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Obesity and elevation of circulating free fatty acids are associated with an accumulation and proinflammatory polarization of macrophages within metabolically active tissues, such as adipose tissue, muscle, liver, and pancreas. Beyond macrophages, neutrophils also accumulate in adipose and muscle tissues during high-fat diets and contribute to a state of local inflammation and insulin resistance. However, the mechanisms by which neutrophils are recruited to these tissues are largely unknown. Here we used a cell culture system as proof of concept to show that, upon exposure to a saturated fatty acid, palmitate, macrophages release nucleotides that attract neutrophils. Moreover, we found that palmitate up-regulates pannexin-1 channels in macrophages that mediate the attraction of neutrophils, shown previously to allow transfer of nucleotides across membranes. These findings suggest that proinflammatory macrophages release nucleotides through pannexin-1, a process that may facilitate neutrophil recruitment into metabolic tissues during obesity. [ABSTRACT FROM AUTHOR]

The gut-brain axis refers to the bidirectional communication between the enteric nervous system and the central nervous system. Mounting evidence supports the premise that the intestinal microbiota plays a pivotal role in its function and has led to the more common and perhaps more accurate term gut-microbiota-brain axis. Numerous studies have identified associations between an altered microbiome and neuroimmune and neuroinflammatory diseases. In most cases, it is unknown if these associations are cause or effect; notwithstanding, maintaining or restoring homeostasis of the microbiota may represent future opportunities when treating or preventing these diseases. In recent years, several studies have identified the diet as a primary contributing factor in shaping the composition of the gut microbiota and, in turn, the mucosal and systemic immune systems. In this review, we will discuss the potential opportunities and challenges with respect to modifying and shaping the microbiota through diet and nutrition in order to treat or prevent neuroimmune and neuroinflammatory disease. [ABSTRACT FROM AUTHOR]

With no available vaccine for Lyme disease or equine anaplasmosis for horses, tick bite prevention is the recommended method to prevent tick-borne diseases (TBDs) transmission. Routine tick checks, which allow horse owners to remove ticks before tick bites, can reduce the incidence of TBD in horses. The objective of this extension program was to engage Pennsylvania (PA) horse owners in community science to conduct weekly tick checks on horses and report tick numbers and locations. Horse owners (n = 35) were recruited who had horses (n = 55) that resided in PA for most of the year. Participants were required to attend a webinar where they learned how to conduct tick checks and then completed a survey assessing their current tick management practices. Participants were mailed a tick-check kit and asked to conduct tick checks twice a week for 7 weeks (April–May 2022). Numbers and locations of ticks were recorded on data sheets; these and the ticks were sent to Penn State for identification. A post-program survey was completed at the end of the program. Most respondents (72%) cared for 2–5 horses. The majority (85%) turned out horses in or near forested habitats from April to November. Each time tick checks were performed, 72% found 1–2 ticks, and the most common location was under the jaw. Most owners used on-animalrepellents (65%) as a primary method of tick control, followed by pasture/landscape management (24%). Data sheets (n = 645) showed 343 ticks found; however, 83% of all reported ticks came from one horse. With this outlier removed, most (32%) ticks were found between the front legs. The post-program survey indicated that knowledge of tick basics, TBDs, and tick checks increased (3.53 ± 1.01, 3.14 ± 0.82, 3.72 ± 1.24, respectively) as a result of participation and that 67% of respondents had "a lot" or "a great deal" higher confidence in performing tick checks. Most respondents (72%) will continue performing full-body tick checks on all or some of their horses and will do so either once a week (39%) or 2–6 times a week (39%). Most respondents (66%) found fewer ticks than they expected. Most respondents (69%) were not any more or less concerned about risk of tick bites than they were before the study. This study shows that horse owners are willing to commit to community science projects and provide data. The numbers and locations of ticks found during the program did not match participants' expectations pre-study. This Extension project resulted in behavior change as a result of education and training. [ABSTRACT FROM AUTHOR]

There is limited data on the occurrence of ticks on horses in Pennsylvania (PA). Additionally, current knowledge of PA horse caretakers on tick-borne diseases (TBDs), tick identification, and tick management practices has not been assessed. The objectives of this study were to determine tick knowledge, concern, and management among PA equine caretakers. An online survey was distributed via e-mail lists, social media, and online advertising. Descriptive statistics and one-way ANOVA tests were used to analyze data. The percentages shown represent the number of respondents who answered that question. The survey received 894 responses (539 completed) from PA equine owners and caretakers. The largest proportion of respondents cared for 3–5 horses (31%), followed by 2 horses (27%). Veterinarian-confirmed diagnosis rates of 2 TBDs, Lyme disease and anaplasmosis, were 38 and 22%, respectively. Most respondents (39%) were moderately confident in recognizing Lyme disease, while most (44%) were not confident at all in recognizing anaplasmosis. Most respondents (69%) were either extremely or very concerned about their horses contracting any TBDs. Horse caretakers (88%) were comfortable performing tick checks and most performed weekly full-body tick checks (40.6%) and daily partial tick checks (47%). A majority (67%) found 1–2 ticks on their horse each timethey checked, with the jaw, throatlatch, and chest being the most common areas ticks were found on horses. The primary method of tick control was on-animal repellants (60%), followed by pasture/landscape management (23%). Ten knowledge-based questions were asked, and the mean correct score was 3.97 ± 2.18. Respondents with horses that had a veterinarian-confirmed Lyme disease diagnosis had a higher knowledge score (4.93 ± 1.69) than those with probable or no Lyme disease diagnosed horses (4.21 ± 1.60 and 4.34 ± 1.65, respectively; P < 0.001). Respondents that were extremely concerned about TBDs had higher knowledge scores (4.8 ± 1.67) than those that were moderately, slightly, or not concerned (4.26 ± 1.65, 3.95 ± 1.59, 3.50 ± 1.68, respectively; P < 0.001). Respondents that performed full-body tick checks daily or weekly scored higher (4.75 ± 1.61, 4.79 ± 1.60, respectively) than those who performed them when they remembered or never conducted tick checks (4.19 ± 1.81, 3.94 ± 1.87; P < 0.001). As TBD concern level and rate of Lyme diagnosis increased, so did knowledge score of respondents. With most PA horse owners finding ticks every time they checked their horses, Extension educators should focus on teaching about TBDs and managing ticks on their horses and farms. [ABSTRACT FROM AUTHOR]

Existing data on the equine hay market and buying preferences in Pennsylvania (PA) is outdated and not statewide. More recent data is needed to inform those who advise horse owners on hay and nutrition. The objective of this project was to characterize the practices and attitudes of PA horse hay buyers. An online survey was advertised via e-mail lists, social media, and print advertisements. It received 435 total responses (of these, 346 were complete responses) from PA horse hay buyers from October 2021 to February 2022. Data presented (descriptive statistics) represents the percentage of respondents answering that question. Most (76%) respondents were in the recreational sector of the horse industry and the majority (62%) purchased hay for 2–5 horses. Small square bales (2-string) were the most commonly purchased (93%), and most respondents bought their hay exclusively by the bale (75%) rather than exclusively by the ton (4%) or either (21%). For those who did not purchase large bales (round or square), the most common reason was not being able to transport or handle them (70%), followed by not having adequate storage (60%). Horse owners were most likely to buy hay directly from local farmers (90%) than any other source. They were more likely to exclusively pick up their hay than to require delivery, while some would consider either (40, 33, and 26%, respectively). The 3 most popular hay species were mixed grasses (64%),orchardgrass (38%), and timothy (35%). Buyers slightly preferred second or later cuttings to first cutting or did not care about cutting (53, 43, and 30%, respectively). Most (47%) believed that second or later cuttings were higher quality than first cutting, but 38% believed that all cuttings can be high-quality. The top 3 most important factors when purchasing hay were absence of mold, absence of weeds, and smell (rated "very important" by 98, 53, and 52% of respondents, respectively). Most respondents did not use hay feeders in stalls or outside (38 and 50%, respectively). Those who did use hay feeders used them primarily to reduce hay waste (56%). Most hay buyers (63%) never have their hay analyzed for nutrient content, but those that are interested in testing hay report wanting to balance the horse's diet around the forage quality and to check certain nutrients for specific health concerns (37 and 34%, respectively). To get answers to hay-related questions, most respondents ask hay producers or veterinarians (25 and 22%, respectively). The data collected from this survey can help hay producers understand buying practices of horse owners and help equine nutritionists identify areas of need for horse owner education about hay. [ABSTRACT FROM AUTHOR]

Summary Insulin resistance is a chronic inflammatory condition accompanying obesity or high fat diets that leads to type 2 diabetes. It is hypothesized that lipids and gut bacterial compounds in particular contribute to metabolic inflammation by activating the immune system; however, the receptors detecting these “instigators” of inflammation remain largely undefined. Here, we show that circulating activators of NOD1, a receptor for bacterial peptidoglycan, increase with high fat feeding in mice, suggesting that NOD1 could be a critical sensor leading to metabolic inflammation. Hematopoietic depletion of NOD1 did not prevent weight gain but protected chimeric mice against diet-induced glucose and insulin intolerance. Mechanistically, while macrophage infiltration of adipose tissue persisted, notably these cells were less pro-inflammatory, had lower CXCL1 production, and consequently, lower neutrophil chemoattraction into the tissue. These findings reveal macrophage NOD1 as a cell-specific target to combat diet-induced inflammation past the step of macrophage infiltration, leading to insulin resistance. [ABSTRACT FROM AUTHOR]

A rise in tissue-embedded macrophages displaying "M1-like" proinflammatory polarization is a hallmark of metabolic inflammation during a high fat diet or obesity. Here we show that bone marrow-derived macrophages (BMDM) from high fat-fed mice retain a memory of their dietary environment in vivo (displaying the elevated proinflammatory genes Cxcl1, Il6, Tnf, Nos2) despite 7-day differentiation and proliferation ex vivo. Notably, 6-h incubation with palmitoleate (PO) reversed the proinflammatory gene expression and cytokine secretion seen in BMDM from high fat-fed mice.BMDMfrom low fat-fed mice exposed to palmitate (PA) for 18 h ex vivo also showed elevated expression of proinflammatory genes (Cxcl1, Il6, Tnf, Nos2, and Il12b) associated with M1 polarization. Conversely, PO treatment increased anti-inflammatory genes (Mrc1, Tgfb1, Il10, Mgl2) and oxidative metabolism, characteristic of M2 macrophages. Therefore, saturated and unsaturated fatty acids bring about opposite macrophage polarization states. Coincubation of BMDMwith both fatty acids counteracted the PA-induced Nos2 expression in a PO dose-dependent fashion. PO also prevented PA-induced IB degradation, RelA nuclear translocation, NO production, and cytokine secretion. Mechanistically, PO exerted its anti-inflammatory function through AMP-activated protein kinase as AMP kinase knockout or inhibition by Compound C offset the PO-dependent prevention of PA-induced inflammation. These results demonstrate a nutritional memory of BMDMex vivo, highlight the plasticity of BMDMpolarization in response to saturated and unsaturated fatty acids, and identify the potential to reverse diet- and saturated fat-induced M1-like polarization by administering palmitoleate. These findings could have applicability to reverse obesity-linked inflammation in metabolically relevant tissues. [ABSTRACT FROM AUTHOR]

Despite the widespread popularity of the Wonderlic Personnel Test, evidence of its validity as a measure of intelligence and personnel selection is limited. The present study sought to better understand the Wonderlic by investigating its relationship to multiple measures of working memory capacity and fluid intelligence. Our results show that Wonderlic has no direct relationship to fluid intelligence once its commonality to working memory capacity is accounted for. Further, we found that the Wonderlic was a significant predictor of working memory capacity for subjects with low fluid intelligence, but failed to discriminate as well among subjects with high fluid intelligence. These results suggest that the predictive power of the Wonderlic could depend on the characteristics of the sample it is administered to, whereas the relationship between fluid intelligence and working memory capacity is robust and invariant to the cognitive capabilities of the sample. [ABSTRACT FROM AUTHOR]

In the present study, the liquidus temperature, mixing enthalpy, and atomic mismatch factor are used to predict and empirically evaluate the amorphisation capability of Co-Fe-B alloys fabricated by melt spinning. Based on this approach, five out of seven alloys have an amorphous structure, confirming the capability of the proposed model in predicting the alloy compositions with higher amorphisation ability in a ternary alloy system in the absence of any costly elements, such as Nb, Mo and Zr. X-ray diffraction, TEM and Mössbauer results show that the other two alloys exhibit different in-situ crystallisation behaviour. In one case, only the free-side crystallises, whereas the crystallisation occurs through the entire thickness of the ribbon in the other alloy. The lower amorphisation ability exhibited by these alloys in relation to the predictive parameters has been evaluated. Additionally, there is a strong correlation between amorphisation ability and crystallisation behaviour of alloys. Alloys, which crystallise through eutectic mode, are more likely to exhibit high amorphisation capability, whereas crystallisation via the primary mechanism can be the sign of lower amorphisation ability. The output of the alloy design process is five amorphous compositions, among which one is magnetically ultra-soft, H c = 2.9 A/m; a surface crystalline alloy, with a low coercivity and higher value of anisotropy field compared to amorphous samples; and a nanocrystalline sample with a very high saturation flux density, B s = 1.57 T. The surface crystallisation can eliminate the need for inducing transverse anisotropy by magnetic annealing. Therefore, optimising the alloy composition through this method can be a universal strategy of composition design for the fabrication of alloys with excellent properties, to be utilised in both high- B s and low- H c applications. • Amorphisation capability (AMC) and structure of alloys can be predicted by designing alloys using AMC parameters. • Bulk and surface crystallisation in Co-based melt-spun ribbons can result in superior DC and AC magnetic propertie. • Alloys with excellent DC magnetic properties are fabricated in ternary Co-Fe-B system in the absence of any costly elements. [ABSTRACT FROM AUTHOR]

High CD103+ intratumoral immune cell (ITIC) abundance is associated with better prognosis in unselected patients with human papilloma virus-associated oropharyngeal squamous cell carcinoma (HPV-associated OPSCC) treated with cisplatin and radiotherapy (CIS/RT). Substituting cetuximab (CETUX) for CIS with RT in HPV-associated OPSCC resulted in inferior efficacy. Our aim was to determine whether quantification of CD103 ITIC could be used to identify a population of HPV-associated OPSCC with superior prognosis. We pooled data from the TROG 12.01 and De-ESCALaTE randomized trials that compared CETUX/70GyRT with CIS/70GyRT in low-risk HPV-associated OPSCC: American Joint Committee on Cancer 7 stage III (excluding T1-2N1) or stage IV (excluding N2b-c if smoking history >10 pack-years and/or distant metastases), including all patients with available tumor samples. The primary endpoint was failure-free survival (FFS) in patients receiving CETUX/RT comparing CD103+ ITIC high (≥30%) versus low (<30%). High and low CD103 were compared using Cox regression adjusting for age, stage and trial. Tumor samples were available in 159/182 patients on TROG 12.01 and 145/334 on De-ESCALaTE. CD103+ ITIC abundance was high in 27% of patients. The median follow-up was 3.2 years. The 3-year FFS in patients treated with CETUX/RT was 93% [95% confidence interval (CI) 79% to 98%] in high CD103 and 74% (95% CI 63% to 81%) in low CD103 [adjusted hazard ratio = 0.22 (95% CI 0.12-0.41), P < 0.001]. The 3-year overall survival in patients treated with CETUX/RT was 100% in high CD103 and 86% (95% CI 76% to 92%) in low CD103, P < 0.001. In patients treated with CIS/RT, there was no significant difference in FFS. CD103+ ITIC expression separates CETUX/RT-treated low-risk HPV-associated OPSCC into excellent and poor prognosis subgroups. The high CD103 population is a rational target for de-intensification trials. • ITIC CD103 expression separates CETUX/RT-treated low-risk HPV-OPSCC into good and poor prognosis groups. • There was an increase in distant and locoregional failures in the low CD103 population treated with CETUX/RT. • In a low-risk HPV-OPSCC population, weekly CIS/RT achieves excellent outcomes in both high and low CD103 groups. • In the high CD103 population, CIS/RT and CETUX/RT achieve similar excellent outcomes. • CD103 expression stratifies CETUX/RT-treated patients with abundant CD8 tumor-infiltrating lymphocytes into distinct prognostic groups. [ABSTRACT FROM AUTHOR]

• Thermodynamic and topological parameters have been used to design an alloy with a tuned amorphisation capability. • Tuned parameters resulted in in-situ nanocrystallisation of Co 7 Fe 3 with very-high B s (1.57 T). • Based on Mössbauer spectrum, it is asserted that cobalt atoms form clusters, and boron atoms undergo short-range ordering. [Display omitted] A thermodynamics-based approach, Calculation of Phase Diagram (CALPHAD), combined with topological instability parameters are proposed and experimentally evaluated, in order to optimise in-situ nanocrystallisation of rapidly quenched CoFeB alloys and exploit their remarkable B s = 1.57 T. The high M s of the alloy is attributed to the precipitation of the metastable Co 7 Fe 3 nanocrystalline phase dispersed heterogeneously in the amorphous matrix. High M s of Co 7 Fe 3 phase can also be inferred from the high hyperfine magnetic field of the Fe nuclei deduced from Mössbauer spectra. It is worth noting that the in-situ nanocrystallisation is a volume phenomenon, instead of surface crystallisation at the air-side of ribbons owning to lower cooling rates. We judge, based on nucleation theory, that the formation of the metastable phase is kinetically favoured, when compared to the equilibrium phases, hence promoting the high M s , when compared with conventional Co-rich amorphous alloys. The local atomic order of nanocrystallised phase was confirmed by X-ray and electron diffraction techniques. Using Mössbauer spectroscopy and the extracted distribution of the hyperfine magnetic field, it is asserted that cobalt atoms form clusters, as they attract each other to form ordered structures, and boron atoms undergo only short-range ordering, likely due to covalent bond formation, governed by the size and electronegativity differences with the atoms in the amorphous matrix. We suggest the proposed CALPHAD-assisted design of nanostructured alloys, along with an in-situ nanocrystallisation, provides a practical scheme to develop novel functional alloys with the best possible balance of coercivity and saturation, exclusively aimed for a high-tech application. [ABSTRACT FROM AUTHOR]

Clinical studies suggest that heightened peripheral inflammation contributes to the pathogenesis of stress-related disorders, including major depressive disorder. However, the molecular mechanisms within peripheral immune cells that mediate enhanced stress vulnerability are not well known. Because microRNAs (miRs) are important regulators of immune response, we sought to examine their role in mediating inflammatory and behavioral responses to repeated social defeat stress (RSDS), a mouse model of stress vulnerability that produces susceptible and resilient phenotypes. We isolated Ly6chigh monocytes via fluorescence-activated cell sorting in the blood of susceptible and resilient mice following RSDS and profiled miR expression via quantitative real-time polymerase chain reaction. Bone marrow chimeric mice were generated to confirm a causal role of the miR-106b∼25 cluster in bone marrow–derived leukocytes in mediating stress resilience versus susceptibility. We found that RSDS produces an increase in circulating Ly6chigh inflammatory monocytes in both susceptible and resilient mice. We next investigated whether intrinsic leukocyte posttranscriptional mechanisms contribute to individual differences in stress response and the resilient phenotype. Of the miRs profiled in our panel, eight were significantly regulated by RSDS within Ly6chigh monocytes, including miR-25-3p, a member of the miR-106b∼25 cluster. Selective knockout of the miR-106b∼25 cluster in peripheral leukocytes promoted behavioral resilience to RSDS. Our results identify the miR-106b∼25 cluster as a key regulator of stress-induced inflammation and depression that may represent a novel therapeutic target for drug development. [ABSTRACT FROM AUTHOR]

Interesterified fats have largely replaced hydrogenated vegetable fat, which is rich in trans fatty acids, in the food industry as an economically viable alternative, generating interest to study their health effects. The aim of this study was to evaluate the effect that interesterification of oils and fat has on lipid-induced metabolic dysfunction, hepatic inflammation and ER stress. Five week-old male Wistar rats were randomly divided into three experimental groups, submitted to either normocaloric and normolipidic diet containing 10% of lipids from unmodified soybean oil (SO) or from interesterified soybean oil (ISO), and one more group submitted to a high fat diet (HFD) containing 60% of fat from lard as a positive control, for 8 or 16 weeks. Metabolic parameters and hepatic gene expression were evaluated. The HFD consumption led to increased body mass, adiposity and impaired glucose tolerance compared to SO and ISO at both time points of diet. However, the ISO group showed an increased body mass gain, retroperitoneal WAT mass, fasting glucose, and impaired glucose tolerance during ipGTT at 16 weeks compared to SO. Moreover, at 8 weeks, hepatic gene expression of Atf3 and Tnf were increased in the ISO group compared to the SO group. Thus, replacement of natural fat with interesterified fat on a normocaloric and normolipidic diet negatively modulated metabolic parameters and resulted in impaired glucose tolerance in rats. [ABSTRACT FROM AUTHOR]

This secondary analysis aimed to identify HNSS and HRQL trajectories during and following CRT for HPVOPC. All 182 evaluable TROG 12.01 patients were included. HNSS was assessed with the MDASI-HN (range 0-10) at baseline (BL), weekly during CRT (weeks (w) 1-7) and then 1, 3, 5, 9 and 13w and 6, 12 and 24 months (m) post CRT. HRQL was assessed using the FACT-G (range 0-108) at BL, and 7w, 6m, 12m and 24m post CRT. Latent class growth mixture modelling (LCMM) was performed to identify trajectories. Mean estimates and 95% confidence intervals (CI) were calculated at each time point. The HNSS model identified 4 trajectory classes (HNSS1-4) distinguished by differences in HNSS at BL, during the peak of treatment symptoms (w7 CRT/1w post CRT) and during early (1w to 9w post CRT) and intermediate recovery (9w to 12m post CRT). The trajectories of all 4 classes were stable beyond 12m. The reference trajectory (HNSS4, n=74) score was 0.1 (CI 0.1-0.2) at BL, peaking at 4.6 (CI 4.2-5.0), with rapid early recovery (1.1, CI 0.8-2.2) and gradual improvement to 12m (0.6, CI 0.5-0.8). HNSS2 ("high BL", n=30) reported higher BL scores (1.4, CI 0.8-2.0) but was otherwise similar, HNSS3 ("low acute", n=53) reported reduced acute symptoms (2.5, CI 2.2-2.9) with stable scores beyond 9w post CRT (1.1, CI 0.9-1.4). HNSS1 ("slow recovery", n=25) had slower recovery from an acute peak of 4.9 (CI 4.3-5.6) to 0.9 (CI 0.6-1.3) at 12m. Compared to HNSS4, the high BL group were younger (mean 53.6 vs 57.4), with fewer ECOG0 (87 vs 99%) or with higher degree (38 vs 69%), and higher baseline anxiety (HADS, mean 6.8 vs 4.4). The low acute group were older (mean 60.1), had fewer ECOG0 patients (87%) and were more likely to have received cetuximab (68% vs 43%). The slow recovery group had fewer with a higher degree (52%). The HRQL model included 2 trajectory classes. The reference trajectory (HRQL2, n=156) scores were 90 (CI 88-92) at BL, similar 7w post CRT (88, CI 85-90) with slow but clinically meaningful improvement to 12m (98, CI 96-100). HRQL1 (n=26) had lower BL mean scores (80, CI 74-86), with a significant decline at 7w post CRT (57, CI 50-63) and a slower recovery to BL scores over 12m (83, CI 72-94). Both trajectories were flat beyond 12m. The slow recovery group were older (mean 61.1 vs 56.8), with worse BL anxiety (mean 6.5 vs 4.4) and depression (mean 4.5 vs 2.1). In addition, LCMM identified 4 trajectories for head and neck symptom interference, 3 for anxiety and 4 for depression, which will be presented. LCMM identified distinct trajectories of HNSS and HRQL during and after CRT. These and their associations with variations in HPVOPC patients' characteristics and treatment factors provide clinically relevant insights into identifying patients who may require increased support during and after CRT. [ABSTRACT FROM AUTHOR]

Background Human monkeypox is a zoonotic disease endemic to parts of Africa. Similar to other orthopoxviruses, virus and host have considerable interactions through immunomodulation. These interactions likely drive the establishment of a productive infection and disease progression, resulting in the range of disease presentations and case fatality rates observed for members of the Orthopoxvirus genus. Objectives Much of our understanding about the immune response to orthopoxvirus infection comes from either in vitro or in vivo studies performed in small animals or non-human primates. Here, we conducted a detailed assessment of cytokine responses to monkeypox virus using serum from acutely ill humans collected during monkeypox active disease surveillance (2005–2007) in the Democratic Republic of the Congo. Study design Nineteen serum samples that were from patients with confirmed monkeypox virus infections were selected for cytokine profiling. Cytokine profiling was performed on the Bio-Rad Bioplex 100 system using a 30-plex human cytokine panel. Results Cytokine profiling revealed elevated cytokine concentrations in all samples. Overproduction of certain cytokines (interleukin [IL]-2R, IL-10, and granulocyte macrophage-colony stimulating factor were observed in patients with serious disease (defined as >250 lesions based on the World Health Organization scoring system). Conclusions The data suggest that cytokine modulation affects monkeypox disease severity in humans. [ABSTRACT FROM AUTHOR]

Abstract: The interferon-inducible, double-stranded (ds)RNA-dependent protein kinase (PKR) plays a major role in antiviral defense mechanisms where it down-regulates translation via phosphorylation of eukaryotic translation initiation factor 2α. PKR is also involved in the activation of nuclear factor κB (NFκB) through activation of the IκB kinase complex. Activation of PKR can occur in the absence of dsRNA and in such case is controlled by intracellular regulators like the PKR-activating protein (PACT), the PKR inhibitor p58IPK, or heat-shock proteins (Hsp). These regulators are activated by stress stimuli, supporting a role for PKR in response to stress; however the final outcome of PKR activation in stress situations is unclear. We present here evidence that expression and activation of PKR contributes to an increased cellular resistance to mercury cytotoxicity. In two cell lines constitutively expressing PKR (THP-1 and Molt-3), treatment with the PKR inhibitor 2-aminopurine increases their sensitivity to mercury. In contrast, Ramos cells, which do not constitutively express PKR, present an increased resistance to mercury when PKR expression is induced by polyIC or interferon-β treatment. This protective effect is inhibited by 2-aminopurine. We also show that exposure of Ramos cells to mercury leads to the induction of Hsp70. Treatment of cells with Hsp70 or NFκB inhibitors suppresses the PKR-dependent protection. We propose a model where PKR, modulated by Hsp70, activates a NFκB-mediated protective pathway. Because the cytotoxicity of mercury is primarily due to the generation of reactive oxygen species, our results suggest a more general function of PKR in the mechanisms of cellular response to oxidative stress. [Copyright &y& Elsevier]