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1.
Nat Immunol ; 23(8): 1169-1182, 2022 08.
Article in English | MEDLINE | ID: mdl-35882934

ABSTRACT

Emergent physical properties of tissues are not readily understood by reductionist studies of their constituent cells. Here, we show molecular signals controlling cellular, physical, and structural properties and collectively determine tissue mechanics of lymph nodes, an immunologically relevant adult tissue. Lymph nodes paradoxically maintain robust tissue architecture in homeostasis yet are continually poised for extensive expansion upon immune challenge. We find that in murine models of immune challenge, cytoskeletal mechanics of a cellular meshwork of fibroblasts determine tissue tension independently of extracellular matrix scaffolds. We determine that C-type lectin-like receptor 2 (CLEC-2)-podoplanin signaling regulates the cell surface mechanics of fibroblasts, providing a mechanically sensitive pathway to regulate lymph node remodeling. Perturbation of fibroblast mechanics through genetic deletion of podoplanin attenuates T cell activation. We find that increased tissue tension through the fibroblastic stromal meshwork is required to trigger the initiation of fibroblast proliferation and restore homeostatic cellular ratios and tissue structure through lymph node expansion.


Subject(s)
Fibroblasts , Lymph Nodes , Animals , Extracellular Matrix/metabolism , Fibroblasts/metabolism , Homeostasis , Lectins, C-Type/metabolism , Mice
2.
Nature ; 2024 Jul 22.
Article in English | MEDLINE | ID: mdl-39038490

ABSTRACT

In dynamic environments, animals make behavioural decisions on the basis of the innate valences of sensory cues and information learnt about these cues across multiple timescales1-3. However, it remains unclear how the innate valence of a sensory stimulus affects the acquisition of learnt valence information and subsequent memory dynamics. Here we show that in the Drosophila brain, interconnected short- and long-term memory units of the mushroom body jointly regulate memory through dopamine signals that encode innate and learnt sensory valences. By performing time-lapse in vivo voltage-imaging studies of neural spiking in more than 500 flies undergoing olfactory associative conditioning, we found that protocerebral posterior lateral 1 dopamine neurons (PPL1-DANs)4 heterogeneously and bidirectionally encode innate and learnt valences of punishment, reward and odour cues. During learning, these valence signals regulate memory storage and extinction in mushroom body output neurons (MBONs)5. During initial conditioning bouts, PPL1-γ1pedc and PPL1-γ2α'1 neurons control short-term memory formation, which weakens inhibitory feedback from MBON-γ1pedc>α/ß to PPL1-α'2α2 and PPL1-α3. During further conditioning, this diminished feedback allows these two PPL1-DANs to encode the net innate plus learnt valence of the conditioned odour cue, which gates long-term memory formation. A computational model constrained by the fly connectome6,7 and our spiking data explains how dopamine signals mediate the circuit interactions between short- and long-term memory traces, yielding predictions that our experiments confirmed. Overall, the mushroom body achieves flexible learning through the integration of innate and learnt valences in parallel learning units sharing feedback interconnections. This hybrid physiological-anatomical mechanism may be a general means by which dopamine regulates memory dynamics in other species and brain structures, including the vertebrate basal ganglia.

3.
Nature ; 608(7923): 528-533, 2022 08.
Article in English | MEDLINE | ID: mdl-35585230

ABSTRACT

Evidence exists that tree mortality is accelerating in some regions of the tropics1,2, with profound consequences for the future of the tropical carbon sink and the global anthropogenic carbon budget left to limit peak global warming below 2 °C. However, the mechanisms that may be driving such mortality changes and whether particular species are especially vulnerable remain unclear3-8. Here we analyse a 49-year record of tree dynamics from 24 old-growth forest plots encompassing a broad climatic gradient across the Australian moist tropics and find that annual tree mortality risk has, on average, doubled across all plots and species over the last 35 years, indicating a potential halving in life expectancy and carbon residence time. Associated losses in biomass were not offset by gains from growth and recruitment. Plots in less moist local climates presented higher average mortality risk, but local mean climate did not predict the pace of temporal increase in mortality risk. Species varied in the trajectories of their mortality risk, with the highest average risk found nearer to the upper end of the atmospheric vapour pressure deficit niches of species. A long-term increase in vapour pressure deficit was evident across the region, suggesting that thresholds involving atmospheric water stress, driven by global warming, may be a primary cause of increasing tree mortality in moist tropical forests.


Subject(s)
Atmosphere , Stress, Physiological , Trees , Tropical Climate , Water , Acclimatization , Atmosphere/chemistry , Australia , Biomass , Carbon/metabolism , Carbon Sequestration , Dehydration , Global Warming/statistics & numerical data , History, 20th Century , History, 21st Century , Humidity , Population Density , Risk , Time Factors , Trees/classification , Trees/growth & development , Trees/metabolism , Water/analysis , Water/metabolism
4.
Proc Natl Acad Sci U S A ; 121(39): e2402233121, 2024 Sep 24.
Article in English | MEDLINE | ID: mdl-39284054

ABSTRACT

A fundamental assumption in plant science posits that leaf air spaces remain vapor saturated, leading to the predominant view that stomata alone control leaf water loss. This concept has been pivotal in photosynthesis and water-use efficiency research. However, recent evidence has refuted this longstanding assumption by providing evidence of unsaturation in the leaf air space of C3 plants under relatively mild vapor pressure deficit (VPD) stress. This phenomenon represents a nonstomatal mechanism restricting water loss from the mesophyll. The potential ubiquity and physiological implications of this phenomenon, its driving mechanisms in different plant species and habitats, and its interaction with other ecological adaptations have. In this context, C4 plants spark particular interest for their importance as crops, bundle sheath cells' unique anatomical characteristics and specialized functions, and notably higher water-use efficiency relative to C3 plants. Here, we confirm reduced relative humidities in the substomatal cavity of the C4 plants maize, sorghum, and proso millet down to 80% under mild VPD stress. We demonstrate the critical role of nonstomatal control in these plants, indicating that the role of the CO2 concentration mechanism in CO2 management at a high VPD may have been overestimated. Our findings offer a mechanistic reconciliation between discrepancies in CO2 and VPD responses reported in C4 species. They also reveal that nonstomatal control is integral to maintaining an advantageous microclimate of relatively higher CO2 concentrations in the mesophyll air space of C4 plants for carbon fixation, proving vital when these plants face VPD stress.


Subject(s)
Mesophyll Cells , Photosynthesis , Vapor Pressure , Zea mays , Mesophyll Cells/metabolism , Zea mays/physiology , Zea mays/metabolism , Photosynthesis/physiology , Plant Leaves/metabolism , Plant Leaves/physiology , Water/metabolism , Stress, Physiological/physiology , Carbon Dioxide/metabolism , Sorghum/metabolism , Sorghum/physiology , Plant Stomata/physiology , Plant Stomata/metabolism
5.
PLoS Genet ; 20(6): e1011101, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38905299

ABSTRACT

Filamins are mechanosensitive actin crosslinking proteins that organize the actin cytoskeleton in a variety of shapes and tissues. In muscles, filamin crosslinks actin filaments from opposing sarcomeres, the smallest contractile units of muscles. This happens at the Z-disc, the actin-organizing center of sarcomeres. In flies and vertebrates, filamin mutations lead to fragile muscles that appear ruptured, suggesting filamin helps counteract muscle rupturing during muscle contractions by providing elastic support and/or through signaling. An elastic region at the C-terminus of filamin is called the mechanosensitive region and has been proposed to sense and counteract contractile damage. Here we use molecularly defined mutants and microscopy analysis of the Drosophila indirect flight muscles to investigate the molecular details by which filamin provides cohesion to the Z-disc. We made novel filamin mutations affecting the C-terminal region to interrogate the mechanosensitive region and detected three Z-disc phenotypes: dissociation of actin filaments, Z-disc rupture, and Z-disc enlargement. We tested a constitutively closed filamin mutant, which prevents the elastic changes in the mechanosensitive region and results in ruptured Z-discs, and a constitutively open mutant which has the opposite elastic effect on the mechanosensitive region and gives rise to enlarged Z-discs. Finally, we show that muscle contraction is required for Z-disc rupture. We propose that filamin senses myofibril damage by elastic changes in its mechanosensory region, stabilizes the Z-disc, and counteracts contractile damage at the Z-disc.


Subject(s)
Drosophila Proteins , Drosophila melanogaster , Filamins , Muscle Contraction , Mutation , Myofibrils , Animals , Actin Cytoskeleton/metabolism , Actin Cytoskeleton/genetics , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Filamins/metabolism , Filamins/genetics , Mechanotransduction, Cellular/genetics , Muscle Contraction/genetics , Muscle Contraction/physiology , Myofibrils/metabolism , Myofibrils/genetics , Phenotype , Sarcomeres/metabolism , Sarcomeres/genetics
6.
Brief Bioinform ; 25(6)2024 Sep 23.
Article in English | MEDLINE | ID: mdl-39367648

ABSTRACT

The application of deep learning to spatial transcriptomics (ST) can reveal relationships between gene expression and tissue architecture. Prior work has demonstrated that inferring gene expression from tissue histomorphology can discern these spatial molecular markers to enable population scale studies, reducing the fiscal barriers associated with large-scale spatial profiling. However, while most improvements in algorithmic performance have focused on improving model architectures, little is known about how the quality of tissue preparation and imaging can affect deep learning model training for spatial inference from morphology and its potential for widespread clinical adoption. Prior studies for ST inference from histology typically utilize manually stained frozen sections with imaging on non-clinical grade scanners. Training such models on ST cohorts is also costly. We hypothesize that adopting tissue processing and imaging practices that mirror standards for clinical implementation (permanent sections, automated tissue staining, and clinical grade scanning) can significantly improve model performance. An enhanced specimen processing and imaging protocol was developed for deep learning-based ST inference from morphology. This protocol featured the Visium CytAssist assay to permit automated hematoxylin and eosin staining (e.g. Leica Bond), 40×-resolution imaging, and joining of multiple patients' tissue sections per capture area prior to ST profiling. Using a cohort of 13 pathologic T Stage-III stage colorectal cancer patients, we compared the performance of models trained on slide prepared using enhanced versus traditional (i.e. manual staining and low-resolution imaging) protocols. Leveraging Inceptionv3 neural networks, we predicted gene expression across serial, histologically-matched tissue sections using whole slide images (WSI) from both protocols. The data Shapley was used to quantify and compare marginal performance gains on a patient-by-patient basis attributed to using the enhanced protocol versus the actual costs of spatial profiling. Findings indicate that training and validating on WSI acquired through the enhanced protocol as opposed to the traditional method resulted in improved performance at lower fiscal cost. In the realm of ST, the enhancement of deep learning architectures frequently captures the spotlight; however, the significance of specimen processing and imaging is often understated. This research, informed through a game-theoretic lens, underscores the substantial impact that specimen preparation/imaging can have on spatial transcriptomic inference from morphology. It is essential to integrate such optimized processing protocols to facilitate the identification of prognostic markers at a larger scale.


Subject(s)
Deep Learning , Transcriptome , Humans , Gene Expression Profiling/methods , Image Processing, Computer-Assisted/methods , Algorithms , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Colorectal Neoplasms/diagnostic imaging
7.
PLoS Pathog ; 20(8): e1012504, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39213446

ABSTRACT

Oropouche fever, a debilitating illness common in South America, is caused by Oropouche virus (OROV), an arbovirus. OROV belongs to the Peribunyaviridae family, a large group of RNA viruses. Little is known about the biology of Peribunyaviridae in host cells, especially assembly and egress processes. Our research reveals that the small GTPase Rab27a mediates intracellular transport of OROV induced compartments and viral release from infected cells. We show that Rab27a interacts with OROV glycoproteins and colocalizes with OROV during late phases of the infection cycle. Moreover, Rab27a activity is required for OROV trafficking to the cell periphery and efficient release of infectious particles. Consistently, depleting Rab27a's downstream effector, Myosin Va, or inhibiting actin polymerization also hinders OROV compartments targeting to the cell periphery and infectious viral particle egress. These data indicate that OROV hijacks Rab27a activity for intracellular transport and cell externalization. Understanding these crucial mechanisms of OROV's replication cycle may offer potential targets for therapeutic interventions and aid in controlling the spread of Oropouche fever.


Subject(s)
Myosin Heavy Chains , Myosin Type V , Virus Release , rab27 GTP-Binding Proteins , rab27 GTP-Binding Proteins/metabolism , Humans , Virus Release/physiology , Myosin Type V/metabolism , Myosin Type V/genetics , Myosin Heavy Chains/metabolism , Bunyaviridae Infections/metabolism , Bunyaviridae Infections/virology , Orthobunyavirus/metabolism , Orthobunyavirus/physiology , Virus Replication/physiology , Animals , Host-Pathogen Interactions
8.
PLoS Biol ; 21(8): e3002209, 2023 08.
Article in English | MEDLINE | ID: mdl-37527210

ABSTRACT

The opportunistic pathogen Pseudomonas aeruginosa causes antibiotic-recalcitrant pneumonia by forming biofilms in the respiratory tract. Despite extensive in vitro experimentation, how P. aeruginosa forms biofilms at the airway mucosa is unresolved. To investigate the process of biofilm formation in realistic conditions, we developed AirGels: 3D, optically accessible tissue-engineered human lung models that emulate the airway mucosal environment. AirGels recapitulate important factors that mediate host-pathogen interactions including mucus secretion, flow and air-liquid interface (ALI), while accommodating high-resolution live microscopy. With AirGels, we investigated the contributions of mucus to P. aeruginosa biofilm biogenesis in in vivo-like conditions. We found that P. aeruginosa forms mucus-associated biofilms within hours by contracting luminal mucus early during colonization. Mucus contractions facilitate aggregation, thereby nucleating biofilms. We show that P. aeruginosa actively contracts mucus using retractile filaments called type IV pili. Our results therefore suggest that, while protecting epithelia, mucus constitutes a breeding ground for biofilms.


Subject(s)
Biofilms , Pseudomonas aeruginosa , Humans , Anti-Bacterial Agents/pharmacology , Mucus , Lung
9.
Nature ; 581(7807): 199-203, 2020 05.
Article in English | MEDLINE | ID: mdl-32404997

ABSTRACT

Recognition of microbe-associated molecular patterns (MAMPs) by pattern recognition receptors (PRRs) triggers the first line of inducible defence against invading pathogens1-3. Receptor-like cytoplasmic kinases (RLCKs) are convergent regulators that associate with multiple PRRs in plants4. The mechanisms that underlie the activation of RLCKs are unclear. Here we show that when MAMPs are detected, the RLCK BOTRYTIS-INDUCED KINASE 1 (BIK1) is monoubiquitinated following phosphorylation, then released from the flagellin receptor FLAGELLIN SENSING 2 (FLS2)-BRASSINOSTEROID INSENSITIVE 1-ASSOCIATED KINASE 1 (BAK1) complex, and internalized dynamically into endocytic compartments. The Arabidopsis E3 ubiquitin ligases RING-H2 FINGER A3A (RHA3A) and RHA3B mediate the monoubiquitination of BIK1, which is essential for the subsequent release of BIK1 from the FLS2-BAK1 complex and activation of immune signalling. Ligand-induced monoubiquitination and endosomal puncta of BIK1 exhibit spatial and temporal dynamics that are distinct from those of the PRR FLS2. Our study reveals the intertwined regulation of PRR-RLCK complex activation by protein phosphorylation and ubiquitination, and shows that ligand-induced monoubiquitination contributes to the release of BIK1 family RLCKs from the PRR complex and activation of PRR signalling.


Subject(s)
Arabidopsis Proteins/chemistry , Arabidopsis Proteins/metabolism , Arabidopsis/immunology , Arabidopsis/metabolism , Plant Immunity/immunology , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/metabolism , Receptors, Pattern Recognition/immunology , Ubiquitin-Protein Ligases/chemistry , Ubiquitin-Protein Ligases/metabolism , Ubiquitination , Arabidopsis/enzymology , Endocytosis , Ligands , Pathogen-Associated Molecular Pattern Molecules/immunology , Phosphorylation , Protein Kinases/metabolism
10.
Mol Cell Proteomics ; 22(12): 100676, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37940003

ABSTRACT

Extracellular vesicles (EVs) are biomolecule carriers for intercellular communication in health and disease. Nef is a HIV virulence factor that is released from cells within EVs and is present in plasma EVs of HIV-1 infected individuals. We performed a quantitative proteomic analysis to fully characterize the Nef-induced changes in protein composition of T cell-derived EVs and identify novel host targets of HIV. Several proteins with well-described roles in infection or not previously associated with HIV pathogenesis were specifically modulated by Nef in EVs. Among the downregulated proteins are the interferon-induced transmembrane 1, 2, and 3 (IFITM1-3) proteins, broad-spectrum antiviral factors known to be cell-to-cell transferable by EVs. We demonstrate that Nef depletes IFITM1-3 from EVs by excluding these proteins from the plasma membrane and lipid rafts, which are sites of EVs biogenesis in T cells. Our data establish Nef as a modulator of EVs' global protein content and as an HIV factor that antagonizes IFITMs.


Subject(s)
Extracellular Vesicles , HIV Infections , HIV-1 , Humans , T-Lymphocytes , Proteome/metabolism , Proteomics , Extracellular Vesicles/metabolism , Interferons/metabolism , HIV Infections/metabolism , Antiviral Agents/metabolism
11.
Am J Physiol Cell Physiol ; 326(3): C999-C1009, 2024 03 01.
Article in English | MEDLINE | ID: mdl-38344799

ABSTRACT

Dysregulation of skeletal muscle morphology and metabolism is associated with chronic diseases such as obesity and type 2 diabetes. The enzyme glycogen synthase kinase 3 (GSK3) is highly involved in skeletal muscle physiology and metabolism, acting as a negative regulator of muscle size, strength, adaptive thermogenesis, and glucose homeostasis. Correspondingly, we have shown that partial knockdown (∼40%) of GSK3 specifically in skeletal muscle increases lean mass, reduces fat mass, and activates muscle-based adaptive thermogenesis via sarco(endo)plasmic reticulum Ca2+ (SERCA) uncoupling in male mice. However, the effects of GSK3 knockdown in female mice have yet to be investigated. Here, we examined the effects of muscle-specific GSK3 knockdown on body composition, muscle size and strength, and whole body metabolism in female C57BL/6J mice. Our results show that GSK3 content is higher in the female soleus versus the male soleus; however, there were no differences in the extensor digitorum longus (EDL). Furthermore, muscle-specific GSK3 knockdown did not alter body composition in female mice, nor did it alter daily energy expenditure, glucose/insulin tolerance, mitochondrial respiration, or the expression of the SERCA uncouplers sarcolipin and neuronatin. We also did not find any differences in soleus muscle size, strength, or fatigue resistance. In the EDL, we found that an increase in absolute and specific force production, but there were no differences in fatigability. Therefore, our study highlights sex differences in the response to genetic reduction of gsk3, with most of the effects previously observed in male mice being absent in females.NEW & NOTEWORTHY Here we show that partial GSK3 knockdown has minimal effects on whole body metabolism and muscle contractility in female mice. This is partly inconsistent with previous results found in male mice, which reveal a potential influence of biological sex.


Subject(s)
Diabetes Mellitus, Type 2 , Glycogen Synthase Kinase 3 , Mice , Female , Male , Animals , Diabetes Mellitus, Type 2/metabolism , Mice, Inbred C57BL , Muscle, Skeletal/metabolism , Glucose/metabolism
12.
Glycobiology ; 34(1)2024 Mar 19.
Article in English | MEDLINE | ID: mdl-37944064

ABSTRACT

During the COVID-19 outbreak, numerous tools including protein-based vaccines have been developed. The methylotrophic yeast Pichia pastoris (synonymous to Komagataella phaffii) is an eukaryotic cost-effective and scalable system for recombinant protein production, with the advantages of an efficient secretion system and the protein folding assistance of the secretory pathway of eukaryotic cells. In a previous work, we compared the expression of SARS-CoV-2 Spike Receptor Binding Domain in P. pastoris with that in human cells. Although the size and glycosylation pattern was different between them, their protein structural and conformational features were indistinguishable. Nevertheless, since high mannose glycan extensions in proteins expressed by yeast may be the cause of a nonspecific immune recognition, we deglycosylated RBD in native conditions. This resulted in a highly pure, homogenous, properly folded and monomeric stable protein. This was confirmed by circular dichroism and tryptophan fluorescence spectra and by SEC-HPLC, which were similar to those of RBD proteins produced in yeast or human cells. Deglycosylated RBD was obtained at high yields in a single step, and it was efficient in distinguishing between SARS-CoV-2-negative and positive sera from patients. Moreover, when the deglycosylated variant was used as an immunogen, it elicited a humoral immune response ten times greater than the glycosylated form, producing antibodies with enhanced neutralizing power and eliciting a more robust cellular response. The proposed approach may be used to produce at a low cost, many antigens that require glycosylation to fold and express, but do not require glycans for recognition purposes.


Subject(s)
COVID-19 , Saccharomycetales , Vaccines , Humans , COVID-19/diagnosis , COVID-19/prevention & control , COVID-19 Testing , Pichia/genetics , Pichia/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Recombinant Proteins/chemistry , Vaccines/metabolism , Antibodies, Neutralizing/metabolism , Antibodies, Viral
13.
Chembiochem ; : e202400296, 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-39008807

ABSTRACT

The human protein Abelson kinase (Abl), a tyrosine kinase, plays a pivotal role in developing chronic myeloid leukemia (CML). Abl's involvement in various signaling pathways underscores its significance in regulating fundamental biological processes, including DNA damage responses, actin polymerization, and chromatin structural changes. The discovery of the Bcr-Abl oncoprotein, resulting from a chromosomal translocation in CML patients, revolutionized the understanding and treatment of the disease. The introduction of targeted therapies, starting with interferon-alpha and culminating in the development of tyrosine kinase inhibitors (TKIs) like imatinib, significantly improved patient outcomes. However, challenges such as drug resistance and side effects persist, indicating the necessity of research into novel therapeutic strategies. This review describes advancements in Abl kinase inhibitor development, emphasizing rational compound design from structural and regulatory information. Strategies, including bivalent inhibitors, PROTACs, and compounds targeting regulatory domains, promise to overcome resistance and minimize side effects. Additionally, leveraging the intricate structure and interactions of Bcr-Abl may provide insights into developing inhibitors for other kinases. Overall, this review highlights the importance of continued research into Abl kinase inhibition and its broader implications for therapeutic interventions targeting kinase-driven diseases. It provides valuable insights and strategies that may guide the development of next-generation therapies.

14.
Planta ; 260(5): 108, 2024 Sep 27.
Article in English | MEDLINE | ID: mdl-39333439

ABSTRACT

MAIN CONCLUSION: Despite modulating senescence and drought responses, the GmERD15-like subfamily members are differentially induced by multiple stresses and diverge partially in stress signaling functions. The PAM2 motif represents a binding site for poly (A)-binding proteins (PABPs), often associated with RNA metabolism regulation. The PAM2-containing protein ERD15 stands out as a critical regulator of diverse stress responses in plants. Despite the relevance of the PAM2 motif, a comprehensive analysis of the PAM2 superfamily and ERD15-like subfamily in the plant kingdom is lacking. Here, we provide an extensive in silico analysis of the PAM2 superfamily and the ERD15-like subfamily in soybean, using Arabidopsis and rice sequences as prototypes. The Glycine max ERD15-like subfamily members were clustered in pairs, likely originating from DNA-based gene duplication, as the paralogs display high sequence conservation, similar exon/intron genome organization, and are undergoing purifying selection. Complementation analyses of an aterd15 mutant demonstrated that the plant ERD15-like subfamily members are functionally redundant in response to drought, osmotic stress, and dark-induced senescence. Nevertheless, the soybean members displayed differential expression profiles, biochemical activity, and subcellular localization, consistent with functional diversification. The expression profiles of Glyma04G138600 under salicylic acid (SA) and abscisic acid (ABA) treatments differed oppositely from those of the other GmERD15-like genes. Abiotic stress-induced coexpression analysis with soybean PABPs showed that Glyma04G138600 was clustered separately from other GmERD15s. In contrast to the AtERD15 stress-induced nuclear redistribution, Glyma04G138600 and Glyma02G260800 localized to the cytoplasm, while Glyma03G131900 fractionated between the cytoplasm and nucleus under normal and stress conditions. These data collectively indicate that despite modulating senescence and drought responses, the GmERD15-like subfamily members are differentially induced by multiple stresses and may diverge partially in stress signaling functions.


Subject(s)
Arabidopsis , Gene Expression Regulation, Plant , Glycine max , Plant Proteins , Stress, Physiological , Glycine max/genetics , Glycine max/physiology , Glycine max/metabolism , Plant Proteins/genetics , Plant Proteins/metabolism , Stress, Physiological/genetics , Arabidopsis/genetics , Droughts , Oryza/genetics , Oryza/metabolism , Oryza/physiology , Phylogeny , Multigene Family
15.
Am J Pathol ; 193(6): 778-795, 2023 06.
Article in English | MEDLINE | ID: mdl-37037284

ABSTRACT

Over 150,000 Americans are diagnosed with colorectal cancer (CRC) every year, and annually >50,000 individuals are estimated to die of CRC, necessitating improvements in screening, prognostication, disease management, and therapeutic options. CRC tumors are removed en bloc with surrounding vasculature and lymphatics. Examination of regional lymph nodes at the time of surgical resection is essential for prognostication. Developing alternative approaches to indirectly assess recurrence risk would have utility in cases where lymph node yield is incomplete or inadequate. Spatially dependent, immune cell-specific (eg, tumor-infiltrating lymphocytes), proteomic, and transcriptomic expression patterns inside and around the tumor-the tumor immune microenvironment-can predict nodal/distant metastasis and probe the coordinated immune response from the primary tumor site. The comprehensive characterization of tumor-infiltrating lymphocytes and other immune infiltrates is possible using highly multiplexed spatial omics technologies, such as the GeoMX Digital Spatial Profiler. In this study, machine learning and differential co-expression analyses helped identify biomarkers from Digital Spatial Profiler-assayed protein expression patterns inside, at the invasive margin, and away from the tumor, associated with extracellular matrix remodeling (eg, granzyme B and fibronectin), immune suppression (eg, forkhead box P3), exhaustion and cytotoxicity (eg, CD8), Programmed death ligand 1-expressing dendritic cells, and neutrophil proliferation, among other concomitant alterations. Further investigation of these biomarkers may reveal independent risk factors of CRC metastasis that can be formulated into low-cost, widely available assays.


Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , Humans , Proteomics , Colorectal Neoplasms/metabolism , Biomarkers/metabolism , Lymph Nodes , Colonic Neoplasms/pathology , Lymphocytes, Tumor-Infiltrating , Tumor Microenvironment , Biomarkers, Tumor/metabolism
16.
J Pediatr ; 276: 114284, 2024 Aug 30.
Article in English | MEDLINE | ID: mdl-39218206

ABSTRACT

OBJECTIVE: To examine specialty pediatric palliative care (SPPC) and end-of-life care for children with advanced heart disease in Alabama, including rates of and disparities in SPPC involvement. STUDY DESIGN: We performed a retrospective study from electronic health records of children (≤21 years at death) who died with advanced heart disease at a single institution between 2012 and 2019 (n = 128). The main outcome was SPPC consult; we assessed clinical and sociodemographic factors associated with SPPC. RESULTS: The median age at death was 6 months (IQR = 1-25 months) with 80 (63%) ≤1 year; 46% were Black and 45% non-Hispanic White. Seventy (55%) children had critical congenital heart disease, 45 (35%) non-critical congenital heart disease, and 13 (10%) acquired heart disease. Twenty-nine children (22%) received SPPC. Children ≤1 year at time of death and Black children were less likely to receive SPPC (aOR [95% CI]: 0.2 [0.1-0.6], reference >1 year; 0.2 [0.1-0.7], reference non-Hispanic White). SPPC was associated with death while receiving comfort-focused care (30.6 [4.5-210]), do not resuscitate orders (8.2 [2.1-31.3]), and hospice enrollment (no children without SPPC care were enrolled in hospice) but not medically intense end-of-life care (intensive care unit admission, mechanical ventilation, hemodialysis, or cardiopulmonary resuscitation) or death outside the intensive care unit. CONCLUSIONS: Children dying with advanced heart disease in Alabama did not have routine SPPC involvement; infants and Black children had lower odds of SPPC. SPPC was associated with more comfort-focused care. Disparities in SPPC utilization for children with advanced heart disease need further examination.

17.
Am J Physiol Regul Integr Comp Physiol ; 326(6): R484-R498, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38406842

ABSTRACT

Salmonid fish include some of the most valued cultured fish species worldwide. Unlike most other fish, the hearts of salmonids, including Atlantic salmon and rainbow trout, have a well-developed coronary circulation. Consequently, their hearts' reliance on oxygenation through coronary arteries leaves them prone to coronary lesions, believed to precipitate myocardial ischemia. Here, we mimicked such coronary lesions by subjecting groups of juvenile rainbow trout to coronary ligation, assessing histomorphological myocardial changes associated with ischemia and scarring in the context of cardiac arrhythmias using electrocardiography (ECG). Notable ECG changes resembling myocardial ischemia-like ECG in humans, such as atrioventricular blocks and abnormal ventricular depolarization (prolonged and fragmented QRS complex), as well as repolarization (long QT interval) patterns, were observed during the acute phase of myocardial ischemia. A remarkable 100% survival rate was observed among juvenile trout subjected to coronary ligation after 24 wk. Recovery from coronary ligation occurred through adaptive ventricular remodeling, coupled with a fast cardiac revascularization response. These findings carry significant implications for understanding the mechanisms governing cardiac health in salmonid fish, a family particularly susceptible to cardiac diseases. Furthermore, our results provide valuable insights into comparative studies on the evolution, pathophysiology, and ontogeny of vertebrate cardiac repair and restoration.NEW & NOTEWORTHY Juvenile rainbow trout exhibit a remarkable capacity to recover from cardiac injury caused by myocardial ischemia. Recovery from cardiac damage occurs through adaptive ventricular remodeling, coupled with a rapid cardiac revascularization response. These findings carry significant implications for understanding the mechanisms governing cardiac health within salmonid fishes, which are particularly susceptible to cardiac diseases.


Subject(s)
Myocardial Ischemia , Oncorhynchus mykiss , Animals , Myocardial Ischemia/physiopathology , Heart Failure/physiopathology , Ventricular Remodeling , Electrocardiography , Fish Diseases/physiopathology , Fish Diseases/pathology , Time Factors
18.
New Phytol ; 243(2): 648-661, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38757766

ABSTRACT

Elevated air temperature (Tair) and vapour pressure deficit (VPDair) significantly influence plant functioning, yet their relative impacts are difficult to disentangle. We examined the effects of elevated Tair (+6°C) and VPDair (+0.7 kPa) on the growth and physiology of six tropical tree species. Saplings were grown under well-watered conditions in climate-controlled glasshouses for 6 months under three treatments: (1) low Tair and low VPDair, (2) high Tair and low VPDair, and (3) high Tair and high VPDair. To assess acclimation, physiological parameters were measured at a set temperature. Warm-grown plants grown under elevated VPDair had significantly reduced stomatal conductance and increased instantaneous water use efficiency compared to plants grown under low VPDair. Photosynthetic biochemistry and thermal tolerance (Tcrit) were unaffected by VPDair, but elevated Tair caused Jmax25 to decrease and Tcrit to increase. Sapling biomass accumulation for all species responded positively to an increase in Tair, but elevated VPDair limited growth. This study shows that stomatal limitation caused by even moderate increases in VPDair can decrease productivity and growth rates in tropical species independently from Tair and has important implications for modelling the impacts of climate change on tropical forests.


Subject(s)
Plant Leaves , Plant Stomata , Rainforest , Temperature , Trees , Vapor Pressure , Trees/physiology , Trees/growth & development , Plant Leaves/physiology , Plant Leaves/growth & development , Plant Stomata/physiology , Tropical Climate , Photosynthesis , Species Specificity , Water/metabolism , Plant Transpiration/physiology , Biomass , Gases/metabolism
19.
New Phytol ; 243(6): 2102-2114, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38634162

ABSTRACT

Mesophyll conductance (gm) is a crucial plant trait that can significantly limit photosynthesis. Measurement of photosynthetic C18O16O discrimination (Δ18O) has proved to be the only viable means of resolving gm in both C3 and C4 plants. However, the currently available methods to exploit Δ18O for gm estimation are error prone due to their inadequacy in constraining the degree of oxygen isotope exchange (θ) during mesophyll CO2 hydration. Here, we capitalized on experimental manipulation of leaf water isotopic dynamics to establish a novel, nonsteady state, regression-based approach for simultaneous determination of gm and θ from online Δ18O measurements. We demonstrated the methodological and theoretical robustness of this new Δ18O-gm estimation approach and showed through measurements on several C3 and C4 species that this approach can serve as a benchmark method against which to identify previously-unrecognized biases of the existing Δ18O-gm methods. Our results highlight the unique value of this nonsteady state-based approach for contributing to ongoing efforts toward quantitative understanding of mesophyll conductance for crop yield improvement and carbon cycle modeling.


Subject(s)
Mesophyll Cells , Oxygen Isotopes , Photosynthesis , Plant Leaves , Water , Mesophyll Cells/metabolism , Mesophyll Cells/physiology , Photosynthesis/physiology , Water/metabolism , Plant Leaves/physiology , Plant Leaves/metabolism , Regression Analysis , Carbon Dioxide/metabolism
20.
New Phytol ; 2024 Aug 28.
Article in English | MEDLINE | ID: mdl-39205457

ABSTRACT

Climate change not only leads to higher air temperatures but also increases the vapour pressure deficit (VPD) of the air. Understanding the direct effect of VPD on leaf gas exchange is crucial for precise modelling of stomatal functioning. We conducted combined leaf gas exchange and online isotope discrimination measurements on four common European tree species across a VPD range of 0.8-3.6 kPa, while maintaining constant temperatures without soil water limitation. In addition to applying the standard assumption of saturated vapour pressure inside leaves (ei), we inferred ei from oxygen isotope discrimination of CO2 and water vapour. ei desaturated progressively with increasing VPD, consistently across species, resulting in an intercellular relative humidity as low as 0.73 ± 0.11 at the highest tested VPD. Assuming saturation of ei overestimated the extent of reductions in stomatal conductance and CO2 mole fraction inside leaves in response to increasing VPD compared with calculations that accounted for unsaturation. In addition, a significant decrease in mesophyll conductance with increasing VPD only occurred when the unsaturation of ei was considered. We suggest that the possibility of unsaturated ei should not be overlooked in measurements related to leaf gas exchange and in stomatal models, especially at high VPD.

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