of GAGs in patient tumors (n=16) and found that chondroitin sulfate is significantly more abundant in FLC tumors by 6-fold. Upon further analysis of GAG-associated proteins we found that versican (VCAN) expression is significantly up-regulated at the mRNA and protein levels, the latter of which was validated by immunohistochemistry. Finally, we performed single-cell assay for transposon-accessible chromatin-sequencing on FLC tumors (n=3), which revealed for the first time the different cell types in FLC tumors and also showed that VCAN is likely produced not only from FLC tumor epithelial cells but also activated stellate cells. Our results reveal a pathologic aberrancy in chondroitin (but not heparan) sulfate proteoglycans in FLC and highlight a potential role for activated stellate cells.

Significance

This study leverages a multi-disciplinary approach, including state-of-the-art chemical analyses and cutting-edge single-cell genomic technologies, to identify for the first time a marked chondroitin sulfate aberrancy in fibrolamellar carcinoma (FLC) that could open novel therapeutic avenues in the future.
The oscillation of mitotic kinase governs cell cycle latches
Authors: Novak Bela , Tyson John J
Published: December 2021

In order to transmit a eukaryotic cell’s genome accurately from mother cell to daughter cells, it is essential that the basic events of the cell division cycle (DNA synthesis and mitosis) occur once and only once per cycle, i.e., that a cell progresses irreversibly from G1 to S to G2 to M and back to G1. Irreversible progression through the cell cycle is assured by a sequence of ‘latching’ molecular switches, based on molecular interactions among cyclin-dependent kinases and their auxiliary partners. Positive feedback loops (++ or −−) create bistable switches with latching properties, and negative feedback loops drive progression from one stage to the next. In budding yeast (Saccharomyces cerevisiae) these events are coordinated by double-negative feedback loops between Clb-dependent kinases (Clb1-6) and their antagonists (APC:Cdh1 and Sic1). If the coordinating signal is compromised, either by deletion of Clb1-5 proteins or expression of non-degradable Clb2, then irreversibility is lost and yeast cells exhibit multiple rounds of DNA replication or mitotic exit events (Cdc14 endocycles). Using mathematical modelling of a stripped-down control network, we show how endocycles arise because the switches fail to latch, and the gates swing back and forth by the action of the negative feedback loops.
Anatomical and neurophysiological data on primary visual cortex suffice for reproducing brain-like robust multiplexing of visual function
Authors: Chen Guozhang , Scherr Franz , Maass Wolfgang
Published: December 2021

Neural networks of the brain that process visual information have structural properties that differ significantly from those of neural networks which are commonly used for visual processing in AI, such as Convolutional Neural Networks (CNNs). But it has remained unknown how these structural differences are related to network function. We analyze visual processing capabilities of a large-scale model for area V1 that arguably provides the most comprehensive accumulation of anatomical and neurophysiological data that is currently available. Its network structure turns out to induce a number of characteristic visual processing capabilities of the brain, in particular the capability to multiplex different visual processing tasks, also on temporally dispersed visual information, with remarkable robustness to noise. This V1 model also exhibits a number of characteristic neural coding properties of the brain, which provide explanations for its superior noise robustness. Since visual processing in the brain is substantially more energy-efficient than implementations of CNNs in common computer hardware, such brain-like neural network models are likely to have also an impact on technology: As blueprints for visual processing in more energy-efficient neuromorphic hardware.

Teaser

A new generation of neural network models based on neurophysiological data can achieve robust multiplexing capabilities.
Microneedle-mediated intratumoral delivery of anti-CTLA-4 promotes cDC1-dependent eradication of oral squamous cell carcinoma with limited irAEs
Authors: Gilardi Mara , Saddawi-Konefka Robert , Wu Victoria H. , Lopez-Ramirez Miguel Angel , Wang Zhiyong , Soto Fernando , Steffen Dana J. , Proietto Marco , Mikulski Zbigniew , Miki Haruka , Sharabi Andrew , Kupor Daniel , Rueda Ricardo , Hollern Daniel P. , Wang Joseph , Gutkind J. Silvio
Published: December 2021

Head and neck squamous cell carcinoma (HNSCC) ranks 6th in cancer incidence worldwide and has a five-year survival rate of only 63%. Immunotherapies – principally immune checkpoint inhibitors (ICI), such as anti-PD-1 and anti-CTLA-4 antibodies that restore endogenous antitumor T-cell immunity – offer the greatest promise for HNSCC treatment. Anti-PD-1 has been recently approved for first line treatment of recurrent and metastatic HNSCC; however less than 20% of patients show clinical benefit and durable responses. In addition, the clinical application of ICI has been limited by immune-related adverse events (irAEs) consequent to compromised peripheral immune tolerance. Although irAEs are often reversible, they can become severe, prompting premature therapy termination or becoming life-threatening. To address the irAEs inherent to systemic ICI therapy, we developed a novel, local delivery strategy based upon an array of soluble microneedles (MN). Using our recently reported syngeneic, tobacco-signature murine HNSCC model, we found that both systemic and local-MN anti-CTLA-4 therapy lead to >90% tumor response, which is dependent on CD8 T cells and conventional dendritic cell type 1 (cDC1). However, local-MN delivery limited the distribution of anti-CTLA-4 antibody from areas distal to draining lymphatic basins. Employing Foxp3-GFPDTR transgenic mice to interrogate irAEs in vivo, we found that local-MN delivery of anti-CTLA-4 protects animals from irAEs observed with systemic therapy. Taken together, our findings support the exploration of MN-intratumoral ICI delivery as a viable strategy for HNSCC treatment with reduced irAEs, and the opportunity to target cDC1s as part of multimodal treatment options to boost ICI therapy.
Inhibitory neurosteroid reverses the dendritic spine disorder caused by gain-of-function GABAAR epilepsy variants
Authors: Hannan Saad , Au Kamei , Smart Trevor G
Published: December 2021

GABAA receptors (GABAARs) are key orchestrators of neuronal activity and several GABAAR variants have been linked to genetic neurodevelopmental disorders (NDDs) and epilepsies. Here, we report two variants (Met263Lys, Leu267Ile) in the predominant GABAAR α1 subunit gene (GABRA1) that increase apparent receptor affinity for GABA and confer spontaneous receptor activity. These gain-of-function features are unusual because GABAAR variants are traditionally thought to cause seizures by reducing inhibitory neurotransmission. Both Met263Lys and Leu267Ile increased tonic and spontaneous GABAergic conductances in neurons revealed by competitive inhibition and channel block of GABAARs. Significantly, α1-subunit variant expression in hippocampal neurons also reduced dendritic spine density. Our results indicate that elevated GABAergic signalling can precipitate genetic epilepsies and NDDs. Furthermore, the mechanistic basis may involve the de-compartmentalisation of excitatory inputs due to the removal of dendritic spines. This aberrant structural plasticity can be reversed by the naturally-occurring, therapeutically-tractable, inhibitory neurosteroid, pregnenolone sulphate.
An efficient decision support system for selecting very light business jet using CRITIC-TOPSIS method
Authors: Dhara Aishwarya , Kaur Gurpreet , Kishan Pon Maa , Majumder Arunava , Yadav Rakesh
Published: December 2021

Purpose

This paper aims to assure the selection of the most suitable very light business aircraft which is preferred by the passengers based on effectiveness and aesthetic comfort. The proposed approach to determine the light business jet aircraft would provide long-range, less travel time, cozy seating arrangements, on-board lavatory facility, other aesthetic ambiance (audio systems, light systems and temperature-noise control) and appliances at reasonable flight cost.

Design/methodology/approach

The selection of a light business jet is obtained through multi-criteria decision-making based on the speed limit ranges from 0.57 to 0.70 Mach number and the distance traveled up to 3,000 km with the best aesthetic comfort level. To validate the approach, case studies of five aircrafts such as Honda Jet HA 420, Cessna Citation jet M2, Embraer Phenom 100, Eclipse 550 and Cessna Citation Mustang are performed. To obtain the best suitable business jet, criteria importance through intercriteria correlation (CRITIC) and technique for order performance by similarity to ideal solution (TOPSIS) is used to determine the rankings of listed aircraft.

Findings

The study concludes that the Cessna Citation jet M2 is chosen as the best Very Light Jet (VLJ) on the basis of speed, range, weight, cost, aesthetic and comfort. Based on the sensitivity, mean absolute percentage error (MAPE) and symmetric mean absolute percentage error analysis (sMAPE), the most and least sensitive criteria for a business jet came out to be cost and speed, respectively.

Originality/value

A real case study for several parameters of five different jets such as Honda Jet HA 420, Cessna Citation jet M2, Embraer Phenom 100, Eclipse 550 and Cessna Citation Mustang are shown in this paper. Based on the case study numerical values are assigned with speed, range, weight, cost, aesthetic and comfort which are applied with CRITIC and TOPSIS to obtain the most suitable business jet among the five mentioned jets which are rarely found in the literature.
Decision model with quantification of buyer-supplier trust in advanced technology enterprises
Authors: Collier Zachary A. , Guin Ujjwal , Sarkis Joseph , Lambert James H.
Published: December 2021

Purpose

In the buyer-supplier relationship of a high-technology enterprise, the concepts of trust and risk are closely intertwined. Entering into a buyer-supplier relationship inherently involves a degree of risk, since there is always an opportunity for one of the parties to act opportunistically. Purchasing and supply managers play an important role in reducing the firm's risk profile, and must make decisions about whether or not to enter into, or remain in, a relationship with a supplier based on a subjective assessment of trust and risk.

Design/methodology/approach

In this paper, the authors seek to explore how trust in the buyer-supplier relationship can be quantitatively modeled in the presence of risk. The authors develop a model of trust between a buyer and supplier as a risk-based decision, in which a buyer decides to place trust in a supplier, who may either act cooperatively or opportunistically. The authors use a case study of intellectual property (IP) piracy in the electronics industry to illustrate the conceptual discussion and model development.

Findings

The authors produce a generalizable model that can be used to aid in decision-making and risk analysis for potential supply-chain partnerships, and is both a theoretical and practical innovation. However, the model can benefit a variety of high-technology enterprises.

Originality/value

While the topic of trust is widely discussed, few studies have attempted to derive a quantitative model to support trust-based decision making. This paper advanced the field of supply chain management by developing a model which relates risk and trust in the buyer-supplier relationship.
Value management implementation barriers for sustainable building: a bibliometric analysis and partial least square structural equation modeling
Authors: Kineber Ahmed Farouk , Othman Idris , Oke Ayodeji Emmanuel , Chileshe Nicholas , Zayed Tarek
Published: December 2021

Purpose

The purpose of this paper is to examine the relationship between overcoming the value management (VM) implementation barriers and VM implementation in the Egyptian building sector.

Design/methodology/approach

A critical review of the literature on VM was used to through bibliometric analysis has been conducted to highlight the studies’ gap and establish the VM barriers. These obstacles were then contextually transformed via a semi-structured interview and a pilot study, and subsequently organized in the form of a theoretical model. The primary data was collected from 335 building stakeholders in Egypt through the administration of questionnaire surveys. Consequently, structural equation models of partial least squares were applied to statistically assess the final model of VM barriers.

Findings

The bibliometric analysis shows that there is an inadequate study on VM implementation barriers in the Egyptian construction industry and insufficient studies on implementing VM in developing countries. Results obtained from the proposed model showed that overcoming the VM barriers has a major connection with successful VM implementation. This is indicated with the value of ß = 0.743, which is necessary when the firm is overcoming 1 unit of VM barriers.

Originality/value

This study fills the knowledge gap by identifying and emphasizing the critical obstacles to VM implementation.
ONE STOP KITCHEN: managing a multi-brand cloud kitchen
Authors: Sharma Aasha Jayant , Dey Debopriyo
Published: December 2021

Subject area

Marketing; Business Expansion Strategy

Case synopsis

Rahul Hazarika, the owner of One Stop Kitchen (OSK), was convinced that expansion of his cloud kitchen had to be aligned at various fronts to compete. He was juggling with thoughts of expanding from B2C to B2B model, whether to expand in the same city or other cities or to introduce new variants in existing B2C so as to use and leverage the existing customer base and network. The competition was growing ablaze, and most of the orders were procured from the third-party aggregators, leaving little chance for OSK to connect to its customer base directly. The growth potential in this upcoming sector was undeniable, and Hazarika was continually trying to bring in relevant business practices to maintain the momentum. The case deals growing cloud kitchen business problems and covers business concepts such as business expansion strategy, product profiling and marketing strategies.

Learning objectives

Students will understand strategies for a Online startup Business in the Cloud Kitchen category. The concept of Product Profiling is also dealt with in the case.

Complexity academic level

Suitable for PG- and Executive-level courses.

Supplementary materials

Teaching notes are available for educators only.

Subject code

CSS 8: Marketing.
Boundary spanner closeness to partner firm as relational governance in turbulent versus stable environments
Authors: Cai Shaohan , Wang Xiaoyan , Ma Yongchao , Zhou Xinyue , Yang Zhilin
Published: December 2021

Purpose

This study aims to explore the overall relationship between a boundary spanner and a partner firm, i.e. boundary spanner closeness to partner firm. Drawing on consumer-service provider relationship literature and the tripartite model of affect-behavior-cognition, the authors identify three key dimensions of such closeness, namely, boundary spanners’ relational ties, customer-specific capabilities and accommodative behaviors, and examine their effects on exchange outcomes in turbulent versus stable environments.

Design/methodology/approach

The paper examines the effects of three dimensions of boundary spanner closeness on various exchange outcomes (i.e. retailers’ cooperation, satisfaction and willingness for investment) using two industries as exemplars, characterized by distinct levels of environmental turbulence – the retailing networks of a major cell phone company and a petroleum company in China.

Findings

The results indicate that the three dimensions individually and jointly affect exchange outcomes and the interplay of customer-specific capabilities and relational ties affect exchange outcomes differently across industry turbulence.

Originality/value

The existing literature lacks a comprehensive understanding of the function of boundary spanners, which serve as a key relational interorganizational governance component. By identifying three key dimensions of boundary spanner closeness and examining their effectiveness in promoting exchange outcomes, this study advances the understanding of the role of boundary spanners in interorganizational governance.
Influence of the length of the spacer group on the performance of the sulfate-based Gemini surfactants
Authors: Yu Wang , Chen Gang , Yang Haiyan , Li Sisi
Published: December 2021

Purpose

A series of sulfate-based Gemini anionic surfactants were synthesized via etherification, ring opening and sulfation reactions using epichlorohydrin, fatty alcohol, ethylene glycol and chlorosulfonic acid as the main raw materials. Orthogonal experiments for 1,8-bisalkoxymethylene-3,6-dioxin-1,8-octane disulfate were performed on the sulfation reaction to determine the optimal reaction conditions.

Design/methodology/approach

A series of sulfate-based Gemini anionic surfactants were synthesized via etherification, ring opening and sulfation reactions using epichlorohydrin, fatty alcohol, ethylene glycol and chlorosulfonic acid as the main raw materials. Orthogonal experiments for 1,8-bisalkoxymethylene-3,6-dioxin-1,8-octane disulfate were performed on the sulfation reaction to determine the optimal reaction conditions. The structures of the intermediate and final products were characterized by FT-IR (Fourier transform infrared spectroscopy analysis),1H-NMR (proton nuclear magnetic resonance spectroscopy) methods. The thermal performance of surfactants was analyzed using thermogravimetric analysis (TGA). The thermogravimetric results showed that the sulfate-based Gemini surfactants had good heat resistance (the thermal decomposition temperature of which was in the range of 140∼170?). The Krafft point, surface tension, foaming, Hydrophile–Lipophile Balance Number (HLB), emulsifying, wetting, and lime-soap dispersing performance were measured by visual observation, hanging drop method, aqueous surfactant solution method and Borghetti–Bergman method, respectively. The results have shown that all the sulfate-based Gemini surfactants had good water solubility and lime-soap dispersing ability. When spacer group was -(CH2)2-, with the increase of the carbon chain length from C12 to C14, the micellar concentration critical micelle concentration and surface tension (CMC) gradually increased from 8.25 × 10–4 mol/L to 8.75 × 10–4 mol/L and 27.5 mN/m to 30.9 mN/m, respectively. Also, the sulfate-based Gemini surfactants with the different length of the spacer group had a different effect on their performance on foaming properties and foam properties, HLB and emulsifying ability and wetting ability.

Findings

In view of the important role of the spacer group and the general use of anionic surfactants in oil fields, this article considers the preparation of a series of sulfate-based Gemini surfactants by changing the spacer group and the chain length of the hydrophobic group and evaluating their surface activity, and finally its Kraffi, on the foam properties, HLB value, emulsifying performance, lime soap dispersing ability etc.

Originality/value

Sulfate-based Gemini surfactants have broad application prospects in the fields of oil and gas exploitation, environmental protection, chemistry and daily chemical industry and so on.