Grazing herbivores reduce herbaceous biomass and fire activity across African savannas.

Fire and herbivory interact to alter ecosystems and carbon cycling. In savannas, herbivores can reduce fire activity by removing grass biomass, but the size of these effects and what regulates them remain uncertain. To examine grazing effects on fuels and fire regimes across African savannas, we combined data from herbivore exclosure experiments with remotely sensed data on fire activity and herbivore density. We show that, broadly across African savannas, grazing herbivores substantially reduce both herbaceous biomass and fire activity. The size of these effects was strongly associated with grazing herbivore densities, and surprisingly, was mostly consistent across different environments. A one-zebra increase in herbivore biomass density (~100 kg/km2 of metabolic biomass) resulted in a ~53 kg/ha reduction in standing herbaceous biomass and a ~0.43 percentage point reduction in burned area. Our results indicate that fire models can be improved by incorporating grazing effects on grass biomass.

Wild herbivores and cattle have differing effects on postfire herbaceous vegetation recovery in an African savanna.

Fire and herbivory have profound effects on vegetation in savanna ecosystems, but little is known about how different herbivore groups influence vegetation dynamics after fire. We assessed the separate and combined effects of herbivory by cattle and wild meso- and megaherbivores on postfire herbaceous vegetation cover, species richness, and species turnover in a savanna ecosystem in central Kenya. We measured these vegetation attributes for five sampling periods (from 2013 to 2017) in prescribed burns and unburned areas located within a series of replicated long-term herbivore exclosures that allow six different combinations of cattle and wild meso- and megaherbivores (elephants and giraffes). Vegetation cover (grasses, mainly) and species richness were initially reduced by burning but recovered by 15-27 months after fire, suggesting strong resilience to infrequent fire. However, the rates of recovery differed in plots accessible by different wild and domestic herbivore guilds. Wildlife (but not cattle) delayed postfire recovery of grasses, and the absence of wildlife (with or without cattle) delayed recovery of forbs. Herbivory by only cattle increased grass species richness in burned relative to unburned areas. Herbivory by cattle (with or without wildlife), however, reduced forb species richness in burned relative to unburned areas. Herbivory by wild ungulates (but not cattle) increased herbaceous species turnover in burned relative to unburned areas. Megaherbivores had negligible modifying effects on these results. This study demonstrates that savanna ecosystems are remarkably resilient to infrequent fires, but postfire grazing by cattle and wild mesoherbivores exerts different effects on recovery trajectories of herbaceous vegetation.

Stereocontrolled synthesis of the aconitine D ring from D-glucose.

The synthesis of a fully oxygenated aconitine D ring precursor from (D)-(+)-glucose is described. The route features a highly diastereoselective alkynyl Grignard ketone addition and a base-mediated enelactone to 1,3-diketone rearrangement.

Clinical Assessment of a Lateral Epicondylar Anatomical Plate for the Stabilization of Humeral Condylar Fractures in Dogs.

OBJECTIVE: To report the use of a Lateral Epicondylar Anatomical Plate for the management of humeral condylar fractures (HCF) in dogs. STUDY DESIGN: Medical records of dogs with HCF stabilized using the Lateral Epicondylar Anatomical Plate at six UK veterinary referral centres between April 2018 and February 2021 were reviewed. Long-term follow-up (>6 months) was obtained via owner questionnaire, which incorporated the Liverpool Osteoarthritis in Dogs clinical metrology instrument. RESULTS: Sixty-two HCF were treated in 61 dogs (44 lateral condylar fractures [LCF] and 18 intracondylar (T/Y) fractures [ICF]). Fifty-one dogs were Spaniels or Spaniel crossbreeds. Intraoperative contouring of the plate was required for one dog-a French Bulldog. Postoperative complications occurred in 14/42 LCF and 6/18 ICF; overall there were 14 minor, 8 major, and 2 catastrophic complications. On final follow-up imaging, there was evidence of partial or complete osseous continuity of the condylar part of the fracture 32/53 HCF (24/39 LCF and 8/14 ICF) and lateral epicondylar part of the fracture in 53/53 HCF (39/39 LCF and 14/14 ICF). At final reexamination, 20/28 dogs with LCF and 5/13 dogs with ICF were not lame and the remaining dogs demonstrated mild lameness. According to the owner questionnaire, 17/17 dogs with LCF and 8/10 dogs with ICF returned to full limb use and median Liverpool Osteoarthritis in Dogs scores were 2/52 for LCF and 6.5/52 for ICF. CONCLUSION: The Lateral Epicondylar Anatomical Plate can be used successfully for the surgical stabilization of HCF in dogs.

Associations between levels of physical literacy and adherence to the 24-h movement guidelines among university students: A cross-sectional study.

Objectives: Emerging evidence indicates that the composition of movement behaviours within a 24-h period is associated with multiple health benefits across the lifespan. A concept that emphasises an individual's active lifestyle is physical literacy (PL), yet empirical research exploring the potential associations between PL and 24-h movement guidelines remains scarce. This study aimed to evaluate the associations between levels of PL and adherence to the guidelines among Chinese university students. Study design: A cross-sectional study. Methods: Seven hundred and ninety-eight university students (390 male, 19.2 ± 1.2 years) completed all the measurements. Levels of PL and participants' adherence to guidelines including physical activity, sedentary behaviour and sleep were self-reported through Perceived Physical Literacy Instrument, International Physical Activity Questionnaire and Pittsburgh Sleep Quality Index, respectively. Two-way ANOVA was conducted to determine the associations between the number of guidelines met (0, 1, 2, or 3) and levels of PL. Results: The results demonstrate that 36.5% (n = 291) of the participants met all the three guidelines, while 4.1% (n = 33) met none. Further analysis indicated that meeting physical activity or sedentary behaviour guidelines was associated with significantly higher total PL scores, and scores in the sub-domains of Confidence and Physical Competence and Motivation. Conclusions: The findings provide evidence that young adults who obtained higher PL scores may meet more guidelines during a 24-h period. Future studies should incorporate accelerometer-based physical activity measurements and investigate the causal relationship between PL and adherence to the movement guidelines.

The effect of a home-based, gamified stability skills intervention on 4-5-year-old children's physical and cognitive outcomes: A pilot study.

BACKGROUND: Stability skills (e.g., static/dynamic balance) are a precursor for other movement skill development (e.g., jumping, catching). However, young children consistently demonstrate low stability and movement skill ability. There is therefore a need to develop effective strategies to improve stability skills in early childhood. AIM: To pilot the effect of a home-based gamified stability skills intervention on 4-5-year-old children's physical skills, self-perceptions and cognitions. METHODS: One-hundred-and-eleven 4-5-year-old children participated from three schools. Two schools were allocated into the intervention group (n = 66 children, 33 boys) and one to the control group (n = 45 children, 25 boys). Stability, fundamental movement skills, perceived motor competence, and cognition were assessed at baseline and at post-intervention. The intervention group was given a booklet detailing the 12-week gamified stability skill intervention. The control group participated in their usual weekly activities. RESULTS: A series of ANCOVAs controlling for baseline values demonstrated significantly higher stability skills (F(1,93) = 24.79, p < 0.001, partial η2 = 0.212), fundamental movement skills (F(1,94) = 15.5, p = < 0.001, partial η2 = 0.139), perceived motor competence (F(1,96) = 5.48, p = 0.021, partial η2 = 0.054) and cognition (F(1,96) = 15.5, p = < 0.001, partial η2 = 0.139) at post-test for the intervention versus control groups. DISCUSSION: This study demonstrates that a home-based, gamified, stability skills intervention enhances stability skills, fundamental movement skills, perceived motor competence and cognition in children aged 4-5-years old.

Interferon-γ signaling in eosinophilic esophagitis has implications for epithelial barrier function and programmed cell death.

Objective: Eosinophilic esophagitis (EoE) is a chronic esophageal inflammatory disorder characterized by eosinophil-rich mucosal inflammation and tissue remodeling. Transcriptional profiling of esophageal biopsies has previously revealed upregulation of type I and II interferon (IFN) response genes. We aim to unravel interactions between immune and epithelial cells and examine functional significance in esophageal epithelial cells. Design: We investigated epithelial gene expression from EoE patients using single-cell RNA sequencing and a confirmatory bulk RNA-sequencing experiment of isolated epithelial cells. The functional impact of interferon signaling on epithelial cells was investigated using in vitro organoid models. Results: We observe upregulation of interferon response signature genes (ISGs) in the esophageal epithelium during active EoE compared to other cell types, single-cell data, and pathway analyses, identified upregulation in ISGs in epithelial cells isolated from EoE patients. Using an esophageal organoid and air-liquid interface models, we demonstrate that IFN-γ stimulation triggered disruption of esophageal epithelial differentiation, barrier integrity, and induced apoptosis via caspase upregulation. We show that an increase in cleaved caspase-3 is seen in EoE tissue and identify interferon gamma (IFNG) expression predominantly in a cluster of majority-CD8+ T cells with high expression of CD69 and FOS. Conclusion: These findings offer insight into the interplay between immune and epithelial cells in EoE. Our data illustrate the relevance of several IFN-γ-mediated mechanisms on epithelial function in the esophagus, which have the potential to impact epithelial function during inflammatory conditions.

Storm and tidal interactions control sediment exchange in mixed-energy coastal systems.

Storms can have devasting effects on shorelines, causing flooding and the destruction of property and infrastructure. As global warming and the frequency and magnitude of tropical storms increase, barrier islands comprising 10% of the world's coast may undergo significant change caused by beach erosion, loss of dunes, and formation of washovers and tidal inlets. Understanding how storms affect sediment transport at tidal inlets is an understudied subject that directly influences barrier island erosional-depositional processes and long-term sediment budgets. This study models hydrodynamics and sediment transport at a conceptualized mixed-energy, mesotidal inlet system using 10 synthetic storm tracks. We investigate the provenance and the role of various storm characteristics and timing between the peak storm surge and high tide on sediment fluxes for different grain sizes. We find that most storms (38 of 40) cause a net import of sediment into the basin that is sourced primarily from the updrift and downdrift nearshore and secondly from the ebb-delta. Very little sediment comes from inlet channel scour. Cumulative (net) transport correlates well with peak significant wave height because wave height influences bottom shear stresses and sediment suspension on the ebb-tidal delta and in the nearshore. The duration of the storm surge also correlates with net transport because it controls the period of flood-directed currents. Our findings help explain the formation of flood deltas inside tidal inlets and the formation of sand shoals in backbarrier regions. Storm-induced enlargement of these deposits represents a permanent long-term loss of sand from barrier islands that will lead to erosion.

Help-seeking intentions of UK construction workers: a cross-sectional study.

BACKGROUND: In response to the high rates of poor mental health in the construction industry, numerous workplace interventions have been designed to address the known and suspected risk factors to employee mental health and well-being. A key challenge of these strategies is low engagement in support services. AIMS: The goals of this research were to investigate the help-seeking intentions of employees in the construction industry, explore levels of mental well-being in this population and provide insight into employee engagement with mental health support strategies. METHODS: Employees from two UK construction companies completed an online cross-sectional questionnaire (n = 119), designed to measure help-seeking intentions, levels of mental well-being and worker attitudes towards workplace mental health support strategies. RESULTS: One-third of the sample reported experiencing an episode of mental health difficulties in the past 6 months. Employees reported a greater preference for seeking support from informal versus formal help sources. Participants were most likely to seek help from a partner and least likely to seek help from a Mental Health First Aider/ Champion. The study also showed some association between help-seeking intention and age of employees. CONCLUSIONS: Given the poor levels of mental well-being in this population, it is essential that adequate workplace support is provided. Whilst formal help sources are important for this population, our study highlights the potential benefits of informal help sources to support employees. Future interventions may therefore wish to consider developing tailored, informal workplace support networks and programmes.

The influence of fear of falling on the control of upright stance across the lifespan.

BACKGROUND: Standing at height, and subsequent changes in emotional state (e.g., fear of falling), lead to robust alterations in balance in adults. However, little is known about how height-induced postural threat affects balance performance in children. Children may lack the cognitive capability necessary to inhibit the processing of threat and fear-related stimuli, and as a result, may show more marked (and perhaps detrimental) changes in postural control compared to adults. This work explored the emotional and balance responses to standing at height in children, and compared responses to young and older adults. METHODS: Children (age: 9.7 ± 0.8 years, n = 38), young adults (age: 21.8 ± 4.0 years, n = 45) and older adults (age: 73.3 ± 5.0 years, n = 15) stood in bipedal stance in two conditions: at ground level and 80 cm above ground. Centre of pressure (COP) amplitude (RMS), frequency (MPF) and complexity (sample entropy) were calculated to infer postural performance and strategy. Emotional responses were quantified by assessing balance confidence, fear of falling and perceived instability. RESULTS: Young and older adults demonstrated a postural adaptation characterised by increased frequency and decreased amplitude of the COP, in conjunction with increased COP complexity (sample entropy). In contrast, children demonstrated opposite patterns of changes: they exhibited an increase in COP amplitude and decrease in both frequency and complexity when standing at height. SIGNIFICANCE: Children and adults adopted different postural control strategies when standing at height. Whilst young and older adults exhibited a potentially protective "stiffening" response to a height-induced threat, children demonstrated a potentially maladaptive and ineffective postural adaptation strategy. These observations expand upon existing postural threat related research in adults, providing important new insight into understanding how children respond to standing in a hazardous situation.

PLAT domain protein 1 (PLAT1/PLAFP) binds to the Arabidopsis thaliana plasma membrane and inserts a lipid.

Robust agricultural yields depend on the plant's ability to fix carbon amid variable environmental conditions. Over seasonal and diurnal cycles, the plant must constantly adjust its metabolism according to available resources or external stressors. The metabolic changes that a plant undergoes in response to stress are well understood, but the long-distance signaling mechanisms that facilitate communication throughout the plant are less studied. The phloem is considered the predominant conduit for the bidirectional transport of these signals in the form of metabolites, nucleic acids, proteins, and lipids. Lipid trafficking through the phloem in particular attracted our attention due to its reliance on soluble lipid-binding proteins (LBP) that generate and solubilize otherwise membrane-associated lipids. The Phloem Lipid-Associated Family Protein (PLAFP) from Arabidopsis thaliana is generated in response to abiotic stress as is its lipid-ligand phosphatidic acid (PA). PLAFP is proposed to transport PA through the phloem in response to drought stress. To understand the interactions between PLAFP and PA, nearly 100 independent systems comprised of the protein and one PA, or a plasma membrane containing varying amounts of PA, were simulated using atomistic classical molecular dynamics methods. In these simulations, PLAFP is found to bind to plant plasma membrane models independent of the PA concentration. When bound to the membrane, PLAFP adopts a binding pose where W41 and R82 penetrate the membrane surface and anchor PLAFP. This triggers a separation of the two loop regions containing W41 and R82. Subsequent simulations indicate that PA insert into the ß-sandwich of PLAFP, driven by interactions with multiple amino acids besides the W41 and R82 identified during the insertion process. Fine-tuning the protein-membrane and protein-PA interface by mutating a selection of these amino acids may facilitate engineering plant signaling processes by modulating the binding response.

Long-term sea level rise modeling of a basin-tidal inlet system reveals sediment sinks.

Much of the world's population lives close to coastlines and this proximity is becoming increasingly impactful because of sea-level rise (SLR). Barrier islands and backbarrier saltmarshes, which comprise >10% of these coasts, are particularly susceptible. To better understand this risk, we model backbarrier morphologic and hydrodynamic evolution over a 200-year period of SLR, incorporating an erodible bed and a range of grain sizes. Here, we show that reduction in intertidal area creates negative feedback, shifting transport of coarse sediment (silt and sand) through the inlet from net export to net import. Imposing a modest marsh vertical accretion rate decreases the period of silt and sand import to 40 years (years 90 to 130) before being exported again. Clay is continuously exported thereby decreasing inorganic deposition on marshes and threatening their sustainability. Simulated marsh loss increases tidal prism and the volume of sand contained in ebb deltas, depleting coastal sand resources.

T cell memory revisited using single telomere length analysis.

The fundamental basis of T cell memory remains elusive. It is established that antigen stimulation drives clonal proliferation and differentiation, but the relationship between cellular phenotype, replicative history, and longevity, which is likely essential for durable memory, has proven difficult to elucidate. To address these issues, we used conventional markers of differentiation to identify and isolate various subsets of CD8+ memory T cells and measured telomere lengths in these phenotypically defined populations using the most sensitive technique developed to date, namely single telomere length analysis (STELA). Naive cells were excluded on the basis of dual expression of CCR7 and CD45RA. Memory subsets were sorted as CD27+CD45RA+, CD27intCD45RA+, CD27-CD45RA+, CD27+CD45RAint, CD27-CD45RAint, CD27+CD45RA-, and CD27-CD45RA- at >98% purity. The shortest median telomere lengths were detected among subsets that lacked expression of CD45RA, and the longest median telomere lengths were detected among subsets that expressed CD45RA. Longer median telomere lengths were also a feature of subsets that expressed CD27 in compartments defined by the absence or presence of CD45RA. Collectively, these data suggested a disconnect between replicative history and CD8+ memory T cell differentiation, which is classically thought to be a linear process that culminates with revertant expression of CD45RA.

Neurodevelopmental outcomes in children and adults with Fetal Valproate Spectrum Disorder: A contribution from the ConcePTION project.

AIM: To describe the neurodevelopmental phenotype of older children and adults with a diagnosis of Fetal Valproate Spectrum Disorder (FVSD). METHODS: In this cross-sectional study, 90 caregivers were recruited and completed a series of questionnaires regarding the neurodevelopmental outcomes of 146 individuals aged 7-37 years (M = 18.1), including individuals with a formal diagnosis of FVSD (n = 99), individuals exposed to Valproate but without an FVSD diagnosis (n = 24), and individuals not exposed to Valproate (N = 23). The mean dose of valproate exposure for individuals with an FVSD diagnosis was 1470 mg/day. RESULTS: Individuals with a diagnosis of FVSD showed significantly higher levels of moderate (43.4%) and severe (14.4%) cognitive impairment than other groups (p = 0.003), high levels of required formal educational support (77.6%), and poorer academic competence than individuals not exposed to Valproate (p = 0.001). Overall psychosocial problems (p = 0.02), internalising problems (p = 0.05) and attention problems (p = 0.001), but not externalising problems, were elevated in individuals with a diagnosis of FVSD. Rates of neurodevelopmental disorders, particularly autistic spectrum disorders (62.9%) and sensory problems (80.6%) are particularly central to the FVSD phenotype. There was no evidence of a statistical dose-dependent effect, possibly due to the high mean dose of exposure having a uniformly negative impact across the sample. Individuals with FVSD had required a significant number of health and child development services. INTERPRETATION: Children and young adults with a diagnosis of FVSD are at an increased risk of a range of altered neurodevelopmental outcomes, highlighting the need for a multidisciplinary approach to clinical management across the lifespan.

Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity.

Chimeric antigen receptor (CAR) T cell therapy effectively treats human cancer, but the loss of the antigen recognized by the CAR poses a major obstacle. We found that in vivo vaccine boosting of CAR T cells triggers the engagement of the endogenous immune system to circumvent antigen-negative tumor escape. Vaccine-boosted CAR T promoted dendritic cell (DC) recruitment to tumors, increased tumor antigen uptake by DCs, and elicited the priming of endogenous anti-tumor T cells. This process was accompanied by shifts in CAR T metabolism toward oxidative phosphorylation (OXPHOS) and was critically dependent on CAR-T-derived IFN-γ. Antigen spreading (AS) induced by vaccine-boosted CAR T enabled a proportion of complete responses even when the initial tumor was 50% CAR antigen negative, and heterogeneous tumor control was further enhanced by the genetic amplification of CAR T IFN-γ expression. Thus, CAR-T-cell-derived IFN-γ plays a critical role in promoting AS, and vaccine boosting provides a clinically translatable strategy to drive such responses against solid tumors.

Expert consensus on neurodevelopmental outcomes in pregnancy pharmacovigilance studies.

Background: Exposure in utero to certain medications can disrupt processes of fetal development, including brain development, leading to a continuum of neurodevelopmental difficulties. Recognizing the deficiency of neurodevelopmental investigations within pregnancy pharmacovigilance, an international Neurodevelopmental Expert Working Group was convened to achieve consensus regarding the core neurodevelopmental outcomes, optimization of methodological approaches and barriers to conducting pregnancy pharmacovigilance studies with neurodevelopmental outcomes. Methods: A modified Delphi study was undertaken based on stakeholder and expert input. Stakeholders (patient, pharmaceutical, academic and regulatory) were invited to define topics, pertaining to neurodevelopmental investigations in medication-exposed pregnancies. Experts were identified for their experience regarding neurodevelopmental outcomes following medicinal, substances of misuse or environmental exposures in utero. Two questionnaire rounds and a virtual discussion meeting were used to explore expert opinion on the topics identified by the stakeholders. Results: Twenty-five experts, from 13 countries and professionally diverse backgrounds took part in the development of 11 recommendations. The recommendations focus on the importance of neurodevelopment as a core feature of pregnancy pharmacovigilance, the timing of study initiation and a core set of distinct but interrelated neurodevelopmental skills or diagnoses which require investigation. Studies should start in infancy with an extended period of investigation into adolescence, with more frequent sampling during rapid periods of development. Additionally, recommendations are made regarding optimal approach to neurodevelopmental outcome measurement, comparator groups, exposure factors, a core set of confounding and mediating variables, attrition, reporting of results and the required improvements in funding for potential later emerging effects. Different study designs will be required depending on the specific neurodevelopmental outcome type under investigation and whether the medicine in question is newly approved or already in widespread use. Conclusion: An improved focus on neurodevelopmental outcomes is required within pregnancy pharmacovigilance. These expert recommendations should be met across a complementary set of studies which converge to form a comprehensive set of evidence regarding neurodevelopmental outcomes in pregnancy pharmacovigilance.

Impacts of large herbivores on terrestrial ecosystems.

Large herbivores play unique ecological roles and are disproportionately imperiled by human activity. As many wild populations dwindle towards extinction, and as interest grows in restoring lost biodiversity, research on large herbivores and their ecological impacts has intensified. Yet, results are often conflicting or contingent on local conditions, and new findings have challenged conventional wisdom, making it hard to discern general principles. Here, we review what is known about the ecosystem impacts of large herbivores globally, identify key uncertainties, and suggest priorities to guide research. Many findings are generalizable across ecosystems: large herbivores consistently exert top-down control of plant demography, species composition, and biomass, thereby suppressing fires and the abundance of smaller animals. Other general patterns do not have clearly defined impacts: large herbivores respond to predation risk but the strength of trophic cascades is variable; large herbivores move vast quantities of seeds and nutrients but with poorly understood effects on vegetation and biogeochemistry. Questions of the greatest relevance for conservation and management are among the least certain, including effects on carbon storage and other ecosystem functions and the ability to predict outcomes of extinctions and reintroductions. A unifying theme is the role of body size in regulating ecological impact. Small herbivores cannot fully substitute for large ones, and large-herbivore species are not functionally redundant - losing any, especially the largest, will alter net impact, helping to explain why livestock are poor surrogates for wild species. We advocate leveraging a broad spectrum of techniques to mechanistically explain how large-herbivore traits and environmental context interactively govern the ecological impacts of these animals.

Cognitive mechanisms and resilience in UK-based general practitioners: cross-sectional findings.

BACKGROUND: Being a general practitioner (GP) is a stressful occupation, and the strain GPs are under can have negative effects on their psychological well-being, as well as on the patients' experience of healthcare. Resilience can help buffer against this and is a dynamic process by which one can cope with adversity and stress. AIMS: This study aimed to identify modifiable cognitive mechanisms related to resilience in GPs, specifically interpretation bias and cognitive reappraisal. METHODS: One hundred and fourteen GPs completed an online cross-sectional correlational study. This comprised questionnaires assessing resilience, emotional distress, work environment and cognitive mechanisms (emotion regulation), as well as a task assessing interpretation bias. RESULTS: Resilience of GPs was negatively correlated with measures of emotional distress. Furthermore, resilience was positively correlated with positive interpretation bias (r = 0.60, ρ = 0.60, P < 0.01) and cognitive reappraisal (r = 0.39, ρ = 0.40, P < 0.01). In a hierarchical regression, positive interpretation bias (B = 0.25, SE B = 0.06, ß = 0.39, P < 0.01) was a significant independent predictor of resilience when controlling for depression, anxiety and stress. CONCLUSIONS: This is the first study to establish an association between resilience and positive interpretation bias and cognitive reappraisal in GPs. Future research should use longitudinal designs to determine if they have a causal role in promoting resilience, and importantly whether interventions focusing on these processes may foster resilience in less resilient GPs.

Tissue-specific abundance of interferon-gamma drives regulatory T cells to restrain DC1-mediated priming of cytotoxic T cells against lung cancer.

Local environmental factors influence CD8+ T cell priming in lymph nodes (LNs). Here, we sought to understand how factors unique to the tumor-draining mediastinal LN (mLN) impact CD8+ T cell responses toward lung cancer. Type 1 conventional dendritic cells (DC1s) showed a mLN-specific failure to induce robust cytotoxic T cells responses. Using regulatory T (Treg) cell depletion strategies, we found that Treg cells suppressed DC1s in a spatially coordinated manner within tissue-specific microniches within the mLN. Treg cell suppression required MHC II-dependent contact between DC1s and Treg cells. Elevated levels of IFN-γ drove differentiation Treg cells into Th1-like effector Treg cells in the mLN. In patients with cancer, Treg cell Th1 polarization, but not CD8+/Treg cell ratios, correlated with poor responses to checkpoint blockade immunotherapy. Thus, IFN-γ in the mLN skews Treg cells to be Th1-like effector Treg cells, driving their close interaction with DC1s and subsequent suppression of cytotoxic T cell responses.

14-3-3 and Smad2/3 are crucial mediators of atypical-PKCs: Implications for neuroblastoma progression.

Neuroblastoma (NB) is a cancer that develops in the neuroblasts. It is the most common cancer in children under the age of 1 year, accounting for approximately 6% of all cancers. The prognosis of NB is linked to both age and degree of cell differentiation. This results in a range of survival rates for patients, with outcomes ranging from recurrence and mortality to high survival rates and tumor regression. Our previous work indicated that PKC-ι promotes cell proliferation in NB cells through the PKC-ι/Cdk7/Cdk2 cascade. We report on two atypical protein kinase inhibitors as potential therapeutic candidates against BE(2)-C and BE(2)-M17 cells: a PKC-ι-specific 5-amino-1-2,3-dihydroxy-4-(methylcyclopentyl)-1H-imidazole-4-carboxamide and a PKC-ζ specific 8-hydroxy-1,3,6-naphthalenetrisulfonic acid. Both compounds induced apoptosis and retarded the epithelial-mesenchymal transition (EMT) of NB cells. Proteins 14-3-3 and Smad2/3 acted as central regulators of aPKC-driven progression in BE(2)-C and BE(2)-M17 cells in relation to the Akt1/NF-κB and TGF-ß pathways. Data indicates that aPKCs upregulate Akt1/NF-κB and TGF-ß pathways in NB cells through an association with 14-3-3 and Smad2/3 that can be diminished by aPKC inhibitors. In summary, both inhibitors appear to be promising potential neuroblastoma therapeutics and merit further research.