bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transgenerational virulence: Maternal pathogen exposure reduces offspring fitness
Authors: McIntirea Kristina M. , Dziuba Marcin K. , Haywood Elizabeth B. , Robertson Miles L. , Vaandrager Megan , Baird Emma , Corcoran Fiona , Nelson Taleah , Cortez Michael H. , Duffy Meghan A. 
Published: March 2023

AbstractThere is intense interest in understanding pathogen virulence – that is, the degree of damage caused to a host by a pathogen. However, despite abundant evidence that effects of stressors can carry across generations, studies of pathogen virulence have focused almost exclusively on a single generation. Here, we describe transgenerational virulence, where parental exposure to a pathogen reduces offspring fitness.Daphniahost exposure to a microsporidian pathogen significantly reduced lifespan and fecundity of offspring. The trans-generational virulent effects of maternal exposure to the microsporidian pathogen matched or even exceeded the within generation effects of a fungal pathogen that is considered highly virulent. Moreover, they did not result simply from immune activation in the host, as the transgenerational effect was seen for infections by the microsporidian but not for infec-tions by two other pathogens. The transgenerational effects of the microsporidian carried to the granddaughters, with grandmaternal exposure influencing neonate size. A parame-terized mathematical model translated these impacts to the population level, finding that transgenerational virulence often reduces host density, infected host density, and infection prevalence, which could have implications for host conservation and spillover risk. Given widespread prior evidence for transgenerational effects of predators, resources, and other factors, we propose that transgenerational virulence may be common.
Single-shot 3D photoacoustic tomography using a single-element detector for ultrafast imaging of hemodynamics
Authors: Zhang Yide , Hu Peng , Li Lei , Cao Rui , Khadria Anjul , Maslov Konstantin , Tong Xin , Zeng Yushun , Jiang Laiming , Zhou Qifa , Wang Lihong V. 
Published: March 2023

AbstractImaging hemodynamics is crucial for the diagnosis, treatment, and prevention of vascular diseases. However, current imaging techniques are limited due to the use of ionizing radiation or contrast agents, short penetration depth, or complex and expensive data acquisition systems. Photoacoustic tomography shows promise as a solution to these issues. However, existing photoacoustic tomography methods collect signals either sequentially or through numerous detector elements, leading to either low imaging speed or high system complexity and cost. To address these issues, here we introduce a method to capture a 3D photoacoustic image of vasculature using a single laser pulse and a single-element detector that functions as 6,400 virtual ones. Our method enables ultrafast volumetric imaging of hemodynamics in the human body at up to 1 kHz and requires only a single calibration for different objects and for long-term operations. We demonstrate 3D imaging of hemodynamics at depth in humans and small animals, capturing the variability in blood flow speeds. This concept can inspire other imaging technologies and find applications such as home-care monitoring, biometrics, point-of-care testing, and wearable monitoring.
Human-exoskeleton interaction force estimation in Indego exoskeleton
Authors: Shushtari Mohammad , Arami Arash 
Published: March 2023

AbstractAccurate interaction force estimation can play an important role in optimization human-robot interaction in exoskeleton. In this work, we propose a novel approach for system identification of exoskeleton dynamics in presence of interaction forces as a whole multi-body system regardless of gait phase or any assumption on human-exoskeleton interaction. We hanged the exoskeleton through a linear spring and excited the exoskeleton joints with chirp commands while measuring the exoskeleton-environment interaction force. Several structures of neural networks have been trained to model the exoskeleton passive dynamics and estimate the interaction force. Our testing results indicated that a deep neural network with 250 neurons and 10 time delays can obtain sufficiently accurate estimation of the interaction force, resulting in 1.23 of RMSE on Z-normalized applied torques and 0.89 of adjustedR2.
Immunogenetic metabolomics revealed key enzymes that modulate CAR-T metabolism and function
Authors: Renauer Paul , Park Jonathan J. , Bai Meizhu , Acosta Arianny , Lee Won-Ho , Lin Guang Han , Zhang Yueqi , Dai Xiaoyun , Wang Guangchuan , Errami Youssef , Wu Terence , Clark Paul , Ye Lupeng , Yang Quanjun , Chen Sidi 
Published: March 2023

AbstractImmune evasion is a critical step of cancer progression that remains a major obstacle for current T cell-based immunotherapies. Hence, we seek to genetically reprogram T cells to exploit a common tumor-intrinsic evasion mechanism, whereby cancer cells suppress T cell function by generating a metabolically unfavorable tumor microenvironment (TME). Specifically, we use anin silicoscreen to identifyADAandPDK1as metabolic regulators, in which gene overexpression (OE) enhances the cytolysis of CD19-specific CD8 CAR-T cells against cognate leukemia cells, and conversely,ADAorPDK1deficiency dampens such effect.ADA-OE in CAR-T cells improves cancer cytolysis under high concentrations of adenosine, the ADA substrate and an immunosuppressive metabolite in the TME. High-throughput transcriptomics and metabolomics in these CAR-Ts reveal alterations of global gene expression and metabolic signatures in bothADA-andPDK1-engineered CAR-T cells. Functional and immunological analyses demonstrate thatADA-OE increases proliferation and decreases exhaustion in α-CD19 and α-HER2 CAR-T cells. ADA-OE improves tumor infiltration and clearance by α-HER2 CAR-T cells in anin vivocolorectal cancer model. Collectively, these data unveil systematic knowledge of metabolic reprogramming directly in CAR-T cells, and reveal potential targets for improving CAR-T based cell therapy.SynopsisThe authors identify the adenosine deaminase gene (ADA) as a regulatory gene that reprograms T cell metabolism. ADA-overexpression (OE) in α-CD19 and α-HER2 CAR-T cells increases proliferation, cytotoxicity, memory, and decreases exhaustion, and ADA-OE α-HER2 CAR-T cells have enhanced clearance of HT29 human colorectal cancer tumorsin vivo.
SMAD4: A Critical Regulator of Cardiac Neural Crest Cell Fate and Vascular Smooth Muscle Differentiation
Authors: Alexander Brianna E. , Zhao Huaning , Astrof Sophie 
Published: March 2023

AbstractBackgroundThe pharyngeal arch arteries (PAAs) are precursor vessels which remodel into the aortic arch arteries (AAAs) during embryonic cardiovascular development. Cardiac neural crest cells (NCs) populate the PAAs and differentiate into vascular smooth muscle cells (vSMCs), which is critical for successful PAA-to-AAA remodeling. SMAD4, the central mediator of canonical TGFβ signaling, has been implicated in NC-to-vSMC differentiation; however, its distinct roles in vSMC differentiation and NC survival are unclear.ResultsHere, we investigated the role of SMAD4 in cardiac NC differentiation to vSMCs using lineage-specific inducible mouse strains in an attempt to avoid early embryonic lethality and NC cell death. We found that with global SMAD4 loss, its role in smooth muscle differentiation could be uncoupled from its role in the survival of the cardiac NCin vivo. Moreover, we found that SMAD4 may regulate the induction of fibronectin, a known mediator of NC-to-vSMC differentiation. Finally, we found that SMAD4 is required in NCs cell-autonomously for NC-to-vSMC differentiation and for NC contribution to and persistence in the pharyngeal arch mesenchyme.ConclusionsOverall, this study demonstrates the critical role of SMAD4 in the survival of cardiac NCs, their differentiation to vSMCs, and their contribution to the developing pharyngeal arches.
Imaging angiogenesis in an intracerebrally induced model of brain macrometastasis using αvβ3-targeted iron oxide microparticles
Authors: Buck Jessica , Perez-Balderas Francisco , Zarghami Niloufar , Johanssen Vanessa , Khrapitchev Alexandre A , Larkin James R , Sibson Nicola R 
Published: March 2023

AbstractBrain metastasis is responsible for a large proportion of cancer mortality, and there are currently no effective treatments. Moreover, the impact of treatments, particularly anti-angiogenic therapeutics, is difficult to ascertain using current magnetic resonance imaging (MRI) methods. Imaging of the angiogenic vasculature has been successfully carried out in solid tumours using microparticles of iron oxide (MPIO) conjugated to a peptide (RGD) targeting the integrin αvβ3. The aim of this study was to determine whether RGD-MPIO could be used to identify angiogenic blood vessels in brain metastasesin vivo.A mouse model of intracerebrally implanted brain macrometastasis was established through intracerebral injection of 4T1-GFP cells. T2* weighted imaging was used to visualize MPIO induced hypointense voxelsin vivo,and Prussian blue staining was used to visualize MPIO and endogenous iron histologicallyex vivo.The RGD-MPIO showed target-specific bindingin vivo,but the sensitivity of the agent for visualizing angiogenic vesselsper sewas reduced by the presence of endogenous iron-laden macrophages in larger metastases, resulting in pre-existing hypointense areas within the tumour. Further, our data suggest that peptide-targeted MPIO, but not antibody-targeted MPIO, are taken up by perivascular macrophages within the macrometastatic microenvironment, resulting in additional nonspecific contrast. Whilst pre-MPIO imaging will circumvent the issues surrounding pre-existing hypointensities and enable detection of specific contrast, our findings suggest that the use of antibodies rather than peptides as the targeting ligand may represent a preferable route forward for new angiogenesis-targeted molecular MRI agents.
Identification of a Micropeptide Linked to Cancer Stem Cell Regulation and Chemoresistance
Authors: Fernando Achala , Liyanage Chamikara , Srinivasan Srilakshmi , Janaththani Panchadsaram , Batra Jyotsna 
Published: March 2023

ABSTRACTShort open reading frames encoding micropeptides (miPEPs) less than 100 amino acids in length have recently emerged as important regulators of diverse biological functions. However, the functional role of cancer-specific miPEPs in cancer progression and therapeutic response remains largely unexplored. Genome-wide association studies have identified an association of Iroquois (IRX) clusters with multiple cancer risk. In this study, we identified 17 miPEPs generated from IRX clusters in prostate, breast, endometrial, and ovarian cancers using SWATH-MS/MS-based proteomic analysis. We found thatIRX4-derived miPEP, IRX4_PEP1, promotes prostate cancer (PCa) cell proliferation, migration, and invasion by interacting with heterogeneous nuclear ribonucleoprotein K (hnRNPK). Overexpression of IRX4_PEP1 leads to dysregulation of stem cell pathways by co-interaction with Catenin beta-1 (CTNB1) and upregulation of prominent PCa stem markers, resulting in docetaxel resistance in PCa. IRX4_PEP1 expression is significantly upregulated in prostate tumour tissues compared to normal and is positively correlated with disease aggressiveness.SIGNIFICANCEOur findings highlight the critical role of IRX4_PEP1 in regulating PCa stem cells and chemotherapy resistance and suggest it as a novel therapeutic target for the treatment of PCa. Moreover, IRX4_PEP1 expression can serve as a novel potential diagnostic and prognostic biomarker for PCa.
Human postmortem studies reveal tissue-specific differences amongst TB-patient groups
Authors: Ahimbisibwe Gift , Nakibuule Marjorie , Ssejoba Marvin Martin , Oyamo David , Mulwana Rose , Nabulime Josephine , Babirye Febronius , Kizito Abdusalaamu , Lekuya Herve , Adakun Akello Suzan , Lukande Robert , Kyazze Andrew , Biraro Irene Andia , Cose Stephen 
Published: March 2023

AbstractIf we are to break new grounds in TB research, we need to have a complete understanding of what is occurring at the site of infection in humans. Postmortem studies give us an opportunity to compare TB-involved and -uninvolved tissues, in both diseased and non-diseased individuals. We examined the feasibility of carrying out a postmortem study in Mulago and Kiruddu National Referral Hospitals in Uganda, to determine whether we could use immune cells collected postmortem for immunological studies. We report that we can consent the Next-of-Kin, perform postmortem procedures and process tissues within 8 hours of death, and that immune cells remain viable and functional up to 14 hours after death. We found subtle differences in T cell subsets within TB groups. We found a depletion of the CD4 CD69+CD103+T cell subset in the lungs and BAL, which was associated with HIV, and that the CD8 CD69+CD103-T cell subset was depleted in BAL only, and was associated with TB. Our data show overall changes Tissue Resident Memory T cells within, and between, TB-infected and TB-uninfected human lungs.SummaryCoroner led postmortem studies are possible in Uganda, samples processed within 8 hours from deathCells from samples collected postmortem are viable and functionalHIV associated depletion of CD4 CD69+/CD103+T cell subset in lungs and BALCD8 CD69+/CD103-depletion in BAL associated with TB
The impact of paediatric epilepsy and co-occurring neurodevelopmental disorders on functional brain networks in wake and sleep
Authors: Junges Leandro , Galvis Daniel , Winsor Alice , Treadwell Grace , Richards Caroline , Seri Stefano , Johnson Samuel , Terry John R. , Bagshaw Andrew P. 
Published: March 2023

AbstractEpilepsy is one of the most common neurological disorders in children. Diagnosing epilepsy in children can be very challenging, especially as it often coexists with neurodevelopmental conditions like autism and ADHD. Functional brain networks obtained from neuroimaging and electrophysiological data in wakefulness and sleep have been shown to contain signatures of neurological disorders, and can potentially support the diagnosis and management of co-occurring neurodevelopmental conditions. In this work, we use electroencephalography (EEG) recordings from children, in restful wakefulness and sleep, to extract functional connectivity networks in different frequency bands. We explore the relationship of these networks with epilepsy diagnosis and with measures of neurodevelopmental traits, obtained from questionnaires used as screening tools for autism and ADHD. We explore differences in network markers between children with and without epilepsy in wake and sleep, and quantify the correlation between such markers and measures of neurodevelopmental traits. Our findings highlight the importance of considering the interplay between epilepsy and neurodevelopmental traits when exploring network markers of epilepsy.
Bacterial hemophilin homologs and their specific type eleven secretor proteins have conserved roles in heme capture and are diversifying as a family
Authors: Grossman Alex S. , Gell David A. , Wu Derek G. , Goodrich-Blair Heidi 
Published: March 2023

AbstractCellular life relies on enzymes that require metal cofactors, which must be acquired from extracellular sources. Bacteria utilize surface and secreted proteins to acquire such valuable nutrients from their environment. These include the cargo proteins of the type eleven secretion system (T11SS), which have been connected to host specificity, metal homeostasis, and nutritional immunity evasion. This Sec-dependent, Gram-negative secretion system is encoded by organisms throughout the phylum Proteobacteria, including human pathogensNeisseria meningitidis, Proteus mirabilis, Acinetobacter baumannii,andHaemophilus influenzae. Experimentally verified T11SS-dependent cargo include host metal acquisition proteinstransferrinbindingprotein B (TbpB) and lactoferrinbindingprotein B (LbpB), as well as the hemophilin homologshemereceptorprotein C (HrpC) andhemophilin A (HphA), the complement immune evasion protein factor-H bindingprotein (fHbp), and the host symbiosis factornematode intestinal localization protein C (NilC). Secretion of each of these cargo proteins relies on a specific T11SS. Here, we examined the specificity of T11SS systems for their cognate cargo proteins using taxonomically distributed homolog pairs of T11SS and hemophilin cargo and explore the ligand binding ability of those hemophilin homologs. Our comparative ligand binding analysis of four hemophilin family proteins identified previously unknown ligand binding diversity within this protein family, which informed our description of structural features that are likely to contribute to heme/porphyrin binding specificity.In vivoexpression of hemophilin homologs revealed that each was secreted in a specific manner by its cognate T11SS protein. Furthermore, secretion assays of chimeric hemophilin proteins revealed that specificity is predominantly dictated by the C-terminal domain of the cognate cargo. Meanwhile, the N-terminal effector domains of these T11SS-dependent cargo proteins feature porphyrin binding pockets that drive ligand binding affinity and specificity. In light of these results, we have termed this N-terminal domain the hemophilin ligand binding domain (Hlb) after its first characterized representative.
Evidence for role of transketolase function in the maintenance of pyridine nucleotide levels inEscherichia coli
Authors: Vimala A. , Harinarayanan R. 
Published: March 2023

SummaryThe transketolase (Tkt) activity provides reversible link between glycolysis and pentose phosphate pathway (PPP). Depending on the metabolic flux, it can catalyse synthesis of glycolytic intermediates, fructose-6-phosphate and glyceraldehyde-3-phosphate from xylulose-5-P and ribose-5-P (PPP intermediates) and synthesis of xylulose-5-P from the above mentioned glycolytic intermediates. UsingE. coli, we addressed the physiological significance of this metabolic flexibility by studying the growth phenotypes and metabolic changes associated with depletion of transketolase activity and the genetic changes or growth conditions that rescued the growth phenotypes. Tkt function was needed for cell growth when glucose was catabolized solely through Oxidative-PPP. Under gluconeogenic growth conditions, either transketolase or UdhA transhydrogenase was needed for growth. Cells depleted of Tkt activity were more sensitive than wild type to genetic changes that perturb pyridine cofactor levels. In LB medium, Tkt function was needed to prevent growth arrest from the accumulation of ribose- 5-P and possibly other pentose phosphates. In cell free extracts, the activity of Zwf and Gnd enzymes that support NADPH synthesis was inhibited by ribose-5-P. These results suggested, Tkt function played an important role in the maintenance of pyridine cofactor pool and this was confirmed by quantification. Metabolomic changes associated with transketolase depletion supported the genetic data.
Opposing, spatially-determined epigenetic forces impose restrictions on stochastic olfactory receptor choice
Authors: Bashkirova Elizaveta V. , Klimpert Nell , Monahan Kevin , Campbell Christine E. , Osinski Jason M. , Tan Longzhi , Schieren Ira , Pourmorady Ariel , Stecky Beka , Barnea Gilad , Xie X. Sunnie , Abdus-Saboor Ishmail , Shykind Benjamin , Jones-Marlin Bianca , Gronostajski Richard M. , Fleischmann Alexander , Lomvardas Stavros 
Published: March 2023

AbstractOlfactory receptor (OR) choice represents an example of genetically hardwired stochasticity, where every olfactory neuron expresses one out of ∼2000 OR alleles in a probabilistic, yet stereotypic fashion. Here, we propose that topographic restrictions in OR expression are established in neuronal progenitors by two opposing forces: polygenic transcription and genomic silencing, both of which are influenced by dorsoventral gradients of transcription factors NFIA, B, and X. Polygenic transcription of OR genes may define spatially constrained OR repertoires, among which one OR allele is selected for singular expression later in development. Heterochromatin assembly and genomic compartmentalization of OR alleles also vary across the axes of the olfactory epithelium and may preferentially eliminate ectopically expressed ORs with more dorsal expression destinations from this “privileged” repertoire. Our experiments identify early transcription as a potential “epigenetic” contributor to future developmental patterning and reveal how two spatially responsive probabilistic processes may act in concert to establish deterministic, precise, and reproducible territories of stochastic gene expression.
Host-induced cell wall remodelling impairs opsonophagocytosis ofStaphylococcus aureusby neutrophils
Authors: Ledger Elizabeth V. K. , Edwards Andrew M. 
Published: March 2023

SummaryThe bacterial pathogenStaphylococcus aureusadapts to the host environment by increasing the thickness of its cell wall. However, the impact of cell wall thickening on susceptibility to host defences is unclear. Here, we show that as bacteria adapted to serum, the resulting increase in cell wall thickness led to a reduction in the exposure of bound antibody and complement and a corresponding reduction in phagocytosis and killing by neutrophils. The exposure of opsonins bound to protein antigens or LTA were most significantly reduced, whilst opsonisation by IgG against wall teichoic acid or peptidoglycan was largely unaffected. Partial digestion of accumulated cell wall in host adapted cells using the enzyme lysostaphin restored opsonin exposure and promoted phagocytosis and killing. Concordantly, the antibiotic fosfomycin inhibited cell wall remodelling and maintained full susceptibility ofS. aureusto opsonophagocytic killing by neutrophils. These findings reveal that the adaptation ofS. aureusto the host environment reduces the ability of the immune system to detect and kill this pathogen through reduced exposure of protein- and LTA-bound opsonins via cell wall remodelling.
Do objectives and key results solve organizational performance measurement issues?
Authors: Rompho Nopadol 
Published: March 2023

PurposeThis study aims to determine whether and how objectives and key results (OKRs) can be used to solve performance measurement issues encountered by organizations.Design/methodology/approachA total of 204 staff members from 26 Thai organizations that adopted OKRs were interviewed. Five senior executives and five operational staff members with experience using OKRs were selected from each organization. Content analysis was also performed.FindingsOKRs facilitate the acceptance of performance indicators and help solve issues of alignment between indicators and organizational strategies as well as improper target setting.Research limitations/implicationsThe results have limited generalizability because of the qualitative approach undertaken in the study. Further research can test whether the results hold true if OKRs are used for longer than six months.Practical implicationsThe results of this study can be used to help managers and employees set challenging targets, utilize their competencies and find a sense of relatedness, which can lead to organizational success.Originality/valueThis study is one of the first to thoroughly investigate the use of OKRs by adopting the self-determination theory (SDT) as the main theoretical framework.