Beyond the Usual Suspects: Examining the Role of Understudied Histone Variants in Breast Cancer.

The incorporation of histone variants has structural ramifications on nucleosome dynamics and stability. Due to their unique sequences, histone variants can alter histone-histone or histone-DNA interactions, impacting the folding of DNA around the histone octamer and the overall higher-order structure of chromatin fibers. These structural modifications alter chromatin compaction and accessibility of DNA by transcription factors and other regulatory proteins to influence gene regulatory processes such as DNA damage and repair, as well as transcriptional activation or repression. Histone variants can also generate a unique interactome composed of histone chaperones and chromatin remodeling complexes. Any of these perturbations can contribute to cellular plasticity and the progression of human diseases. Here, we focus on a frequently overlooked group of histone variants lying within the four human histone gene clusters and their contribution to breast cancer.

B cells in the pneumococcus-infected lung are heterogeneous and require CD4+ T cell help including CD40L to become resident memory B cells.

Recovery from respiratory pneumococcal infections generates lung-localized protection against heterotypic bacteria, mediated by resident memory lymphocytes. Optimal protection in mice requires re-exposure to pneumococcus within days of initial infection. Serial surface marker phenotyping of B cell populations in a model of pneumococcal heterotypic immunity revealed that bacterial re-exposure stimulates the immediate accumulation of dynamic and heterogeneous populations of B cells in the lung, and is essential for the establishment of lung resident memory B (BRM) cells. The B cells in the early wave were activated, proliferating locally, and associated with both CD4+ T cells and CXCL13. Antagonist- and antibody-mediated interventions were implemented during this early timeframe to demonstrate that lymphocyte recirculation, CD4+ cells, and CD40 ligand (CD40L) signaling were all needed for lung BRM cell establishment, whereas CXCL13 signaling was not. While most prominent as aggregates in the loose connective tissue of bronchovascular bundles, morphometry and live lung imaging analyses showed that lung BRM cells were equally numerous as single cells dispersed throughout the alveolar septae. We propose that CD40L signaling from antigen-stimulated CD4+ T cells in the infected lung is critical to establishment of local BRM cells, which subsequently protect the airways and parenchyma against future potential infections.

Comparison of Gas Treatments of High Oxygen, Carbon Monoxide, and Nitric Oxide on Ground Beef Color in Modified Atmosphere Packaging.

The objective of this study was to evaluate the viability and performance of nitric oxide modified-atmosphere packaging (MAP) as a novel alternative to high oxygen and carbon monoxide MAP for ground beef. Packages of ground beef under high oxygen (HI-OX), carbon monoxide (CO), and nitric oxide (NO) atmospheres were evaluated for descriptive and instrumental color every 12 h during a 120 h display period. Surface myoglobin percentages, internal cooked color, thiobarbituric acid reactive substances (TBARS), and residual nitrite and nitrate were also evaluated. There were gas × time interactions for descriptive color, discoloration, a* values, b* values, deoxymyoglobin percentages, and metmyoglobin percentages (p < 0.05). There were also gas-type main effects for cooked color and TBARS (p < 0.05). Carbon monoxide maintained the most redness and least discoloration throughout the display period, while HI-OX started with a bright red color but rapidly browned (p < 0.05). Nitric oxide started as dark red to tannish-red but transitioned to a dull red (p < 0.05). However, NO had increased redness and a* values for internal cooked color (p < 0.05). Although CO outperformed NO packages, NO exhibited a unique color cycle warranting further research to optimize its use.

Green isolation of cellulosic materials from recycled pulp and paper sludge: a Box-Behnken design optimization.

Cellulose was isolated from recycled pulp and paper sludge and used to synthesize cellulose nanocrystals. Response surface methodology and Box-Behnken design model were used to predict, improve, and optimize the cellulose isolation process. The optimal conditions were a reaction temperature of 87.5 °C, 180 min with 4% sodium hydroxide. SEM and TEM results revealed that the isolated cellulose had long rod-like structures of different dimensions than CNCs with short rod-like structures. The crystallinity index from XRD significantly increased from 41.33%, 63.7%, and 75.6% for Kimberly mill pulp sludge (KMRPPS), chemically purified cellulose and cellulose nanocrystals, respectively. The TGA/DTG analysis showed that the isolated cellulosic materials possessed higher thermal stability. FTIR analysis suggested that the chemical structures of cellulose and CNCs were modified by chemical treatment. The cellulose surface was highly hydrophilic compared to the CNCs based on the high water holding capacity of 65.31 ± 0.98% and 83.14 ± 1.22%, respectively. The synthesized cellulosic materials portrayed excellent properties for high-end industrial applications like biomedical engineering, advanced materials, nanotechnology, sustainable packaging, personal care products, environmental remediation, additive manufacturing, etc.

A pragmatic, open-label, randomized controlled trial of Plasma-Lyte-148 versus standard intravenous fluids in children receiving kidney transplants (PLUTO).

Acute electrolyte and acid-base imbalance is experienced by many children following kidney transplant. This is partly because doctors give very large volumes of artificial fluids to keep the new kidney working. When severe, fluid imbalance can lead to seizures, cerebral edema and death. In this pragmatic, open-label, randomized controlled trial, we randomly assigned (1:1) pediatric kidney transplant recipients to Plasma-Lyte-148 or standard of care perioperative intravenous fluids (predominantly 0.45% sodium chloride and 0.9% sodium chloride solutions). We then compared clinically significant electrolyte and acid-base abnormalities in the first 72 hours post-transplant. The primary outcome, acute hyponatremia, was experienced by 53% of 68 participants in the Plasma-Lyte-148 group and 58% of 69 participants in the standard fluids group (odds ratio 0·77 (0·34 - 1·75)). Five of 16 secondary outcomes differed with Plasma-Lyte-148: hypernatremia was significantly more frequent (odds ratio 3·5 (1·1 - 10·8)), significantly fewer changes to fluid prescriptions were made (rate ratio 0·52 (0·40-0·67)), and significantly fewer participants experienced hyperchloremia (odds ratio 0·17 (0·07 - 0·40)), acidosis (odds ratio 0·09 (0·04 - 0·22)) and hypomagnesemia (odds ratio 0·21 (0·08 - 0·50)). No other secondary outcomes differed between groups. Serious adverse events were reported in 9% of participants randomized to Plasma-Lyte-148 and 7% of participants randomized to standard fluids. Thus, perioperative Plasma-Lyte-148 did not change the proportion of children who experienced acute hyponatremia compared to standard fluids. However fewer fluid prescription changes were made with Plasma-Lyte-148, while hyperchloremia and acidosis were less common.

GL7 ligand expression defines a novel subset of CD4+ TRM cells in lungs recovered from pneumococcus.

Streptococcus pneumoniae is the most common etiology of bacterial pneumonia, one of the leading causes of death in children and the elderly worldwide. During non-lethal infections with S. pneumoniae, lymphocytes accumulate in the lungs and protect against reinfection with serotype-mismatched strains. Cluster of differentiation CD4+ resident memory T (TRM) cells are known to be crucial for this protection, but the diversity of lung CD4+ TRM cells has yet to be fully delineated. We aimed to identify unique subsets and their contributions to lung immunity. After recovery from pneumococcal infections, we identified a distinct subset of CD4+ T cells defined by the phenotype CD11ahiCD69+GL7+ in mouse lungs. Phenotypic analyses for markers of lymphocyte memory and residence demonstrated that GL7+ T cells are a subset of CD4+ TRM cells. Functional studies revealed that unlike GL7- TRM subsets that were mostly (RAR-related Orphan Receptor gamma T) RORγT+, GL7+ TRM cells exhibited higher levels of (T-box expressed in T cells) T-bet and Gata-3, corresponding with increased synthesis of interferon-γ, interleukin-13, and interleukin-5, inherent to both T helper 1 (TH1) and TH2 functions. Thus, we propose that these cells provide novel contributions during pneumococcal pneumonia, serving as important determinants of lung immunity.

Involvement of cortical input to the rostromedial tegmental nucleus in aversion to foot shock.

The rostromedial tegmental nucleus (RMTg) encodes negative reward prediction error (RPE) and plays an important role in guiding behavioral responding to aversive stimuli. Previous research has focused on regulation of RMTg activity by the lateral habenula despite studies revealing RMTg afferents from other regions including the frontal cortex. The current study provides a detailed anatomical and functional analysis of cortical input to the RMTg of male rats. Retrograde tracing uncovered dense cortical input to the RMTg spanning the medial prefrontal cortex, the orbitofrontal cortex and anterior insular cortex. Afferents were most dense in the dorsomedial subregion of the PFC (dmPFC), an area that is also implicated in both RPE signaling and aversive responding. RMTg-projecting dmPFC neurons originate in layer V, are glutamatergic, and collateralize to select brain regions. In-situ mRNA hybridization revealed that neurons in this circuit are predominantly D1 receptor-expressing with a high degree of D2 receptor colocalization. Consistent with cFos induction in this neural circuit during exposure to foot shock and shock-predictive cues, optogenetic stimulation of dmPFC terminals in the RMTg drove avoidance. Lastly, acute slice electrophysiology and morphological studies revealed that exposure to repeated foot shock resulted in significant physiological and structural changes consistent with a loss of top-down modulation of RMTg-mediated signaling. Altogether, these data reveal the presence of a prominent cortico-subcortical projection involved in adaptive behavioral responding to aversive stimuli such as foot shock and provide a foundation for future work aimed at exploring alterations in circuit function in diseases characterized by deficits in cognitive control over reward and aversion.

Effects of Message Framing and Information Source on Consumers' Attitudes toward an Amino Acid-Based Alternative Meat Curing System.

Recently, meat scientists have developed an innovative amino acid-based alternative meat curing system (AAACS). However, consumer skepticism toward novel foods presents challenges regarding the acceptance of food innovations like the AAACS. Effective communication about this and other food technologies is critical. Our study was a 2 × 4 randomized factorial between-groups experiment that investigated how two peripheral cues-message frame and information source-impact attitudes toward the AAACS. We used Qualtrics to randomly assign participants to one of eight treatment groups. Each group viewed a different video about the AAACS. Then, all participants were asked about their attitudes toward the alternative meat curing system. Data were analyzed using a two-way multivariate analysis of variance (MANOVA). The two-way MANOVA determined concurrently the experimental effects of message frame and information source on information recall, trust, source expertise, source credibility, and anticipated consumption behavior. A significant MANOVA was followed up using Discriminant Function Analysis (DFA). A significant main effect was found for information source. The DFA revealed only one significant underlying function and that source expertise was the most powerful discriminating variable for information source.

Epigenomic reprogramming in iAs-mediated carcinogenesis.

Arsenic is a naturally occurring metal carcinogen found in the Earth's crust. Millions of people worldwide are chronically exposed to arsenic through drinking water and food. Exposure to inorganic arsenic has been implicated in many diseases ranging from acute toxicities to malignant transformations. Despite the well-known deleterious health effects of arsenic exposure, the molecular mechanisms in arsenic-mediated carcinogenesis are not fully understood. Since arsenic is non-mutagenic, the mechanism by which arsenic causes carcinogenesis is via alterations in epigenetic-regulated gene expression. There are two possible ways by which arsenic may modify the epigenome-indirectly through an arsenic-induced generation of reactive oxygen species which then impacts chromatin remodelers, or directly through interaction and modulation of chromatin remodelers. Whether directly or indirectly, arsenic modulates epigenetic gene regulation and our understanding of the direct effect of this modulation on chromatin structure is limited. In this chapter we will discuss the various ways by which inorganic arsenic affects the epigenome with consequences in health and disease.

Prospective Cohort Study Comparing Ligament Reconstruction with Tendon Interposition and Suture-Only Suspension Arthroplasty.

BACKGROUND: Basal joint arthritis is a common form of osteoarthritis. There is no consensus procedure for maintenance of trapezial height following trapeziectomy. Suture-only suspension arthroplasty (SSA) is a simple method for stabilizing the thumb metacarpal following trapeziectomy. METHODS: This single-institution, prospective, cohort study compares trapeziectomy followed by either ligament reconstruction with tendon interposition (LRTI) or SSA for the treatment of basal joint arthritis. Patients underwent LRTI or SSA from May of 2018 to December of 2019. Visual analogue scale pain scores; Disabilities of the Arm, Shoulder and Hand questionnaire functional scores; clinical thumb range of motion, pinch, and grip strength data; and patient-reported outcomes were recorded and analyzed preoperatively and at 6 weeks and 6 months postoperatively. RESULTS: Total number of study participants was 45 (LRTI, n = 26; SSA, n = 19). Mean ± SE age was 62.4 ± 1.5 years; 71% were female patients; and 51% underwent surgery on the dominant side. Visual analogue scale scores improved for LRTI and SSA ( P < 0.0001) over 6 months, with no differences between groups at any time point ( P > 0.3). Disabilities of the Arm, Shoulder and Hand questionnaire scores improved for LRTI and SSA over 6 months ( P < 0.0001), with no differences between groups at any time point ( P > 0.3). Following SSA, opposition improved ( P = 0.02), but not as well for LRTI ( P = 0.16). Grip and pinch strength decreased following LRTI and SSA at 6 weeks but recovered similarly for both groups over 6 months. Patient-reported outcomes were generally no different between groups at all time points. CONCLUSION: LRTI and SSA are similar procedures following trapeziectomy relative to pain, function, and strength recovery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Resection of an oropharyngeal venous malformation.

BACKGROUND: Venous malformations (VMs) are congenital vascular lesions caused by enlarged and ectatic venous channels. Current methods of treatment for VMs involve a combination of sclerotherapy, laser therapy, and surgical resection. While sclerotherapy remains the most commonly used treatment for small VMs, surgery remains an important tool for isolated VMs or larger VMs with higher flow due to potential local and systemic side effects associated with the use of certain sclerosing agents. METHODS/RESULTS: Here we present a case of a patient with a naso- and oropharyngeal venous malformation which was successfully resected with endoscopic-assisted transoral surgery. CONCLUSIONS: This is a low-fingerprint technique to tumors of the oropharynx with excellent visualization and maneuverability in cases where TORS is not an option. This technique does not require palate splitting or excessive retraction, allows multiple surgeons to work simultaneously, and is associated with significantly lower morbidity than transcervical techniques. LEVEL OF EVIDENCE: N/A.

Molecular and spatial heterogeneity of microglia in Rasmussen encephalitis.

Rasmussen encephalitis (RE) is a rare childhood neurological disease characterized by progressive unilateral loss of function, hemispheric atrophy and drug-resistant epilepsy. Affected brain tissue shows signs of infiltrating cytotoxic T-cells, microglial activation, and neuronal death, implicating an inflammatory disease process. Recent studies have identified molecular correlates of inflammation in RE, but cell-type-specific mechanisms remain unclear. We used single-nucleus RNA-sequencing (snRNA-seq) to assess gene expression across multiple cell types in brain tissue resected from two children with RE. We found transcriptionally distinct microglial populations enriched in RE compared to two age-matched individuals with unaffected brain tissue and two individuals with Type I focal cortical dysplasia (FCD). Specifically, microglia in RE tissues demonstrated increased expression of genes associated with cytokine signaling, interferon-mediated pathways, and T-cell activation. We extended these findings using spatial proteomic analysis of tissue from four surgical resections to examine expression profiles of microglia within their pathological context. Microglia that were spatially aggregated into nodules had increased expression of dynamic immune regulatory markers (PD-L1, CD14, CD11c), T-cell activation markers (CD40, CD80) and were physically located near distinct CD4+ and CD8+ lymphocyte populations. These findings help elucidate the complex immune microenvironment of RE.

Unsupervised pattern-recognition and radiological risk assessment applied to the evaluation of behavior of rare earth elements, Th, and U in monazite sand.

The Brazilian coast is rich in monazite which is found in beach sand deposits. In this study, the composition of the monazite sands from beaches of State of Espírito Santo, Brazil, was investigated. The concentrations of rare earth elements (REEs), Th, and U were determined by inductively coupled plasma mass spectrometry (ICP-MS). In the studied region, the mean concentration of investigated elements increased in the following order: Tm < Yb < Ho < Lu < Eu < Er < Tb < Dy < U < Y < Th < Gd < Sm < Pr < Nd < La < Ce. The sampling sites were classified into three clusters and discriminated by the concentrations of REEs, Th, and U found. In general, the radiological risk indices were higher than the established limits, and the risk of developing cancer was estimated to be higher than the world average.

Reassessing the Value of CSF Protein and Glucose Measurement in Pediatric Infectious Meningitis.

OBJECTIVES: Infectious meningitis (IM) in US children is increasingly rare and new rapid multiplex PCR-based testing is increasingly available. We evaluated the added value of cerebrospinal fluid (CSF) protein and glucose tests to predict IM when compared with information provided by CSF white blood cell count (WBC) and multiplex polymerase chain reaction (PCR). METHODS: We retrospectively reviewed CSF results from October 2015 to August 2017 in patients 0 to 18 years at a US children's hospital. Noninfectious evaluations were excluded. Test characteristics were calculated for CSF WBC, protein, and glucose in isolation and in parallel for prediction of microbiologically confirmed IM. Chart review was performed to identify consideration of protein and glucose in medical decision-making (MDM). RESULTS: We identified 735 patients including 446 <2 months; 45 (6.1%) had microbiologically-confirmed IM, including 23 (5.2%) age <2 months. Multiplex PCR and/or CSF WBC identified all IM patients. When added to CSF WBC, measurement of glucose made no contribution to sensitivity, specificity, positive predictive value (PPV) or negative predictive value (NPV), and protein had no impact on sensitivity and decreased the specificity, PPV, and NPV compared with CSF WBC alone. Abnormal protein was documented in MDM in 6 (0.8%) patients, all of whom had elevated WBC counts also cited. Glucose was not mentioned in MDM. CONCLUSIONS: Multiplex PCR testing and WBC may be sufficient to predict meningitis in children in low incidence settings. Protein and glucose did not contribute significant additional information. More intentional use of protein and glucose testing in patients with suspected IM may achieve higher value care.

Recruitment and training of alveolar macrophages after pneumococcal pneumonia.

Recovery from pneumococcal pneumonia remodels the pool of alveolar macrophages so that they exhibit new surface marker profiles, transcriptomes, metabolomes, and responses to infection. Mechanisms mediating alveolar macrophage phenotypes after pneumococcal pneumonia have not been delineated. IFN-γ and its receptor on alveolar macrophages were essential for certain, but not all, aspects of the remodeled alveolar macrophage phenotype. IFN-γ was produced by CD4+ T cells plus other cells, and CD4+ cell depletion did not prevent alveolar macrophage remodeling. In mice infected or recovering from pneumococcus, monocytes were recruited to the lungs, and the monocyte-derived macrophages developed characteristics of alveolar macrophages. CCR2 mediated the early monocyte recruitment but was not essential to the development of the remodeled alveolar macrophage phenotype. Lineage tracing demonstrated that recovery from pneumococcal pneumonias converted the pool of alveolar macrophages from being primarily of embryonic origin to being primarily of adult hematopoietic stem cell origin. Alveolar macrophages of either origin demonstrated similar remodeled phenotypes, suggesting that ontogeny did not dictate phenotype. Our data reveal that the remodeled alveolar macrophage phenotype in lungs recovered from pneumococcal pneumonia results from a combination of new recruitment plus training of both the original cells and the new recruits.

Climatic and soil factors explain the two-dimensional spectrum of global plant trait variation.

Plant functional traits can predict community assembly and ecosystem functioning and are thus widely used in global models of vegetation dynamics and land-climate feedbacks. Still, we lack a global understanding of how land and climate affect plant traits. A previous global analysis of six traits observed two main axes of variation: (1) size variation at the organ and plant level and (2) leaf economics balancing leaf persistence against plant growth potential. The orthogonality of these two axes suggests they are differently influenced by environmental drivers. We find that these axes persist in a global dataset of 17 traits across more than 20,000 species. We find a dominant joint effect of climate and soil on trait variation. Additional independent climate effects are also observed across most traits, whereas independent soil effects are almost exclusively observed for economics traits. Variation in size traits correlates well with a latitudinal gradient related to water or energy limitation. In contrast, variation in economics traits is better explained by interactions of climate with soil fertility. These findings have the potential to improve our understanding of biodiversity patterns and our predictions of climate change impacts on biogeochemical cycles.

Comparison of trace element mobility from MSWI ash before and after plasma vitrification.

A common perception of plasma arc treatment systems for municipal solid waste incineration ash is that the resulting vitrified slag is inert from an environmental perspective. Research was conducted to examine this hypothesis and to assess whether reduced pollutant release results from pollutant depletion during the process of the ash with plasma, or encapsulation in the glassy vitrified matrix. The concentrations of four discrete municipal solid waste incineration ash samples before and after plasma arc vitrification in a bench-scale unit were compared. Slag and untreated ash samples were leached using several standardized approaches and mobility among the four metals of interest (e.g. As, Cd, Pb and Sb) varied across samples, but was generally high (as high as 100% for Cd). Comparison across methods did not indicate substantial encapsulation in the vitrified slag, which suggests that reduced pollutant release from plasma arc vitrified slag is due to pollutant depletion by volatilization, not encapsulation. This has significant implications for the management of air pollution control residues from waste-to-energy facilities using plasma arc vitrification.

Antigen presentation by lung epithelial cells directs CD4+ TRM cell function and regulates barrier immunity.

Barrier tissues are populated by functionally plastic CD4+ resident memory T (TRM) cells. Whether the barrier epithelium regulates CD4+ TRM cell locations, plasticity and activities remains unclear. Here we report that lung epithelial cells, including distinct surfactant protein C (SPC)lowMHChigh epithelial cells, function as anatomically-segregated and temporally-dynamic antigen presenting cells. In vivo ablation of lung epithelial MHC-II results in altered localization of CD4+ TRM cells. Recurrent encounters with cognate antigen in the absence of epithelial MHC-II leads CD4+ TRM cells to co-express several classically antagonistic lineage-defining transcription factors, changes their cytokine profiles, and results in dysregulated barrier immunity. In addition, lung epithelial MHC-II is needed for surface expression of PD-L1, which engages its ligand PD-1 to constrain lung CD4+ TRM cell phenotypes. Thus, we establish epithelial antigen presentation as a critical regulator of CD4+ TRM cell function and identify epithelial-CD4+ TRM cell immune interactions as core elements of barrier immunity.

Lung-resident memory B cells protect against bacterial pneumonia.

Lung-resident memory B cells (BRM cells) are elicited after influenza infections of mice, but connections to other pathogens and hosts - as well as their functional significance - have yet to be determined. We postulate that BRM cells are core components of lung immunity. To test this, we examined whether lung BRM cells are elicited by the respiratory pathogen pneumococcus, are present in humans, and are important in pneumonia defense. Lungs of mice that had recovered from pneumococcal infections did not contain organized tertiary lymphoid organs, but did have plasma cells and noncirculating memory B cells. The latter expressed distinctive surface markers (including CD69, PD-L2, CD80, and CD73) and were poised to secrete antibodies upon stimulation. Human lungs also contained B cells with a resident memory phenotype. In mice recovered from pneumococcal pneumonia, depletion of PD-L2+ B cells, including lung BRM cells, diminished bacterial clearance and the level of pneumococcus-reactive antibodies in the lung. These data define lung BRM cells as a common feature of pathogen-experienced lungs and provide direct evidence of a role for these cells in pulmonary antibacterial immunity.

Arsenic-induced epigenetic changes in cancer development.

Arsenic is a ubiquitous metalloid whose high levels of toxicity pose major health concerns to millions of people worldwide by increasing susceptibility to various cancers and non-cancer illnesses. Since arsenic is not a mutagen, the mechanism by which it causes changes in gene expression and disease pathogenesis is not clear. One possible mechanism is through generation of reactive oxygen species. Another equally important mechanism still very much in its infancy is epigenetic dysregulation. In this review, we discuss recent discoveries underlying arsenic-induced epigenetic changes in cancer development. Importantly, we highlight the proposed mechanisms targeted by arsenic to drive oncogenic gene expression.