bluuebunny/crossref_metadata_2025 huggingface dataset:
Bacterial diversity dominates variable macrophage responses of tuberculosis patients in Tanzania
Authors: Hiza Hellen , Zwyer Michaela , Hella Jerry , Arbués Ainhoa , Sasamalo Mohamed , Borrell Sonia , Xu Zhi Ming , Ross Amanda , Brites Daniela , Fellay Jacques , Reither Klaus , Gagneux Sébastien , Portevin Damien
Published: December 2023

TheMycobacterium tuberculosiscomplex (MTBC) comprises nine human-adapted lineages that differ in their geographical distribution. Local adaptation of specific MTBC genotypes to the respective human host population has been invoked in this context. Here, we generated macrophages from cryopreserved blood mononuclear cells of Tanzanian tuberculosis patients, from which the infecting MTBC strains had previously been phylogenetically characterized. We infected these macrophages ex vivo with a phylogenetically similar MTBC strain (“matched infection”) or with strains representative of other MTBC lineages (“mismatched infection”). We found that L1 infections resulted in a significantly lower bacterial burden and that the intra-cellular replication rate of L2 strains was significantly higher compared the other MTBC lineages, irrespective of the MTBC lineage originally infecting the patients. Moreover, L4-infected macrophages released significantly greater amounts of TNF-α, IL-6, IL-10, MIP-1β, and IL-1β compared to macrophages infected by all other strains. Taken together, while our results revealed no measurable effect of local adaptation, they further highlight the strong impact of MTBC phylogenetic diversity on the variable outcome of the host-pathogen interaction in human tuberculosis.
Allantoic fluid-based qPCR for early-onsetin ovosexing
Authors: Santos Simão , Corion Matthias , De Ketelaere Bart , Lammertyn Jeroen , Spasic Dragana
Published: December 2023

The culling of day-old male chickens remains an important welfare issue in the poultry industry. Several governments (e.g., Germany, France or Italy) have prohibited this practice, pushing the hatcheries to look for alternatives. Although different solutions exist for solving this problem, sex determination during embryo’s incubation (so calledin ovosexing) is considered the most suitable both for consumers and the industry since it aligns with the increasing demand for ethical and sustainable agriculture. However, to be applied in the market,in ovosexing technologies have to meet a number of requirements, such as being compatible with all egg colors and early developmental stages, while maintaining high hatchability rate and accuracy at low cost and high throughput. To meet these requirements, we studied the use of the sexual genesHINTW(female-specific) andDMRT-1(present in both males and females) between incubation days 6 and 9. By utilizing quantitative polymerase chain reaction (qPCR) as analysis method and allantoic fluid (AF) as sample, our study confirmed specific detection of these genes in AF, remarkably already at day 6 of development. In a blind study performed with 80 eggs, we achieved a 95% accuracy rate in sorting embryos when using theHINTWgene alone and an outstanding 100% accuracy rate when using Δλ values (difference between theHINTWandDMRT-1qPCR cycle threshold (Ct)). Importantly, the AF sampling procedure did not reveal any significant detrimental effects on hatchability or embryo development, revealing high potential for this understudied type of sample to be used. In conclusion, the developed assay can provide more in-depth information about AF as a sample for genomicin ovosexing and open new industrial possibilities for developing faster and cheaper assays.

Research highlights

A highly reliable and accurate method forin ovosexing in early incubation stages is established.

Allantoic fluid can be easily extracted with minimal invasiveness while providing the necessary genomic material for sexual sorting.

HINTWwas found to be present in both female and male samples due to possible maternal contamination.

HINTWalone or combined withDMRT-1gene enables early-onset sexing with 100% accuracy.
Cone-driven, geniculo-cortical responses in canine models of outer retinal disease
Authors: Taskin Huseyin O. , Wivel Jacqueline , Aguirre Gustavo D. , Beltran William A. , Aguirre Geoffrey K.
Published: December 2023

Purpose

Canine models of inherited retinal degeneration are used for proof-of-concept of emerging gene and cell-based therapies that aim to produce functional restoration of cone-mediated vision. We examined functional MRI measures of the post-retinal response to cone-directed stimulation in wild type (WT) dogs, and in three different retinal disease models.

Methods

Temporal spectral modulation of a uniform field of light around a photopic background was used to target the canine L/M (hereafter “L”) and S cones and rods. Stimuli were designed to separately target the post-receptoral luminance (L+S) and chrominance (L–S) pathways, the rods, and all photoreceptors jointly (light flux). These stimuli were presented to WT, and mutantPDE6B-RCD1,RPGR-XLPRA2, andNPHP5-CRD2 dogs during pupillometry and fMRI.

Results

Pupil responses in WT dogs to light flux, L+S, and rod-directed stimuli were consistent with responses being driven by cone signals alone. For WT animals, both luminance and chromatic (L–S) stimuli evoked fMRI responses in the lateral geniculate nucleus (LGN) or visual cortex; RCD1 animals with predominant rod loss had similar responses. Responses to cone-directed stimulation were reduced in XLPRA2 and absent in CRD2. NPHP5 gene augmentation restored the cortical response to luminance stimulation in a CRD2 animal.

Conclusions

Cone-directed stimulation during fMRI can be used to measure the integrity of luminance and chrominance responses in the dog visual system. TheNPHP5-CRD2 model is appealing for studies of recovered cone function.

Translational Relevance

fMRI assessment of cone driven cortical response provides a tool to translate cell/gene therapies for vision restoration.
A complex regulatory network governs the production of an antibiotic with unusual cell-density-dependence
Authors: Hindra  , Elliot Marie A.
Published: December 2023

Streptomycesbacteria are renowned both for their antibiotic production capabilities, and for their cryptic metabolic potential. Here, we leveraged the activity of an Lsr2 knockdown construct to enhance antibiotic production in the wildStreptomycesisolate WAC07094. We determined the new activity stemmed from increased levels of the angucycline-like family member saquayamycin. Saquayamycin has both antibiotic and anti-cancer activities, and intriguingly, beyond Lsr2-mediated repression, we found saquayamycin production was also suppressed at high density on solid or in liquid growth media. This density-dependent control was exerted at the level of the cluster-situated regulatory genesqnRand was mediated in part through the activity of the PhoRP two component regulatory system; deletingphoRPled to both constitutive antibiotic production andsqnRexpression, suggesting that PhoP functions to repress the expression ofsqnRat high cell density. We further discovered that magnesium supplementation could also alleviate this cell density dependence, although its action was independent of PhoP. Finally, we revealed that the nitrogen-responsive regulators GlnR and AfsQ1 could relieve the repression exerted by Lsr2 and PhoP. This unusual density-dependent production of saquayamycin was not unique to WAC07094; we found that saquayamycin production by another wild isolate was also density-dependent, suggesting this spatial control may serve an important ecological function in their native environments.

IMPORTANCE

Streptomycesspecialized metabolic gene clusters are subject to complex regulation, and their products are frequently not observed under standard laboratory growth conditions. For the wildStreptomycesisolate WAC07094, production of the angucycline-family compound saquayamycin is subject to a unique constellation of control factors. Notably, it is produced primarily at low cell density, in contrast to the high cell density production typical of most antibiotics. This unusual density dependence is conserved in other saquayamycin producers and is driven by the pathway-specific regulator SqnR, whose expression is influenced by both nutritional and genetic elements. Collectively, this work provides new insights into an intricate regulatory system governing antibiotic production and indicates there may be benefits to including low density cultures in antibiotic screening platforms.
In SilicoCharacterization of Intracellular Localization Signals and Structural Features of Mosquito Densovirus (MDV) Viral Proteins
Authors: Barik Tapan K , Swain Surya N , Sahu Sushil Kumar , Acharya Usha R , Metz Hillery C. , Rasgon Jason L
Published: December 2023

As entomopathogenic viruses, mosquito densoviruses (MDVs) are widely studied for their potential as biocontrol agents and molecular laboratory tools for mosquito manipulation. The nucleus of the mosquito cell is the site for MDV genome replication and capsid assembly, however the nuclear localization signals (NLSs) and nuclear export signals (NES) for MDV proteins have not yet been identified. We carried out anin silicoanalysis to identify putative NLSs and NESs in the viral proteins of densoviruses that infect diverse mosquito genera (Aedes, Anopheles, andCulex) and identified putative phosphorylation and glycosylation sites on these proteins. These analyses lead to a more comprehensive understanding of how MDVs are transported into and out of the nucleus and lay the foundation for the potential use of densoviruses in mosquito control and basic research.

Data summary

Data used in this article were obtained from the GenBank database using accession numbers AYH52680, AYH52678, AYH52679, ABX83665, ABX83663, ABX83664, ABU95013, ABU95011, ABU95012, and AXQ04861.

Impact statement

Mosquito densoviruses (MDVs) are of interest as mosquito biocontrol agents and as laboratory research tools. The trafficking of viral proteins to the cell nucleus is a critical step in viral replication. We usedin silicoapproaches to identify putative nuclear localization signals and nuclear export signals for MDVs that infect the three major genera of pathogen-transmitting mosquitoes (Aedes, Anopheles, andCulex). These analyses lead a more comprehensive understanding of how MDVs are transported into and out of the nucleus and lay the foundation for the potential use of densoviruses in mosquito control and basic research.
Natural reversal of cavefish heart asymmetry is controlled by Sonic Hedgehog effects on the left-right organizer
Authors: Ng Mandy , Ma Li , Shi Janet , Jeffery William R.
Published: December 2023

The direction of left-right (L-R) visceral asymmetry is conserved in vertebrates. Deviations of the asymmetric pattern are rare, and the underlying mechanisms are not understood. Here we use the teleostAstyanax mexicanus, a single species consisting of surface fish with normal left-oriented heart asymmetry and cavefish with high levels of reversed right-oriented heart asymmetry, to explore natural changes in L-R determination. We show that Sonic Hedgehog (Shh) signaling is increased at the posterior midline, Kupffers Vesicle (KV), the teleost L-R Organizer (LRO), is enlarged and contains longer cilia, and the number of dorsal forerunner cells, the KV precursors, is increased in cavefish. Furthermore, Shh overexpression in surface fish induces KV modifications and changes in heart asymmetry resembling the cavefish phenotype. Asymmetric expression of the Nodal antagonistdand5is equalized or reversed in the cavefish KV, and Shh overexpression in surface fish mimics changes in cavefish L-Rdand5asymmetry and shifts Nodal laterality in the lateral plate mesoderm. Our results show that naturally occurring modifications in cavefish heart asymmetry are controlled by the effects of enhanced Shh signaling on LRO function.

Natural reversal of cavefish heart asymmetry is controlled by enhanced Sonic Hedgehog signaling at the posterior midline, which modifies left-right organizer function and subsequent Nodal laterality.
Arabidopsis actin-binding protein WLIM2A links PAMP-triggered immunity and cytoskeletal organization
Authors: Manickam Prabhu , Abulfaraj Aala A , Alhoraibi Hanna M , Veluchamy Alaguraj , Almeida-Trapp Marilia , Hirt Heribert , Rayapuram Naganand
Published: December 2023

MAPKs are a family of highly conserved serine/threonine protein kinases that link upstream receptors to their downstream targets which can be localized in the cytoplasm or the nucleus. Pathogens produce pathogen-associated molecular patterns (PAMPs) that trigger the activation of MAPK cascades in plants. Phosphoproteomic analysis of PAMP-inducedArabidopsisplants led to the identification of several putative MAPK targets, WLIM2A. Here, we investigated the role of WLIM2A in plant immunity via a reverse-genetics approach generatingwlim2aknockout lines using CRISPR-Cas9, as well as complementation and phosphosite mutatedWLIM2Aexpression lines in thewlim2abackground. Thewlim2alines were compromised in their response toPstDC3000 but showed enhanced resistance to fungal infection byBotrytis cinereae. Transcriptome analyses revealed that immune hormone signaling and biosynthesis genes of salicylic acid (SA), jasmonic acid (JA), and ethylene (ET) are differentially regulated in thewlim2aknockout lines. Pathogen assays withPst DC3000showed altered stomatal phenotypes inwlim2amutants. Importantly,WLIM2Aphosphomutants had opposing stomatal behaviour and resistance phenotypes in response toPstDC3000 infection. Overall, these data show that phosphorylation of WLIM2A by MAPKs regulatesArabidopsisstomatal immunity.
ROR2 regulates cellular plasticity in pancreatic neoplasia and adenocarcinoma
Authors: Benitz Simone , Steep Alec , Nasser Malak , Preall Jonathan , Mahajan Ujjwal M. , McQuithey Holly , Loveless Ian , Davis Erick T. , Wen Hui-Ju , Long Daniel W. , Metzler Thomas , Zwernik Samuel , Louw Michaela , Rempinski Donald , Salas-Escabillas Daniel , Brender Sydney , Song Linghao , Huang Ling , Zhang Zhenyu , Steele Nina G. , Regel Ivonne , Bednar Filip , Crawford Howard C.
Published: December 2023

Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells into precancerous lesions to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We discovered that normal acinar cell differentiation, maintained by the transcription factor Pdx1, suppresses a broad gastric cell identity that is maintained in metaplasia, neoplasia, and the classical subtype of PDAC in mouse and human. We have identified the receptor tyrosine kinase Ror2 as marker of a gastric metaplasia (SPEM)-like identity in the pancreas. Ablation ofRor2in a mouse model of pancreatic tumorigenesis promoted a switch to a gastric pit cell identity that largely persisted through progression to the classical subtype of PDAC. In both human and mouse pancreatic cancer, ROR2 activity continued to antagonize the gastric pit cell identity, strongly promoting an epithelial to mesenchymal transition, conferring resistance to KRAS inhibition, and vulnerability to AKT inhibition.

Significance

We discovered the receptor tyrosine kinase ROR2 as an important regulator of cellular identity in pancreatic precancerous lesions and pancreatic cancer. ROR2 drives an aggressive PDAC phenotype and confers resistance to Kras inhibitors, suggesting that targeting ROR2 will enhance sensitivity to this new generation of targeted therapies.
Feature attention graph neural network for estimating brain age and identifying important neural connections in mouse models of genetic risk for Alzheimer’s disease
Authors: Moon Hae Sol , Mahzarnia Ali , Stout Jacques , Anderson Robert J , Badea Cristian T. , Badea Alexandra
Published: December 2023

Alzheimer’s disease (AD) remains one of the most extensively researched neurodegenerative disorders due to its widespread prevalence and complex risk factors. Age is a crucial risk factor for AD, which can be estimated by the disparity between physiological age and estimated brain age. To model AD risk more effectively, integrating biological, genetic, and cognitive markers is essential. Here, we utilized mouse models expressing the major APOE human alleles and human nitric oxide synthase 2 to replicate genetic risk for AD and a humanized innate immune response. We estimated brain age employing a multivariate dataset that includes brain connectomes, APOE genotype, subject traits such as age and sex, and behavioral data. Our methodology used Feature Attention Graph Neural Networks (FAGNN) for integrating different data types. Behavioral data were processed with a 2D Convolutional Neural Network (CNN), subject traits with a 1D CNN, brain connectomes through a Graph Neural Network using quadrant attention module. The model yielded a mean absolute error for age prediction of 31.85 days, with a root mean squared error of 41.84 days, outperforming other, reduced models. In addition, FAGNN identified key brain connections involved in the aging process. The highest weights were assigned to the connections between cingulum and corpus callosum, striatum, hippocampus, thalamus, hypothalamus, cerebellum, and piriform cortex. Our study demonstrates the feasibility of predicting brain age in models of aging and genetic risk for AD. To verify the validity of our findings, we compared Fractional Anisotropy (FA) along the tracts of regions with the highest connectivity, the Return-to-Origin Probability (RTOP), Return-to-Plane Probability (RTPP), and Return-to-Axis Probability (RTAP), which showed significant differences between young, middle-aged, and old age groups. Younger mice exhibited higher FA, RTOP, RTAP, and RTPP compared to older groups in the selected connections, suggesting that degradation of white matter tracts plays a critical role in aging and for FAGNN’s selections. Our analysis suggests a potential neuroprotective role of APOE2, relative to APOE3 and APOE4, where APOE2 appears to mitigate age-related changes. Our findings highlighted a complex interplay of genetics and brain aging in the context of AD risk modeling.
Bacteriophage cocktail shows no toxicity and improves the survival ofGalleria mellonellainfected withKlebsiellaspp.
Authors: Kelly Lucy , Jameson Eleanor
Published: December 2023

Klebsiellaspp. are causative agents of healthcare associated infections in patients who are immunocompromised and use medical devices. The antibiotic resistance crisis has led to an increase in infections caused by these bacteria, which can develop into potentially life-threatening illness if not treated swiftly and effectively. Thus, new treatment options forKlebsiellaare urgently required. Phage therapy can offer an alternative to ineffective antibiotic treatments for antibiotic-resistant bacteria infections. The aim of the present study was to produce a safe and effective phage cocktail treatment againstK. pneumoniaeandK. oxytoca, both in liquidin vitroculture and anin vivo Galleria mellonellainfection model. The phage cocktail was significantly more effective at killingK. pneumoniaeandK. oxytocastrains compared with monophage treatments. Preliminary phage cocktail safety was demonstrated through application in thein vivo G. mellonellamodel: where the phage cocktail induced no toxic side effects inG. mellonella. In addition, the phage cocktail significantly improved the survival ofG. mellonellawhen administered as a prophylactic treatment, compared with controls. In conclusion, our phage cocktail was demonstrated to be safe and effective againstKlebsiellaspp. in theG. mellonellainfection model. This provides a strong case for future treatment forKlebsiellainfections, either as an alternative, or adjunct to, antibiotics.
Integrin Mechanosensing relies on Pivot-clip Mechanism to Reinforce Cell Adhesion
Authors: Montes Andre R. , Barroso Anahi , Wang Wei , O’Connell Grace D. , Tepole Adrian B. , Mofrad Mohammad R.K.
Published: December 2023

Cells intricately sense mechanical forces from their surroundings, driving biophysical and biochemical activities. This mechanosensing phenomenon occurs at the cell-matrix interface, where mechanical forces resulting from cellular motion, such as migration or matrix stretching, are exchanged through surface receptors, primarily integrins, and their corresponding matrix ligands. A pivotal player in this interaction is theα5β1integrin and fibronectin (FN) bond, known for its role in establishing cell adhesion sites for migration. However, upregulation of theα5β1-FN bond is associated with uncontrolled cell metastasis. This bond operates through catch bond dynamics, wherein the bond lifetime paradoxically increases with greater force. The mechanism sustaining the characteristic catch bond dynamics ofα5β1-FN remains unclear. Leveraging molecular dynamics simulations, our approach unveils a pivot-clip mechanism. Two key binding sites on FN, namely the synergy site and the RGD (arg-gly-asp) motif, act as active points for structural changes inα5β1integrin. Conformational adaptations at these sites are induced by a series of hydrogen bond formations and breaks at the synergy site. We disrupt these adaptations through a double mutation on FN, known to reduce cell adhesion. A whole-cell finite element model is employed to elucidate how the synergy site may promote dynamicα5β1-FN binding, resisting cell contraction. In summary, our study integrates molecular and cellular-level modeling to propose that FN’s synergy site reinforces cell adhesion through enhanced binding dynamics and a mechanosensitive pivot-clip mechanism. This work sheds light on the interplay between mechanical forces and cell-matrix interactions, contributing to our understanding of cellular behaviors in physiological and pathological contexts.

SIGNIFICANCE

α5β1integrin serves as a mediator of cell-matrix adhesion and has garnered attention as a target for impeding cancer metastasis. Despite its importance, the mechanism underlying the formation of a catch bond betweenα5β1integrin and its primary ligand, fibronectin, has remained elusive. Our study aims to address this gap by proposing a pivot-clip mechanism. This mechanism elucidates howα5β1integrin and fibronectin collaboratively reinforce cell adhesion through conformational changes induced by the dynamic interaction of a key binding motif known as the synergy site.
Engineering self-propelled tumor-infiltrating CAR T cells using synthetic velocity receptors
Authors: Johnston Adrian C. , Alicea Gretchen M. , Lee Cameron C. , Patel Payal V. , Hanna Eban A. , Vaz Eduarda , Forjaz André , Wan Zeqi , Nair Praful R. , Lim Yeongseo , Chen Tina , Du Wenxuan , Kim Dongjoo , Nichakawade Tushar D. , Rebecca Vito W. , Bonifant Challice L. , Fan Rong , Kiemen Ashley L. , Wu Pei-Hsun , Wirtz Denis
Published: December 2023

Chimeric antigen receptor (CAR) T cells express antigen-specific synthetic receptors, which upon binding to cancer cells, elicit T cell anti-tumor responses. CAR T cell therapy has enjoyed success in the clinic for hematological cancer indications, giving rise to decade-long remissions in some cases. However, CAR T therapy for patients with solid tumors has not seen similar success. Solid tumors constitute 90% of adult human cancers, representing an enormous unmet clinical need. Current approaches do not solve the central problem of limited ability of therapeutic cells to migrate through the stromal matrix. We discover that T cells at low and high density display low- and high-migration phenotypes, respectively. The highly migratory phenotype is mediated by a paracrine pathway from a group of self-produced cytokines that include IL5, TNFα, IFNγ, and IL8. We exploit this finding to “lock-in” a highly migratory phenotype by developing and expressing receptors, which we call velocity receptors (VRs). VRs target these cytokines and signal through these cytokines’ cognate receptors to increase T cell motility and infiltrate lung, ovarian, and pancreatic tumors in large numbers and at doses for which control CAR T cells remain confined to the tumor periphery. In contrast to CAR therapy alone, VR-CAR T cells significantly attenuate tumor growth and extend overall survival. This work suggests that approaches to the design of immune cell receptors that focus on migration signaling will help current and future CAR cellular therapies to infiltrate deep into solid tumors.
Towards Ecological Measurement of Complex Cognitive Processes: Functional-Near Infrared Spectroscopy of Brain Activity During Reading
Authors: Čeko Marta , Hirshfield Leanne , Doherty Emily , Southwell Rosy , D’Mello Sidney
Published: December 2023

Functional magnetic resonance imaging (fMRI) has provided unparalleled insights into the fundamental neural mechanisms governing human cognition, including complex processes such as reading. Here, we leverage the wealth of prior fMRI work to capture reading outside the MRI scanner using functional near infra-red spectroscopy (fNIRS). In a large sample of participants (n = 82) we observe significant prefrontal and temporal fNIRS activations during reading, which are largely reliable across participants, therefore providing a robust validation of prior fMRI work on reading-related language processing. These results lay the groundwork towards developing adaptive systems capable of assisting these higher-level processes, for example to support readers and language learners. This work also contributes to bridging the gap between laboratory findings and real-world applications in the realm of cognitive neuroscience.
Systemic Sclerosis dermal fibroblast exosomes trigger a Type 1 interferon response in keratinocytes through the TBK/JAK/STAT signalling axis
Authors: Bryon Jessica , Wasson Christopher W , Koeppen Katja , Chandler Francesca , Willis Leon F , Klein Elliott , Zeqiraj Elton , Ross Rebecca L , Del Galdo Francesco
Published: December 2023

Background

Activation of Type I IFN response has been shown to correlates with disease activity in systemic sclerosis. It is currently unknown whether the tissue-specific Type I IFN activation is a consequence of the response observed in blood or rather its source. Exosomes from SSc fibroblasts were recently shown to activate macrophagesin vitro. Here, we aimed to determine the source of Type I IFN signature in SSc skin biopsies and the potential role of exosomes from SSc dermal fibroblasts in the process.

Methods

Skin biopsies were obtained from healthy and SSc patients’ forearms and processed for dermal fibroblasts and keratinocytes. Exosomes were isolated from healthy and SSc dermal fibroblast supernatants by ultracentrifugation and added to human skin keratinocytes. Keratinocyte transcriptome was analysed by RNA-seq analysis. TANK-binding kinase (TBK) and JAK were inhibited using a small molecule inhibitor (GSK8612) and Tofacitinib, respectively.

Results

SSc skin biopsies showed highest levels of Type I IFN response in the epidermal layer. RNA-seq analysis of keratinocytes transcriptome following exposure to dermal fibroblast exosomes showed strong upregulation of IFN signature genes induced by SSc exosomes compared to Healthy control. Inhibition of TBK or JAK activity suppressed the upregulation of the IFN signature induced by SSc exosomes.

Conclusion

IFN activation of SSc keratinocytes is dependent on their crosstalk with dermal fibroblasts and inducible by extracellular exosomes. Our data indicates that SSc fibroblasts exosomes may carry the ‘‘signal zero’’ of local Type I IFN activation through activation of pattern recognition receptors upstream of TBK.

Key Messages

SSc patient skin exhibit a type 1 IFN signature with keratinocytes being the major source of the signature

Cross talk between the fibroblasts and keratinocytes through exosomes may be signal zero for the type 1 IFN signature

Blocking JAK in the keratinocytes with Tofacitinib disrupts the type 1 IFN signature
Evolution in microbial microcosms is highly parallel regardless of the presence of interacting species
Authors: Meroz Nittay , Livny Tal , Toledano Gal , Sorokin Yael , Tovi Nesli , Friedman Jonathan
Published: December 2023

During laboratory evolution, replicate bacterial populations often follow similar trajectories, thus their evolution is potentially predictable. However, predicting the evolution of natural populations, which are commonly embedded in multispecies communities, would prove extremely difficult if adaptations are contingent on the identity of the interacting species. The extent to which adaptations typically depend on coevolving partners remains poorly understood, since coevolution is commonly studied using small-scale experiments involving few species, making it challenging to extract general trends. To address this knowledge gap, we study the adaptations that occurred in strains of each of 11 species that were either evolved in monoculture or in multiple pairwise co-cultures. While we detect slight but significant partner-specific effects we find that the majority of evolutionary changes that occur are robust across strains that evolved with different partners; species’ growth abilities increase by a similar factor regardless of partners’ identity, shifts in community compositions and interactions are similar between pairs of coevolved and separately evolved strains, and the majority of parallelly mutated genes were detected in multiple biotic conditions. We hypothesized that these results might arise from the fact that ancestral strains are maladapted to the abiotic environment, thus having a pool of adaptations that are beneficial regardless of the biotic partners. Therefore, we conducted a second experiment with strains that were pre-adapted to the abiotic conditions before being co-cultured. We find that even after ∼400 generations of pre-adaptation, evolution is surprisingly non-partner-specific. Further work is required in order to elucidate the factors that influence partner-specificity of coevolution, but our results suggest that selection imposed by the biotic environment may play a secondary role to that imposed by abiotic conditions, making predictions regarding coevolutionary dynamics less challenging than previously thought.
Extensive variation and strain-specificity in dengue virus susceptibility among AfricanAedes aegyptipopulations
Authors: Dabo Stéphanie , Henrion-Lacritick Annabelle , Lecuyer Alicia , Jiolle Davy , Paupy Christophe , Ayala Diego , da Veiga Leal Silvânia , Badolo Athanase , Vega-Rúa Anubis , Sylla Massamba , Akorli Jewelna , Otoo Sampson , Lutomiah Joel , Sang Rosemary , Mutebi John-Paul , Saleh Maria-Carla , Rose Noah H. , McBride Carolyn S. , Lambrechts Louis
Published: December 2023

African populations of the mosquitoAedes aegyptiare usually considered less susceptible to infection by human-pathogenic flaviviruses than globally invasive populations found outside Africa. Although this contrast has been well documented for Zika virus (ZIKV), it is unclear to what extent it is true for dengue virus (DENV), the most prevalent flavivirus of humans. Addressing this question is complicated by substantial genetic diversity among DENV strains, most notably in the form of four genetic types (DENV1 to DENV4), that can lead to genetically specific interactions with mosquito populations. Here, we carried out a continent-wide survey of DENV susceptibility using a panel of field-derivedAe. aegypticolonies from across the African range of the species and a colony from Guadeloupe, French West Indies as non-African reference. We found considerable variation in the ability of AfricanAe. aegyptipopulations to acquire and replicate a panel of six DENV strains spanning the four DENV types. Although AfricanAe. aegyptipopulations were generally less susceptible than the reference non-African population from Guadeloupe, in several instances some African populations were equally or more susceptible than the Guadeloupe population. Moreover, the relative level of susceptibility between African mosquito populations depended on the DENV strain, indicating genetically specific interactions. We conclude that unlike ZIKV susceptibility, there is no clear-cut dichotomy in DENV susceptibility between African and non-AfricanAe. aegypti. DENV susceptibility of AfricanAe. aegyptipopulations is highly heterogeneous and largely governed by the specific pairing of mosquito population and DENV strain.

Author summary

African populations of the mosquitoAedes aegyptiare usually thought to be less likely to get infected by flaviviruses compared toAe. aegyptimosquitoes found outside Africa. While this has been well-demonstrated for Zika virus, it is not clear if the same is true for dengue virus, which is the most common flavivirus in humans. Studying this is complicated by the strain diversity of dengue virus, including four main genetic types, potentially causing different interactions. In this study, we compared several mosquito populations and found that, in general, African mosquitoes were less likely to get infected by dengue virus compared to mosquitoes from outside Africa. However, in some cases, African mosquitoes were just as or even more likely to get infected. The specific strain of dengue virus also influenced how likely African mosquitoes were to get infected, showing that the relationship between African mosquitoes and dengue virus is complex.
A root-specific NLR network confers resistance to plant parasitic nematodes
Authors: Lüdke Daniel , Sakai Toshiyuki , Kourelis Jiorgos , Toghani AmirAli , Adachi Hiroaki , Posbeyikian Andrés , Frijters Raoul , Pai Hsuan , Harant Adeline , Ernst Karin , Ganal Martin , Verhage Adriaan , Wu Chih-Hang , Kamoun Sophien
Published: December 2023

Nucleotide-binding domain and leucine-rich repeat immune receptors (NLRs) confer disease resistance to a multitude of foliar and root parasites of plants. However, the extent to which NLR immunity is expressed differentially between plant organs is poorly known. Here, we show that a large cluster of tomato genes, which encodes the cyst and root-knot nematode disease resistance proteins Hero and MeR1 as well as the NLR-helper NRC6, exhibits nearly exclusive expression in the roots. This root-specific gene cluster emerged inSolanumspecies about 21 million years ago through gene duplication from the ancient NRC network of asterid plants. NLR-sensors in this gene cluster exclusively signal through NRC6 helpers to trigger the hypersensitive cell death immune response. These findings indicate that the NRC6 gene cluster has sub-functionalized from the larger NRC network to specialize for resistance against root pathogens, including cyst and root-knot nematodes. We propose that NLR gene clusters and networks have evolved organ-specific gene expression as an adaptation to particular parasites and to reduce the risk of autoimmunity.
A Novel Role for CSA in the Regulation of Nuclear Envelope Integrity: Uncovering a Non-Canonical Function
Authors: Yang Denny , Lai Austin , Davies Amelie , Janssen Anne FJ , Larrieu Delphine
Published: December 2023

Cockayne syndrome (CS) is an autosomal recessive premature ageing condition mainly characterized by microcephaly, growth failure, and neurodegeneration. It is caused by mutations inERCC6orERCC8genes which encode for Cockayne Syndrome B (CSB) and Cockayne Syndrome A (CSA) proteins, respectively. CSA and CSB have well-characterised roles in transcription-coupled nucleotide excision repair (TC-NER), responsible for the removal of bulky DNA lesions, including those caused by UV irradiation. Here, we report that CSA knockout cells and CSA patient cells (CS-A) carrying a loss-of-function mutation in theERCC8gene exhibit defects in nuclear envelope (NE) integrity. NE dysfunction is a characteristic phenotype of cells from progeroid disorders caused by mutation in NE proteins, such as Hutchinson-Gilford Progeria Syndrome (HGPS). However, it has never been reported in Cockayne Syndrome. We observed that CS-A cells displayed reduced levels of LAP2-emerin-MAN1 (LEM)-domain 2 (LEMD2) at the NE resulting in decreased formation of LEMD2-lamin A/C complexes. In addition, loss of CSA function caused increased actin stress fibers that contributed to enhanced mechanical stress to the NE. Altogether, these led to NE blebbing and ruptures in interphase, causing activation of the innate/immune cGAS/STING signaling pathway. Disrupting the linker of the nucleoskeleton and cytoskeleton (LINC) complex that is responsible for anchoring the cytoskeleton to the NE, rescued the NE phenotypes and reduced the activation of cGAS/STING pathway. This work has revealed a previously uncharacterized role for CSA in regulating NE integrity and shed light on mechanisms that may further explain some of the clinical phenotypes observed in CS patients such as neuroinflammation. This is to our knowledge, the first study showing NE dysfunction in a progeroid syndrome caused by mutations in a DNA damage repair protein, reinforcing the connection between NE deregulation and ageing.
Neuroepithelial depletion schedules cessation of neurogenesis in theDrosophilaoptic lobes
Authors: Nguyen Phuong-Khanh , Cheng Louise Y
Published: December 2023

The brain is consisted of diverse neurons arising from a limited number of neural stem cells.Drosophilaneural stem cells called neuroblasts (NBs) produces specific neural lineages of various lineage sizes depending on their location in the brain. In theDrosophilavisual processing centre – the optic lobes (OLs), medulla NBs derived from the neuroepithelium (NE) give rise to neurons and glia cells of the medulla cortex. The timing and the mechanisms responsible for the cessation of medulla NBs are so far not known. In this study, we show that the termination of medulla NBs during pupal development is determined by the exhaustion of the NE stem cell pool. Altering NE-NB transition during larval neurogenesis disrupts the timely termination of medulla NBs. Medulla NBs terminate neurogenesis via a combination of cell death, terminal symmetric division, and a switch to gliogenesis. We show that temporal progression is not required for the termination of medulla NBs. The timing of NB cessation can be altered through the acquisition of a glial cell fate via Glial cells missing, or through conversion to type II NB cell fate via Tailless, or by inhibition of differentiation via Prospero knockdown. As theDrosophilaOL shares a similar mode of division with mammalian neurogenesis, determining how and when these progenitors cease proliferation during development can have important implications for mammalian brain size determination and regulation of its overall function.
Assessing and mitigating privacy risks of sparse, noisy genotypes by local alignment to haplotype databases
Authors: Emani Prashant S. , Geradi Maya N. , Gürsoy Gamze , Grasty Monica R. , Miranker Andrew , Gerstein Mark B.
Published: December 2023

Single nucleotide polymorphisms (SNPs) from omics data create a reidentification risk for individuals and their relatives. Although the ability of thousands of SNPs (especially rare ones) to identify individuals has been repeatedly shown, the availability of small sets of noisy genotypes, from environmental DNA samples or functional genomics data, motivated us to quantify their informativeness. We present a computational tool suite, termed Privacy Leakage by Inference across Genotypic HMM Trajectories (PLIGHT), using population-genetics-based hidden Markov models (HMMs) of recombination and mutation to find piecewise alignment of small, noisy SNP sets to reference haplotype databases. We explore cases in which query individuals are either known to be in the database, or not, and consider several genotype queries, including those from environmental sample swabs from known individuals and from simulated “mosaics” (two-individual composites). Using PLIGHT on a database with ∼5000 haplotypes, we find for common, noise-free SNPs that only ten are sufficient to identify individuals, ∼20 can identify both components in two-individual mosaics, and 20–30 can identify first-order relatives. Using noisy environmental-sample-derived SNPs, PLIGHT identifies individuals in a database using ∼30 SNPs. Even when the individuals are not in the database, local genotype matches allow for some phenotypic information leakage based on coarse-grained SNP imputation. Finally, by quantifying privacy leakage from sparse SNP sets, PLIGHT helps determine the value of selectively sanitizing released SNPs without explicit assumptions about population membership or allele frequency. To make this practical, we provide a sanitization tool to remove the most identifying SNPs from genomic data.
C-SPAM: an open-source time-resolved specimen vitrification device with light-activated molecules
Authors: Montaño Romero Alejandra , Bonin Calli , Twomey Edward C.
Published: December 2023

Molecular structures can be determined in vitro and in situ with cryo-electron microscopy (cryo-EM). Specimen preparation is a major obstacle in cryo-EM. Typical sample preparation is orders of magnitude slower than biological processes. Time-resolved cryo-EM (TR-cryo-EM) can capture short-lived states. Here, Cryo-EM sample preparation with light-activated molecules (C-SPAM) is presented, an open-source, photochemistry-coupled device for TR-cryo-EM that enables millisecond resolution and tunable timescales across broad biological applications.
Exploring practices that impact women’s career advancement within the workplace: a qualitative approach
Authors: Fitong Ketchiwou Gaelle , Naong Matsidiso Nehemia
Published: December 2023

Purpose

This study aims to explore organizational factors that impact women’s career advancement. Knowledge of organizational practices that promote or obstruct women’s career progress is vital for women, firms and governments.

Design/methodology/approach

A total of 237 women participated in the study from the service sector in Johannesburg (South Africa). Participants were selected using a convenient sampling approach. Researchers used a questionnaire, consisting of demographic and open-ended questions, to gather data. Comments were analyzed using a thematic content analysis approach.

Findings

Findings reveal that prioritizing women, offering skills development opportunities, providing growth opportunities, assisting women in managing their careers, offering mentorship and having work-family support initiatives are practices that promote women’s career advancement. Conversely, practices that foster stagnation of women’s careers, distrust in women’s leadership abilities, preference for external candidates, people–related malpractices, male domination/preference, lack of role models and work-family balance support, hamper women’s career advancement.

Practical implications

The findings of this study will contribute to women’s empowerment. Organizations should provide a conducive atmosphere by instituting practices that promote their female employees' career advancement. Firms also should intentionally take practical steps to address practices that impede women’s career progression. The results of this study will also help the government to design appropriate policies that will promote the career progression of women employees.

Originality/value

This study presents findings from an analysis of qualitative data collected from 237 women to provide insight into the experiences of women working within the service industry in Johannesburg, South Africa.
How to unleash innovative work behavior of SMEs workers through clan culture? “Testing the mediating role of knowledge sharing”
Authors: Marampa Adriana Madya , Garnasih Raden Lestari , Pariyanti Eka
Published: December 2023

Purpose

The purpose of this paper is to examine perceived supervisory support (PSS) and the impact of the antecedents of sharing knowledge, namely, clan culture (CC) as well as trust in innovative work behavior (IWB).

Design/methodology/approach

This research focuses on small and medium-sized enterprise (SME) employees, especially SMEs located around tourist attractions in Indonesia. Data collection was carried out by distributing questionnaires. The distribution of the questionnaire was carried out in two ways, namely, the offline and online systems via the Google form. Data analysis tool using structural equation modeling.

Findings

The findings reveal that PSS, knowledge sharing (KS), CC as well as trust are positively related to IWB. In addition, it was also found that KS was proven to mediate CC relationships as well as the trust which had a positive relationship with IWB.

Research limitations/implications

The research design uses cross-sectional data. This means that the measurement of variables is based on self-reports and is carried out at one time, which can lead to method bias that can affect the results of the study. Thus, further research is recommended to collect data longitudinally, which will make the findings stronger.

Practical implications

Theoretically, this study extends previous research by outlining a set of organizational elements that tend to influence KS behavior and their impact on IWB in the SMEs context.

Social implications

Managers and owners of SMEs need to create a CC because the creation of a family or CC will more easily foster a culture of sharing knowledge within the organization, which will ultimately increase IWB.

Originality/value

This study emphasizes that it is not only internal factors within employees that can foster IWB but there are external factors that play an important role in increasing IWB, such as CC, PSS, trust and KS. And to the best of the authors’ knowledge, this is the first study to include all the constructs in one model and the context of SMEs.
How do CCIs contribute to regional innovation?
Authors: Huang Elle Xiaoyan , Zou Xueying
Published: December 2023

Purpose

This paper aims to understand how cultural and creative industries (CCIs) contribute to regional innovation.

Design/methodology/approach

This paper explores the process of CCIs contributing to regional innovation and assesses the accumulated outcome of this process.

Findings

The authors conclude that CCIs contribute to a city’s innovation involving five dimensions (time, space, tangible, intangible and division) and four phases (people, tool, collaboration and brokerage) and the contributions are accumulated into positive innovation outcome; however, a highly developed economy is relatively unsupportive of CCIs contributing to regional innovation.

Originality/value

The main contributions are that the authors configured the detailed process of CCIs contributing to regional innovation and the authors quantitatively measured the impact of CCIs on regional innovation, using the Porter diamond model and Shannon entropy to construct the CCI index.