bluuebunny/crossref_metadata_2025 huggingface dataset:
Vibrio parahaemolyticusT6SS2 effector repertoires
Authors: Tchelet Daniel , Keppel Kinga , Bosis Eran , Salomon Dor
Published: November 2022

All strains of the marine bacteriumVibrio parahaemolyticusharbor a type VI secretion system (T6SS) named T6SS2, suggesting that this system plays an important role in the life cycle of this emerging pathogen. Although T6SS2 was recently shown to play a role in interbacterial competition, its effector repertoire remains unknown. Here, we employed proteomics to investigate the T6SS2 secretome of twoV. parahaemolyticusstrains, and we identified several antibacterial effectors encoded outside of the main T6SS2 gene cluster. We revealed two T6SS2-secreted proteins that are conserved in this species, indicating that they constitute the core secretome of T6SS2; other identified effectors are found only in subsets of strains, suggesting that they comprise an accessory effector arsenal of T6SS2. Remarkably, a conserved Rhs repeat-containing effector serves as a quality control checkpoint and is required for T6SS2 activity. Our results reveal the effector repertoire of a conserved T6SS, some of which have no known activity and have not been previously associated with T6SSs.
Familial Alzheimer’s disease mutation undermines axonal transport by enhancing dynactin recruitment to the APP motor assemblies
Authors: Feole Monica , Stokin Gorazd B.
Published: November 2022

Experiments in flies, mice and humans suggest a significant role of impaired axonal transport in the pathogenesis of Alzheimer’s disease (AD), however, the underlying mechanisms remain unknown1,2. We report that the Swedish familial AD (FAD) mutation perturbs fast anterograde axonal transport of the amyloid precursor protein (APP) by altering directionality of its movement. APP thus spends more time in retrograde movement and accumulates in the soma. We found that the Swedish mutation enhances recruitment of dynactin 1 to the APP transport assemblies. Given that dynactin 1 activates the retrograde motor dynein3, this hampers physiological anterograde axonal transport of APP. We last show that the Swedish mutation perturbs also the axonal transport of early endosomes, which rely on the same molecular motors as APP. Our findings reveal extensive impairment of the axonal transport pathways by a FAD mutation, which reflects dysregulation of the cargo motor assemblies.
Whole genome error-corrected sequencing for sensitive circulating tumor DNA cancer monitoring
Authors: Cheng Alexandre Pellan , Widman Adam J. , Arora Anushri , Rusinek Itai , Hooper William F. , Murray Rebecca , Halmos Daniel , Langanay Theophile , Inghirami Giorgio , Germer Soren , Marton Melissa , Manaa Dina , Helland Adrienne , Furatero Rob , McClintock Jaime , Winterkorn Lara , Steinsnyder Zoe , Wang Yohyoh , Rajagopalan Srinivas , Alimohamed Asrar I. , Malbari Murtaza S. , Saxena Ashish , Callahan Margaret K. , Frederick Dennie T. , Spain Lavinia , Jaimovich Ariel , Lipson Doron , Turajlic Samra , Zody Michael C. , Altorki Nasser K. , Wolchok Jedd D. , Postow Michael A. , Robine Nicolas , Boland Genevieve , Landau Dan A.
Published: November 2022

Circulating cell-free DNA (ccfDNA) sequencing for low-burden cancer monitoring is limited by sparsity of circulating tumor DNA (ctDNA), the abundance of genomic material within a plasma sample, and pre-analytical error rates due to library preparation, and sequencing errors. Sequencing costs have historically favored the development of deep targeted sequencing approaches for overcoming sparsity in ctDNA detection, but these techniques are limited by the abundance of ccfDNA in samples, which imposes a ceiling on the maximal depth of coverage in targeted panels. Whole genome sequencing (WGS) is an orthogonal approach to ctDNA detection that can overcome the low abundance of ccfDNA by supplanting sequencing depth with breadth, integrating signal across the entire tumor mutation landscape. However, the higher cost of WGS limits the practical depth of coverage and hinders broad adoption. Lower sequencing costs may thus allow for enhanced ctDNA cancer monitoring via WGS. We therefore applied emerging lower-cost WGS (Ultima Genomics, 1USD/Gb) to plasma samples at ∼120x coverage. Copy number and single nucleotide variation profiles were comparable between matched Ultima and Illumina datasets, and the deeper WGS coverage enabled ctDNA detection at the parts per million range. We further harnessed these lower sequencing costs to implement duplex error-corrected sequencing at the scale of the entire genome, demonstrating a ∼1,500x decrease in errors in the plasma of patient-derived xenograft mouse models, and error rates of ∼10−7in patient plasma samples. We leveraged this highly de-noised plasma WGS to undertake cancer monitoring in the more challenging context of resectable melanoma without matched tumor sequencing. In this context, duplex-corrected WGS allowed us to harness known mutational signature patterns for disease monitoring without matched tumors, paving the way for de novo cancer monitoring.
Adaptation toex vivoculture drives human haematopoietic stem cell loss of repopulation capacity in a cell cycle independent manner
Authors: Johnson Carys S. , Sham Kendig , Belluschi Serena , Wang Xiaonan , Lau Winnie , Kaufmann Kerstin B. , Krivdova Gabriela , Calderbank Emily F. , Mende Nicole , McLeod Jessica , Mantica Giovanna , Williams Matthew J. , Grey-Wilson Charlotte , Drakopoulos Michael , Sinha Shubhankar , Diamanti Evangelia , Basford Christina , Green Anthony R. , Wilson Nicola K. , Howe Steven J. , Dick John E. , Göttgens Bertie , Francis Natalie , Laurenti Elisa
Published: November 2022

Loss of long-term haematopoietic stem cell function (LT-HSC) hampers the success ofex vivoHSC gene therapy and expansion procedures, but the kinetics and the mechanisms by which this occurs remain incompletely characterized. Here through time-resolved scRNA-Seq, matchedin vivofunctional analysis and the use of a reversiblein vitrosystem of early G1arrest, we define the sequence of transcriptional and functional events occurring during the firstex vivodivision of human LT-HSCs. We demonstrate that contrary to current assumptions, loss of long-term repopulation capacity during culture is independent of cell cycle progression. Instead it is a rapid event that follows an early period of adaptation to culture, characterised by transient gene expression dynamics and constrained global variability in gene expression. Cell cycle progression however contributes to the establishment of differentiation programmes in culture. Our data have important implications for improving HSC gene therapy and expansion protocols.
ACC neural ensemble dynamics are structured by strategy prevalence
Authors: Proskurin Mikhail , Manakov Maxim , Karpova Alla Y.
Published: November 2022

Medial frontal cortical areas are thought to play a critical role in the brain’s ability to flexibly deploy strategies that are effective in complex settings. Still, the specific circuit computations that underpin this foundational aspect of intelligence remain unclear. Here, by examining neural ensemble activity in rats that sample different strategies in a self-guided search for latent task structure, we demonstrate a robust tracking of individual strategy prevalence in the anterior cingulate cortex (ACC), especially in an area homologous to primate area 32D. Prevalence encoding in the ACC is wide-scale, independent of reward delivery, and persists through a substantial ensemble reorganization that tags ACC representations with contextual content. Our findings argue that ACC ensemble dynamics is structured by a summary statistic of recent behavioral choices, raising the possibility that ACC plays a role in estimating – through statistical learning – which actions promote the occurrence of events in the environment.
Spatially-embedded recurrent neural networks reveal widespread links between structural and functional neuroscience findings
Authors: Achterberg Jascha , Akarca Danyal , Strouse DJ , Duncan John , Astle Duncan E
Published: November 2022

Brain networks exist within the confines of resource limitations. As a result, a brain network must overcome metabolic costs of growing and sustaining the network within its physical space, while simultaneously implementing its required information processing. To observe the effect of these processes, we introduce the spatially-embedded recurrent neural network (seRNN). seRNNs learn basic task-related inferences while existing within a 3D Euclidean space, where the communication of constituent neurons is constrained by a sparse connectome. We find that seRNNs, similar to primate cerebral cortices, naturally converge on solving inferences using modular small-world networks, in which functionally similar units spatially configure themselves to utilize an energetically-efficient mixed-selective code. As all these features emerge in unison, seRNNs reveal how many common structural and functional brain motifs are strongly intertwined and can be attributed to basic biological optimization processes. seRNNs can serve as model systems to bridge between structural and functional research communities to move neuroscientific understanding forward.
Evolutionary insights from profiling LINE-1 activity at allelic resolution in a single human genome
Authors: Yang Lei , Metzger Genevieve A. , Del Valle Ricky Padilla , Rubalcaba Diego Delgadillo , McLaughlin Richard N.
Published: November 2022

Transposable elements including LINE-1 (Long INterspersed Element-1) impact genome variation, function, regulation, and disease. LINE-1s seem to have expanded as distinct consecutive lineages, but the drivers of lineage emergence and disappearance are unknown. Reference genomes provide a snapshot of LINE-1 evolution; however, the ongoing retrotransposition of LINE-1s in humans is not evident in these mosaic assemblies. Utilizing long-read-based haploid assemblies, we identified the sequence and location of all the youngest LINE-1s in these genomes at allelic resolution. We cloned and assayed thein vitroretrotransposition activity of the subset of LINE-1s with intact open reading frames and found 34 were measurably active. Yet, among individuals, these same LINE-1s varied in their presence, allelic sequences, and activity. Using a measure ofin vivoretrotransposition of closely related groups of LINE-1, we found that recently retrotransposed LINE-1s tend to be activein vitroand polymorphic in the population. However, for a considerable number of LINE-1s, their measuredin vitroactivity and inferredin vivofitness were uncorrelated, regardless of their frequency in the population. Some of these unexpected patterns come from rare allelic forms of old LINE-1s that retain activity, suggesting older LINE-1 lineages can persist much longer than expected. Finally, some LINE-1s showed mutations that were potentially adaptive, increasing their replication in the genome. These key mutations specific to LINE-1s with bothin vitroactivity andin vivofitness represent promising candidates for the future mechanistic investigation of the drivers of LINE-1 evolution which may contribute to disease susceptibility.
Branched germline cysts and female-specific cyst fragmentation facilitate oocyte determination in mice
Authors: Ikami Kanako , Shoffner Suzanne , Weh Malgorzata Gosia Tyczynska , Schnell Santiago , Ma Jingqun , Yoshida Shosei , Miranda Edgar Diaz , Ko Sooah , Lei Lei
Published: November 2022

During mouse gametogenesis, germ cells derived from the same progenitor are connected via intercellular bridges forming germline cysts, within which asymmetrical or symmetrical cell fate occurs in female and male germ cells respectively. Here, we have identified branched cyst structures in mice, and investigated their formation and function in oocyte determination. In fetal female cysts, 16.8% of the germ cells are connected by three or four bridges, namely branching germ cells. These germ cells are preferentially protected from cell death and cyst fragmentation, and to accumulate organelles and cytoplasm from sister germ cells to become primary oocytes. Changes in cyst structure and single-cell mRNA profiles suggested that cytoplasmic transport in germline cysts is conducted in a directional manner, in which cellular content is first transported locally between peripheral germ cells and further enriched in branching germ cells, a process causing selective germ cell loss in cysts. Cyst fragmentation occurs extensively in female cysts, but not in male cysts. Male cysts in fetal and adult testes have branched cyst structures, without differential cell fates between germ cells. During cyst formation, E-cadherin junctions between germ cells position intercellular bridges to form branched cysts. Disrupted junction formation in E-cadherin-depleted cysts led to an altered ratio in branched cysts. Germ cell-specific E-cadherin knockout resulted in reductions in primary oocyte number and oocyte size. These findings shed light on the mechanism of how the size of the ovarian reserve, the number of primary oocytes available to sustain adult ovarian function, is determined during ovary formation.
Measuring the non-selective effects of motor inhibition using isometric force recordings
Authors: Rangel Benjamin O. , Novembre Giacomo , Wessel Jan R.
Published: November 2022

Inhibition is a key cognitive control mechanism. When rapidly exerted, inhibitory control has broad, non-selective motor effects, typically demonstrated using cortico-spinal excitability measurements (CSE) elicited by transcranial magnetic stimulation (TMS). For example, during rapid action-stopping, CSE is suppressed at both stopped and task-unrelated muscles. While such TMS-based CSE measurements provide crucial insights into the fronto-basal ganglia circuitry underlying non-selective inhibition, they have several downsides. TMS is contraindicated in many populations (e.g., epilepsy, deep-brain stimulation patients), has limited temporal resolution, produces distracting auditory and haptic stimulation, is difficult to combine with other imaging methods, and necessitates expensive, immobile equipment. Here, we attempted to measure the non-selective motor effects of inhibitory control using a method unaffected by these shortcomings. 30 participants exerted isometric force on a hand-held force transducer while performing a foot-response stop-signal task. Indeed, when foot movements were stopped, force output at the task-irrelevant hand was suppressed as well. Moreover, this non-selective reduction of isometric force was highly correlated with stop-signal performance and showed frequency dynamics similar to established inhibitory signatures typically found in neural and muscle recordings. Together, we demonstrate that isometric force recordings capture the non-selective effects of motor inhibition, enabling many applications that are impossible with TMS.
IκBα controls dormancy induction in Hematopoietic stem cell development via retinoic acid
Authors: Thambyrajah Roshana , Fadlullah Zaki , Proffitt Martin , Neo Wen Hao , Guillén Yolanda , Casado-Pelaez Marta , Herrero-Molinero Patricia , Brujas Carla , Castelluccio Noemi , González Jessica , Iglesias Arnau , Marruecos Laura , Ruiz-Herguido Cristina , Esteller Manel , Mereu Elisabetta , Lacaud Georges , Espinosa Lluis , Bigas Anna
Published: November 2022

Recent findings are challenging the classical hematopoietic model in which long-term hematopoietic stem cells (LT-HSC) are the base of the hematopoietic system. Clonal dynamics analysis of the hematopoietic system indicate that LT-HSC are not the main contributors of normal hemapoiesis in physiological conditions and the hematopoietic system is mainly maintained by multipotent progenitors (MPPs, hereafter HPC) and LT-HSCs are mostly in a non-active state. The first HSCs emerge from the aorta-gonad and mesonephros (AGM) region along with hematopoietic progenitors (HPC) within hematopoietic clusters. Molecular pathways that determine the HSC fate instead of HPC are still unknown, although inflammatory signaling, including NF-κB has been implicated in the development of HSCs. Here, we identify a chromatin binding function for IκBα (also known as the inhibitor of NF-κB) that is Polycomb repression complex 2 (PRC2)-dependent and specifically determines dormant vs proliferating HSCs from the onset of their emergence in the AGM. We find a specific reduction of LT-HSCs in the IκBα knockout new-born pups. This defect is manifested at the FL stage already, and traceable to the first emerging HSCs in the E11.5 AGM, without affecting the general HPC population. IκBα deficient LT-HSCs express dormancy signature genes, are less proliferative and can robustly respond to activation stimuli such asin vitroculture and serial transplantation. At the molecular level, we find decreased PRC2-dependent H3K27me3 at the promoters of several retinoic acid signaling elements in the IκBα - deficient aortic endothelium and E14.5 FL LT-HSCs. Additionally, IκBα binding itself is found in the promoters of retinoic acid receptors rarα in the AGM, and rarγ in the LT-HSC of FL. Overall, we demonstrate that the retinoic acid pathway is over-activated in the hematopoietic clusters of IκBα-deficient AGMs leading to premature dormancy of LT-HSCs that persists in the FL LT-HSCs.
Potently neutralizing human monoclonal antibodies against the zoonotic pararubulavirus Sosuga virus
Authors: Parrington Helen M. , Kose Nurgun , Armstrong Erica , Handal Laura , Diaz Summer , Reidy Joseph , Dong Jinhui , Stewart-Jones Guillaume B. E. , Shrivastava-Ranjan Punya , Jain Shilpi , Albariño César G. , Carnahan Robert H. , Crowe James E.
Published: November 2022

Sosuga virus (SOSV) is a recently discovered paramyxovirus with a single known human case of disease. There has been little laboratory research on SOSV pathogenesis or immunity, and no approved therapeutics or vaccines are available. Here, we report the discovery of human monoclonal antibodies (mAbs) from the circulating memory B cells of the only known human case and survivor of SOSV infection. We isolated six mAbs recognizing the functional attachment protein (HN) and 18 mAbs against the fusion (F) protein. The anti-HN mAbs all target the globular head of the HN protein and can be organized into 4 competition-binding groups that exhibit epitope diversity. The anti-F mAbs can be divided into pre- or post-fusion conformation-specific categories and further into 8 competition-binding groups. Generally, pre-fusion conformation-specific anti-F mAbs showed higher potency in neutralization assays than did mAbs only recognizing the post-fusion conformation of F protein. Most of the anti-HN mAbs were more potently neutralizing than the anti-F mAbs, with mAbs in one of the HN competition-binding groups possessing ultra-potent (<1 ng/mL) half maximal inhibitory (IC50) virus neutralization values. These findings provide insight into the molecular basis for human antibody recognition of paramyxovirus surface proteins and the mechanisms of SOSV neutralization.
Cellular Maturation of Oligodendrocytes is Governed by Transient Gene Melting
Authors: Allan Kevin C. , Miller Tyler E. , Morton Andrew R. , Scavuzzo Marissa A. , Elitt Matthew S. , Clayton Benjamin L.L. , Hu Lucille R. , Vrabic Jost K. , Olsen Hannah E. , Factor Daniel C. , Henninger Jonathan E. , Young Richard A. , Lin Charles Y. , Scacheri Peter C. , Tesar Paul J.
Published: November 2022

Pluripotent stem cells (PSCs) provide an unlimited source for generating somatic cell types. However, generating fully mature cells constitutes a bottleneck for realizing their full potential in research and medicine. Here, we report a transcriptional mechanism that governs the timing of cellular maturation in post-mitotic oligodendrocytes. During differentiation of PSCs to oligodendrocytes, the transcription factor SOX6 redistributes from nearly all super enhancers in proliferating oligodendrocyte progenitor cells to cluster across specific gene bodies in immature oligodendrocytes. These sites exhibit ‘gene melting’, a process of extensive chromatin decondensation and transcription, which abruptly turns off upon maturation. Suppression of SOX6 deactivates these immaturity loci, resulting in rapid transition to mature myelinating oligodendrocytes. Cells harboring this immature oligodendrocyte SOX6 gene signature are specifically enriched in multiple sclerosis patient brains, suggestive that failed maturation may contribute to limited myelin regeneration in disease. Collectively, our finding that maturation rate is controlled by transient transcriptional clusters may inform approaches to accelerate the generation and regeneration of mature cell types.

HIGHLIGHTS

Transcription factors (TFs) can act as gatekeepers of post-mitotic cellular maturation

In oligodendrocytes, clustering of SOX6 controls the immaturity program through transient gene melting

Suppressing SOX6 deactivates immaturity genes and unlocks oligodendrocyte maturation

SOX6 immaturity signature is enriched in oligodendrocytes in multiple sclerosis patients
Neural noise is associated with age-related neural dedifferentiation
Authors: Pichot Rachelle E. , Henreckson Daniel J. , Foley Morgan , Koen Joshua D.
Published: November 2022

Age-related neural dedifferentiation – reductions in the selectivity and precision of neural representations – contributes to cognitive aging and is thought to result from age increases in neural noise. This research has primarily used fMRI to examine age-related reductions in neural selectivity for different categories of visual stimuli. The present experiment used EEG to examine the link between neural noise and age-related neural dedifferentiation indexed by the scene-selective (P200) and face-selective (N170) ERP components. Young and older adults viewed images of scenes, objects, and faces during a 1-back task. Whereas both the P200 and N170 showed age-related slowing of peak latency, only the P200 showed age-related reductions in amplitude that were independent of visual and contrast acuity. We also examined the relationship between the ERP peak measures and an index of neural noise, namely the 1/f exponent of the frequency power spectrum. For the P200 amplitude, higher levels of neural noise were associated with smaller P200 amplitudes in young, but not older adults. In contrast, there was an age-invariant relationship between neural noise and N170 amplitude in the left hemisphere with higher levels of neural noise being associated reduced N170 amplitudes. While the present findings provide novel empirical evidence broadly consistent with predictions from computational models of neural dedifferentiation, the results also highlight potential limitations of the computational model that necessitate revision. The results also suggest that, at least for the P200, maintaining levels of neural noise similar to young adults might preserve levels of neural selectivity.

Significance Statement

A prominent theory of cognitive aging proposes that age-related cognitive decline results from increases in neural noise that reduce the selectivity of neural representations. We examined this predicted link between neural selectivity and neural noise with ERP components that show selectivity for scenes (P200) and faces (N170) and the 1/f aperiodic exponent measure of neural noise. The amplitude for the scene-selective, but not face-selective, ERP component was reduced in older adults, with both components showing age-related slowing. Critically, older adults with higher levels of neural noise showed lower levels of neural selectivity for scenes, but not faces. While these results provide some evidence supporting computational models of neural dedifferentiation, they also highlight important limitations of the model that require revision.
Validity of a deep learning algorithm for detecting wheezes and crackles from lung sound recordings in adults
Authors: Melbye Hasse , Ravn Johan , Pabiszczak Mikolaj , Bongo Lars Ailo , Aviles Solis Juan Carlos
Published: November 2022

We validated our state-of-the-art deep learning algorithm for detection of wheezes and crackles in sound files by comparing the classification of our algorithm with those of human experts. We had two validation sets classified by experienced raters that were not used to train the algorithm with 615 (A) and 120 (B) sound files, respectively. We calculated Area Under Curve (AUC) of the algorithm’s probability scores for wheezes and crackles. We dichotomized the scores and calculated sensitivity and specificity as well as kappa agreement. In set A, the AUC was 0.88 (95% CI 0.84 – 0.92) for wheezes and 0.88 (95% CI 0.84 – 0.92) for crackles. The sensitivities and specificities of the labels were 81% and 89% for wheezes and 67% and 96% for crackles. In set B, the kappa agreement between the algorithm and the validation set was 0.78 (95% CI 0.58 – 0.99) for wheezes and 0.75 (95% CI 0.59 – 0.92) for crackles. The 24 observers who had rated the same 120 sound files agreed less with the reference classification with a mean kappa of 0.68 for wheezes and 0.55 for crackles. We found the algorithm to be superior to doctors in detecting wheezes and crackles in lung sound files.
The contribution of population age-sex structure to the excess mortality estimates of 2020–2021 in Denmark, Finland, Iceland, Norway, and Sweden
Authors: Kepp Kasper P. , Björk Jonas , Emilsson Louise , Lallukka Tea
Published: November 2022

Background

The Nordic countries are an ideal case study of the COVID-19 pandemic due to their comparability, high data quality, and variable responses. Excess mortality is a key metric but it is sensitive to data quality, model assumptions, and population structure, with diverse estimates published so far.

Methods

We investigated the age- and sex-specific mortality patterns during 2020−2021 for the five Nordic countries using annualized age- and sex specific death rates and populations. We compared the total age- and sex-adjusted excess deaths, ratios of actual vs. expected death rates, and age-standardized excess death estimates. We estimated excess deaths with several time periods and sensitivity tests, using 42 sex and age groups. Our models are less sensitive to outlier years than models based on 5 years of data.

Results

Age-specific death rates have declining trends that reflect real improving health demographics. Our total excess mortality is close to WHO’s estimates, except higher for Norway and lower for Sweden, partly due to data used. Total excess deaths were dominated by the age group 70−89 years, was not identified in children, and more pronounced in men than women. Sweden had more excess deaths in 2020 than 2021 whereas Finland, Norway, and Denmark had the opposite. Denmark has the highest death rates before and during the pandemic, whereas Sweden in 2020 had the largest mortality increase. The age-standardized mortality of Denmark, Iceland and Norway was lowest in 2020, and 2021 was one of the lowest mortality years for all Nordic countries. We show that neutral baseline methods underestimate excess deaths and we document the importance of outlier mortality years.

Conclusions

We provide excess mortality estimates mortality of the Nordic countries in relation to sex and age, with several metrics important in combination for a full understanding and comparison of the countries. We additionally identify important effects such as mortality displacement and sensitivities that affect our estimates and those of other excess mortality models.
Drug repositioning for immunotherapy in breast cancer using single-cell and spatial transcriptomics analysis
Authors: Mohammadi Elyas , Jin Han , Zhang Cheng , Shafizade Neda , Dashty Samira , Lam Simon , Tahmoorespur Mojtaba , Mardinoglu Adil , Sekhavati Mohammad Hadi
Published: November 2022

Background

Immunomodulatory peptides are capable of stimulating or suppressing the immune system. Hence, deregulation of them can be considered as an immunotherapy approach. These peptides may have dual behavior in response to different infections. For instance, an antimicrobial peptide may act as an anticancer, tumor marker or even cause cancer progression.

Methods

In this study, we used single-cell RNA sequencing and spatial transcriptomiocs analysis to investigate the deregulation of immunomodulatory peptides in malignant versus normal human breast epithelial cells. We validated the obtained results in chromatin accessibility level. Furthermore, we used a drug repositioning approach to change the expression of these peptides based on their role in cancer biology.

Results

Ten immunomodulatory peptides were upregulated in breast cancer versus normal. Chromatin was more accessible for these peptides in cancer cell lines versus normal. Among these ten peptides, five of them were tumor drivers (i.e., BST2, GAPDH, S100A8, S100A9 and HMGB1), three of them were anticancer (i.e., H2AFJ, SCGB2A1 and HMGN2), S100A7 had dual behavior in different cancers and ZG16B was a tumor marker. Using the LINCS L1000 database, we proposed a list of drugs that can deregulate the candidate peptides according to their role in the progression of malignancy.

Conclusions

Immunomodulatory peptides can be considered as drug targets based on their role in cancer biology.
Impact of malaria diagnostic choice on monitoring ofPlasmodium falciparumprevalence estimates in the Democratic Republic of the Congo and relevance to control programs in high-burden countries
Authors: Diallo Alpha Oumar , Banek Kristin , Kashamuka Melchior Mwandagalirwa , Mavungu Bala Joseph Alexandre , Nkalani Marthe , Kihuma Georges , Nseka Tommy Mambulu , Atibu Joseph Losoma , Mahilu Georges Emo , McCormick Lauren , White Samuel J. , Sendor Rachel , Sinai Cyrus , Keeler Corinna , Herman Camelia , Emch Michael , Sompwe Eric , Thwai Kyaw Lay , Dinglasan Rhoel R. , Rogier Eric , Juliano Jonathan J. , Tshefu Antoinette Kitoto , Parr Jonathan B.
Published: November 2022

Malaria programs rely upon a variety of diagnostic assays, including rapid diagnostic tests (RDTs), microscopy, polymerase chain reaction (PCR), and bead-based immunoassays (BBA), to monitor malaria prevalence and support control and elimination efforts. Data comparing these assays are limited, especially from high-burden countries like the Democratic Republic of the Congo (DRC). Using cross-sectional and routine data, we compared diagnostic performance andPlasmodium falciparumprevalence estimates across health areas of varying transmission intensity to illustrate the relevance of assay performance to malaria control programs. Data and samples were collected between March-June 2018 during a cross-sectional household survey across three health areas with low, moderate, and high transmission intensities within two health zones of Kinshasa province, DRC.

Samples from 1,431 participants were evaluated using RDT, microscopy, PCR, and BBA.P. falciparumparasite prevalence varied between diagnostic methods across all health areas, with the highest prevalence estimates observed in Bu (57.4-72.4% across assays), followed by Kimpoko (32.6-53.2%), and Voix du Peuple (3.1-8.4%). Using latent class analysis to compare these diagnostic methods against an “alloyed gold standard,” the most sensitive diagnostic method was BBA in Bu (high prevalence) and Voix du Peuple (low prevalence), while PCR diagnosis was most sensitive in Kimpoko (moderate prevalence). RDTs were consistently the most specific diagnostic method in all health areas. Among 9.0 million people residing in Kinshasa Province in 2018, the estimatedP. falciparumprevalence by microscopy, PCR, and BBA were nearly double that of RDT.

Comparison of malaria RDT, microscopy, PCR, and BBA results confirmed differences in sensitivity and specificity that varied by endemicity, with PCR and BBA performing best for detecting anyP. falciparuminfection. Prevalence estimates varied widely depending on assay type for parasite detection. Inherent differences in assay performance should be carefully considered when using community survey and surveillance data to guide policy decisions.
Estimating the impact of COVID-19 vaccine allocation inequities: a modeling study
Authors: Gozzi Nicolò , Chinazzi Matteo , Dean Natalie E. , Longini Ira M. , Halloran M. Elizabeth , Perra Nicola , Vespignani Alessandro
Published: November 2022

Access to COVID-19 vaccines on the global scale has been drastically impacted by structural socio-economic inequities. Here, we develop a data-driven, age-stratified epidemic model to evaluate the effects of COVID-19 vaccine inequities in twenty lower middle and low income countries (LMIC) sampled from all WHO regions. We focus on the first critical months of vaccine distribution and administration, exploring counterfactual scenarios where we assume the same per capita daily vaccination rate reported in selected high income countries. We estimate that, in this high vaccine availability scenario, more than 50% of deaths (min-max range: [56% − 99%]) that occurred in the analyzed countries could have been averted. We further consider a scenario where LMIC had similarly early access to vaccine doses as high income countries; even without increasing the number of doses, we estimate an important fraction of deaths (min-max range: [7% − 73%]) could have been averted. In the absence of equitable allocation, the model suggests that considerable additional non-pharmaceutical interventions would have been required to offset the lack of vaccines (min-max range: [15% − 75%]). Overall, our results quantify the negative impacts of vaccines inequities and call for amplified global efforts to provide better access to vaccine programs in low and lower middle income countries.
Design and validation of an exposure system for efficient inter-animal SARS-CoV-2 airborne transmission in Syrian hamsters
Authors: Kuehl Philip J. , Dearing Justin , Werts Adam , Cox Jason , Irshad Hammad , Barrett Edward G. , Tucker Sean N. , Langel Stephanie N.
Published: November 2022

SARS-CoV-2 is a highly transmissible respiratory pathogen whose main transmission route is airborne. Development of an animal model and exposure system that recapitulates airborne transmission of SARS-CoV-2 is integral for understanding the dynamics of SARS-CoV-2 spread in individuals and populations. Here we designed, built, and characterized a hamster transmission caging and exposure system that allows for efficient SARS-CoV-2 airborne transmission from an infected index animal to naïve recipients under unidirectional airflow, without contribution from fomite or direct contact transmission. To validate our system, we assessed a 1:1 or 1:4 ratio of infected index to naive recipient hamsters and compared their virological and clinical measurements after eight hours of airborne exposure. Airborne exposure concentrations and pulmonary deposited dose of SARS-CoV-2 in index and naïve hamsters, respectively, were similar in both groups. Daily nasal viral RNA levels, and terminal (day 5) lung viral RNA and infectious virus, and fecal viral RNA levels were statistically similar among 1:1 and 1:4 naive animals. However, virological measurements in the 1:4 naïve animals were more variable than the 1:1 naïve animals, likely due to hamster piling behavior creating uneven SARS-CoV-2 exposure during the grouped 1:4 airborne exposure. This resulted in slight, but not statistically significant, changes in daily body weights between the 1:1 and 1:4 naive groups. Our report describes a multi-chamber caging and exposure system that allowed for efficient SARS-CoV-2 airborne transmission in single and grouped hamsters. This system can be used to better define airborne transmission dynamics and test transmission-blocking therapeutic strategies against SARS-CoV-2.

Importance

The main route of SARS-CoV-2 transmission is airborne. However, there are few experimental systems that can assess airborne transmission dynamics of SARS-CoV-2 in vivo. Here, we designed, built, and characterized a hamster transmission caging and exposure system that allows for efficient SARS-CoV-2 airborne transmission in Syrian hamsters, without contributions from fomite or direct contact transmission. We successfully measured SARS-CoV-2 viral RNA in aerosols and demonstrated that SARS-CoV-2 is transmitted efficiently at either a 1:1 or 1:4 infected index to naïve recipient hamster ratio. This is meaningful as a 1:4 infected index to naïve hamster ratio would allow for simultaneous comparisons of various interventions in naïve animals to determine their susceptibility of infection by aerosol transmission of SARS-CoV-2. Our SARS-CoV-2 exposure system allows for testing viral airborne transmission dynamics and transmission-blocking therapeutic strategies against SARS-CoV-2 in Syrian hamsters.
Rising SARS-CoV-2 Seroprevalence and Patterns of Cross-Variant Antibody Neutralization in UK Domestic Cats
Authors: Tyson Grace B , Jones Sarah , Logan Nicola , McDonald Michael , Murcia Pablo R , Willett Brian J , Weir William , Hosie Margaret J
Published: November 2022

Recent evidence confirming cat-to-human SARS-CoV-2 transmission has highlighted the importance of monitoring infection in domestic cats. Although the effects of SARS-CoV-2 infection on feline health are poorly characterized, cats have close contact with humans, and with both domesticated and wild animals. Accordingly, they could act as a reservoir of infection, an intermediate host and a source of novel variants. To investigate the spread of the virus in the cat population, serum samples were tested for SARS-CoV-2 antibodies by ELISA and a pseudotype-based virus neutralization assay, designed to detect exposure to variants known to be circulating in the human population. Overall seroprevalence was 3.2%, peaking at 5.3% in autumn 2021. Variant-specific neutralizing antibody responses were detected with titers waning over time. The variant-specific response in the feline population correlated with and trailed the variants circulating in the human population, indicating multiple ongoing human-to-cat spill-over events.
System dynamics modeling and robustness analysis for capital-constrained supply chain under disruption
Authors: Zhang Xiaoming , Shi Yangyan , Zhang Peng , Xu Fang , Jiang Chaozhe
Published: November 2022

Purpose

The purpose of this study is to explore mitigation measures for cash flow interruption during the epidemic and provide decision support to ensure the regular operation and robustness of the supply chain (SC).

Design/methodology/approach

Considering the scenarios of production capacity and demand disruption during the epidemic, the authors adopt system dynamics (SD) to construct a three-echelon SC financial system consisting of a core manufacturer, a capital-constrained retailer and the customer. In different interruption scenarios, through the decision adjustments of stakeholders, the differences in performance are compared to explore solutions for SC robust optimization.

Findings

The results show that partial credit guarantee (PCG) could solve cash flow interruption and maintain the regular operation of the SC. During epidemic, with the product price increases, the revenue of stakeholders and the robustness are generally negatively correlated. But when the manufacturer's production capacity is fully interrupted, increasing product price is the right decision for the retailer and could simultaneously promote performance and robustness.

Originality/value

This paper primarily focuses on the PCG under the cash flow interruption caused by epidemics. The authors adopt the supply chain finance (SCF) theory and SD method to supplement and expand existing research on interruption management of SC. It is a pioneering study to explore the robustness of the SC financial system under disruptions.
Digital transformation and human resources planning: the mediating role of innovation
Authors: Demir Mahmut , Yaşar Emre , Demir Şirvan Şen
Published: November 2022

Purpose

This study aims to examine the relationship between digital transformation (DigiTr), innovation and human resources planning (HRP) in hotels to investigate the impact of DigiTr on innovations and HRP and to test the mediating impact of innovation on the DigiTr-HRP relationship.

Design/methodology/approach

The authors used a quantitative research method in this study, specifically by conducting a hybrid face-to-face and online survey to collect data from 462 human resources (HR) managers, department managers and HR professionals at four- and five-star hotels in Turkey. The structured questionnaire assessed DigiTr, innovations in business models, services and processes and quantitative and qualitative changes in HR. The authors used covariance-based structural equation modeling to test the hypotheses.

Findings

DigiTr affected both innovations and HR planning in hotels, and also the effect of innovations on HR planning. In addition, DigiTr and innovations increased qualitative changes in HR planning but reduced quantitative changes. Finally, innovations mediated the relationship between DigiTr and HR planning.

Practical implications

These findings indicate that employers and employees need to be aware of developments in employment in the tourism industry, as these can significantly impact HR planning via DigiTr and innovations.

Originality/value

This study differs from the existing literature by providing empirical evidence to fill the knowledge gap regarding how DigiTr and innovation affect HR planning.
Determinant factors in entrepreneurial intention among Social Work degree students: the moderating effect of entrepreneurship education
Authors: García-Uceda Esperanza , Murillo-Luna Josefina L. , Asín Lafuente Jesús
Published: November 2022

Purpose

The purpose of this study is to examine the factors that determine the entrepreneurial intention (EI) among Social Work degree students. This study considers the direct influence of personal traits, demographic characteristics, informal education and entrepreneurship education (EE) and, in addition, the possible moderating effect of EE on the other factors.

Design/methodology/approach

A sample of 139 undergraduate students registered in the Social Work degree offered by the University of Zaragoza (Spain) is analyzed, by using a longitudinal system based on questionnaires that were passed at two different times – before and after receiving the EE. Logistic regression models are built and estimated according to the explicative variables.

Findings

The results indicate that demographic factors, personality traits, professional experience and EE are significant factors in fostering social entrepreneurship among Social Work students. Additionally, EE has a moderating effect on the other variables, but only partially and not always positive.

Practical implications

The entrepreneurial initiative of social workers can make a very valuable contribution through the start-up of social enterprises. The findings suggest the convenience of promoting EE in the Social Work degree, with teaching contents and methodologies adapted to social entrepreneurship. Nevertheless, the interaction of educational methodologies with the other determinants does not always have a positive impact on EI.

Originality/value

This paper investigates EI in the context of undergraduate Social Work students, and this is a novel methodological approach. In addition to the analysis of the direct influence of the determinants of EI, we add the possible moderating effect of EE on the influence of the other explanatory variables.
Standardised empirical dispersal kernels emphasise the pervasiveness of long‐distance dispersal in European birds
Authors: Fandos Guillermo , Talluto Lauren , Fiedler Wolfgang , Robinson Robert A. , Thorup Kasper , Zurell Damaris
Published: November 2022

Dispersal is a key life‐history trait for most species and is essential to ensure connectivity and gene flow between populations and facilitate population viability in variable environments. Despite the increasing importance of range shifts due to global change, dispersal has proved difficult to quantify, limiting empirical understanding of this phenotypic trait and wider synthesis.

Here, we introduce a statistical framework to estimate standardised dispersal kernels from biased data. Based on this, we compare empirical dispersal kernels for European breeding birds considering age (average dispersal; natal, before first breeding; and breeding dispersal, between subsequent breeding attempts) and sex (females and males) and test whether different dispersal properties are phylogenetically conserved.

We standardised and analysed data from an extensive volunteer‐based bird ring‐recoveries database in Europe (EURING) by accounting for biases related to different censoring thresholds in reporting between countries and to migratory movements. Then, we fitted four widely used probability density functions in a Bayesian framework to compare and provide the best statistical descriptions of the different age and sex‐specific dispersal kernels for each bird species.

The dispersal movements of the 234 European bird species analysed were statistically best explained by heavy‐tailed kernels, meaning that while most individuals disperse over short distances, long‐distance dispersal is a prevalent phenomenon in almost all bird species. The phylogenetic signal in both median and long dispersal distances estimated from the best‐fitted kernel was low (Pagel's λ < 0.25), while it reached high values (Pagel's λ >0.7) when comparing dispersal distance estimates for fat‐tailed dispersal kernels. As expected in birds, natal dispersal was on average 5 km greater than breeding dispersal, but sex‐biased dispersal was not detected.

Our robust analytical framework allows sound use of widely available mark‐recapture data in standardised dispersal estimates. We found strong evidence that long‐distance dispersal is common among European breeding bird species and across life stages. The dispersal estimates offer a first guide to selecting appropriate dispersal kernels in range expansion studies and provide new avenues to improve our understanding of the mechanisms and rules underlying dispersal events.
Incidence, management, and outcome of lung cancer in patients with long‐term oxygen therapy
Authors: Lambert Timothée , El Husseini Kinan , Zysman Maeva , Duchemann Boris , Gillibert André , Campedel Luca , Dantoing Edouard , Rolland‐Debord Camille , Patout Maxime
Published: November 2022

Background

Here, we aimed to assess the specific features of lung cancer in patients with long‐term oxygen therapy (LTOT), and compare their outcomes with patients suffering from lung cancer without LTOT.

Methods

This retrospective, case‐controlled study included patients with LTOT and an incident diagnosis of lung cancer treated at Rouen University Hospital.

Results

Out of 2201 patients with LTOT, 31 were diagnosed with lung cancer. Among 24 patients with proven lung cancer, the most frequent histological type was squamous cell carcinoma (n = 12/24, 50%). Active treatment of any type was given in 19/31 (61%) and 41/62 (66%) of patients in the LTOT and control groups, respectively (p = 0.83). In the LTOT group, median survival was 38 days with best supportive care and 462 days with active treatment (p = 0.003). However, when adjusting on performance status and disease stage, LTOT was not significantly associated with a worse outcome. Hazard ratio (HR): 1.56 (95% confidence interval [CI]: 0.87 to 2.81) (p = 0.137). Administration of any treatment was associated with a better prognostic: HR: 0.35 (95% CI: 0.19 to 0.66). Both groups had a similar treatment safety profile.

Conclusion

Incidence of lung cancer in patients with LTOT was comparable to the general population. The proportion of LTOT patients who received active treatment was similar to controls, and overall survival did not differ from controls in a multivariate analysis. Although reaching a histological diagnosis may be challenging in LTOT patients, the efficacy and safety of the management strategies of lung cancer seem preserved.