Modeling Structure-Building in the Brain With CCG Parsing and Large Language Models.

To model behavioral and neural correlates of language comprehension in naturalistic environments, researchers have turned to broad-coverage tools from natural-language processing and machine learning. Where syntactic structure is explicitly modeled, prior work has relied predominantly on context-free grammars (CFGs), yet such formalisms are not sufficiently expressive for human languages. Combinatory categorial grammars (CCGs) are sufficiently expressive directly compositional models of grammar with flexible constituency that affords incremental interpretation. In this work, we evaluate whether a more expressive CCG provides a better model than a CFG for human neural signals collected with functional magnetic resonance imaging (fMRI) while participants listen to an audiobook story. We further test between variants of CCG that differ in how they handle optional adjuncts. These evaluations are carried out against a baseline that includes estimates of next-word predictability from a transformer neural network language model. Such a comparison reveals unique contributions of CCG structure-building predominantly in the left posterior temporal lobe: CCG-derived measures offer a superior fit to neural signals compared to those derived from a CFG. These effects are spatially distinct from bilateral superior temporal effects that are unique to predictability. Neural effects for structure-building are thus separable from predictability during naturalistic listening, and those effects are best characterized by a grammar whose expressive power is motivated on independent linguistic grounds.

Beneficial modulation of human health in the oral cavity and beyond using bacteriocin-like inhibitory substance-producing streptococcal probiotics.

The human oral cavity contains a diversity of microbial habitats that have been adopted and adapted to as homeland by an amazingly heterogeneous population of microorganisms collectively referred to as the oral microbiota. These microbes generally co-habit in harmonious homeostasis. However, under conditions of imposed stress, as with changes to the host's physiology or nutritional status, or as a response to foreign microbial or antimicrobial incursions, some components of the oral "microbiome" (viz. the in situ microbiota) may enter a dysbiotic state. This microbiome dysbiosis can manifest in a variety of guises including streptococcal sore throats, dental caries, oral thrush, halitosis and periodontal disease. Most of the strategies currently available for the management or treatment of microbial diseases of the oral cavity focus on the repetitive "broad sweep" and short-term culling of oral microbe populations, hopefully including the perceived principal pathogens. Both physical and chemical techniques are used. However, the application of more focused approaches to the harnessing or elimination of key oral cavity pathogens is now feasible through the use of probiotic strains that are naturally adapted for oral cavity colonization and also are equipped to produce anti-competitor molecules such as the bacteriocins and bacteriocin-like inhibitory substances (viz BLIS). Some of these probiotics are capable of suppressing the proliferation of a variety of recognized microbial pathogens of the human mouth, thereby assisting with the restoration of oral microbiome homeostasis. BLIS K12 and BLIS M18, the progenitors of the BLIS-producing oral probiotics, are members of the human oral cavity commensal species Streptococcus salivarius. More recently however, a number of other streptococcal and some non-streptococcal candidate oral probiotics have also been promoted. What is becoming increasingly apparent is that the future for oral probiotic applications will probably extend well beyond the attempted limitation of the direct pathological consequences of oral microbiome dysbiosis to also encompass a plethora of systemic diseases and disorders of the human host. The background to and the evolving prospects for the beneficial modulation of the oral microbiome via the application of BLIS-producing S. salivarius probiotics comprises the principal focus of the present review.

A Case Report of Rotational Thromboelastometry-Assisted Decision Analysis for Two Pregnant Patients With Platelet Storage Pool Disorder.

Platelet storage pool disorders (PSPDs) constitute a diverse group of hematologic abnormalities, which share the common feature of a deficiency in the ability of platelets to aggregate. Parturients with PSPD can present management challenges to their care team when they present for childbirth, especially with regard to neuraxial anesthesia. We report a series of 2 deliveries from unrelated patients affected by PSPD. In particular, we highlight the utility of rotational thromboelastometry (ROTEM) and the need for a multidisciplinary approach to the care of patients with this hematologic abnormality.

Interferon Gamma Response in Human Saliva Following Exposure to the Oral Probiotic Streptococcus salivarius BLIS K12.

Streptococcus salivarius BLIS K12 is a probiotic strain developed for application to the oral cavity. The strain was originally characterised for its in vitro antibacterial activity against the prominent oral pathogen Streptococcus pyogenes. More recent research has expanded its applications to include reducing halitosis, preventing otitis media and protecting against virus infections of the respiratory tract. A potential mechanism for this anti-viral activity could be the stimulation of salivary interferon gamma (IFN-γ) production in the oral cavity. The aim of this study was to investigate whether the ingestion of and oral cavity colonisation by S. salivarius BLIS K12 is associated with enhancement of IFN-γ levels in saliva. Application of ELISA demonstrated that consumption of S. salivarius BLIS K12 effected an increase in salivary IFN-γ, and this response was more consistent with use of viable cells than following ingestion of heat-killed S. salivarius BLIS K12. Interestingly, those subjects who more successfully colonised with S. salivarius BLIS K12 did not experience a relatively larger increase in their IFN-γ levels, indicating that the observed IFN-γ response occurs independently of colonisation efficacy. In summary, the consumption of S. salivarius BLIS K12 increases salivary levels of IFN-γ, an effect that may contribute to protection of the host against certain virus infections.

Le Petit Prince multilingual naturalistic fMRI corpus.

Neuroimaging using more ecologically valid stimuli such as audiobooks has advanced our understanding of natural language comprehension in the brain. However, prior naturalistic stimuli have typically been restricted to a single language, which limited generalizability beyond small typological domains. Here we present the Le Petit Prince fMRI Corpus (LPPC-fMRI), a multilingual resource for research in the cognitive neuroscience of speech and language during naturalistic listening (OpenNeuro: ds003643). 49 English speakers, 35 Chinese speakers and 28 French speakers listened to the same audiobook The Little Prince in their native language while multi-echo functional magnetic resonance imaging was acquired. We also provide time-aligned speech annotation and word-by-word predictors obtained using natural language processing tools. The resulting timeseries data are shown to be of high quality with good temporal signal-to-noise ratio and high inter-subject correlation. Data-driven functional analyses provide further evidence of data quality. This annotated, multilingual fMRI dataset facilitates future re-analysis that addresses cross-linguistic commonalities and differences in the neural substrate of language processing on multiple perceptual and linguistic levels.

Neural correlates of semantic number: A cross-linguistic investigation.

One aspect of natural language comprehension is understanding how many of what or whom a speaker is referring to. While previous work has documented the neural correlates of number comprehension and quantity comparison, this study investigates semantic number from a cross-linguistic perspective with the goal of identifying cortical regions involved in distinguishing plural from singular nouns. Three fMRI datasets are used in which Chinese, French, and English native speakers listen to an audiobook of a children's story in their native language. These languages are selected because they differ in their number semantics. Across these languages, several well-known language regions manifest a contrast between plural and singular, including the pars orbitalis, pars triangularis, posterior temporal lobe, and dorsomedial prefrontal cortex. This is consistent with a common brain network supporting comprehension across languages with overt as well as covert number-marking.

HMGB1-mediated restriction of EPO signaling contributes to anemia of inflammation.

Anemia of inflammation, also known as anemia of chronic disease, is refractory to erythropoietin (EPO) treatment, but the mechanisms underlying the EPO refractory state are unclear. Here, we demonstrate that high mobility group box-1 protein (HMGB1), a damage-associated molecular pattern molecule recently implicated in anemia development during sepsis, leads to reduced expansion and increased death of EPO-sensitive erythroid precursors in human models of erythropoiesis. HMGB1 significantly attenuates EPO-mediated phosphorylation of the Janus kinase 2/STAT5 and mTOR signaling pathways. Genetic ablation of receptor for advanced glycation end products, the only known HMGB1 receptor expressed by erythroid precursors, does not rescue the deleterious effects of HMGB1 on EPO signaling, either in human or murine precursors. Furthermore, surface plasmon resonance studies highlight the ability of HMGB1 to interfere with the binding between EPO and the EPOR. Administration of a monoclonal anti-HMGB1 antibody after sepsis onset in mice partially restores EPO signaling in vivo. Thus, HMGB1-mediated restriction of EPO signaling contributes to the chronic phase of anemia of inflammation.

Skin Microbiome-The Next Frontier for Probiotic Intervention.

The skin is the largest organ in the human body, and it orchestrates many functions that are fundamentally important for our survival. Although the skin might appear to present a relatively inhospitable or even hostile environment, a multitude of commensals and also some potentially pathogenic microorganisms have successfully adapted to survive and/or thrive within the diverse ecological niches created by the skin's topographical architecture. Dysbiosis within these microbial populations can result in the emergence and pathological progression of skin diseases. Unsurprisingly, this has led to a new focus of research both for the medical dermatology and cosmetic industries that is concerned with modulation of the skin microbiome to help address common microbially mediated or modulated conditions such as acne, body odour, and atopic dermatitis. This review presents an overview of our current understanding of the complex relationship of the skin with its microbiome and then introduces the concept of probiotic intervention for the management of microbial dysbiosis within the skin ecosystem.

Decoding the silence: Neural bases of zero pronoun resolution in Chinese.

Chinese is one of many languages that can drop subjects. We report an fMRI study of language comprehension processes in these "zero pronoun" cases. The fMRI data come from Chinese speakers who listened to an audiobook. We conducted both univariate GLM and multivariate pattern analysis (MVPA) on these data. We found increased left Temporal Lobe activity for zero pronouns compared to overt subjects, suggesting additional effort searching for an antecedent during zero pronoun resolution. MVPA further revealed that the intended referent of a zero pronoun can be decoded in the Parahippocampal Gyrus and the Precuneus shortly after its presentation. This highlights the role of memory and discourse-level processing in resolving referential expressions, including unspoken ones, in naturalistic language comprehension.

αI-spectrin represents evolutionary optimization of spectrin for red blood cell deformability.

Spectrin tetramers of the membranes of enucleated mammalian erythrocytes play a critical role in red blood cell survival in circulation. One of the spectrins, αI, emerged in mammals with enucleated red cells after duplication of the ancestral α-spectrin gene common to all animals. The neofunctionalized αI-spectrin has moderate affinity for ßI-spectrin, whereas αII-spectrin, expressed in nonerythroid cells, retains ancestral characteristics and has a 10-fold higher affinity for ßI-spectrin. It has been hypothesized that this adaptation allows for rapid make and break of tetramers to accommodate membrane deformation. We have tested this hypothesis by generating mice with high-affinity spectrin tetramers formed by exchanging the site of tetramer formation in αI-spectrin (segments R0 and R1) for that of αII-spectrin. Erythrocytes with αIIßI presented normal hematologic parameters yet showed increased thermostability, and their membranes were significantly less deformable; under low shear forces, they displayed tumbling behavior rather than tank treading. The membrane skeleton is more stable with αIIßI and shows significantly less remodeling under deformation than red cell membranes of wild-type mice. These data demonstrate that spectrin tetramers undergo remodeling in intact erythrocytes and that this is required for the normal deformability of the erythrocyte membrane. We conclude that αI-spectrin represents evolutionary optimization of tetramer formation: neither higher-affinity tetramers (as shown here) nor lower affinity (as seen in hemolytic disease) can support the membrane properties required for effective tissue oxygenation in circulation.

Human Systemic Immune Response to Ingestion of the Oral Probiotic Streptococcus salivarius BLIS K12.

Streptococcus salivarius K12 is an oral probiotic known to contribute to protection against oral pathogenic bacteria in humans. Studies of immune responses to S. salivarius K12 have focused on the oral cavity, and systemic immune responses have not yet been reported. The aim of this study was to identify acute systemic immune responses to the commercial product, S. salivarius BLIS K12, in a double-blinded, placebo-controlled human clinical trial. It was hypothesised that consumption of S. salivarius BLIS K12 would induce an anti-inflammatory response and a decrease in pro-inflammatory cytokines. Blood samples were obtained from participants prior to a single dose of S. salivarius BLIS K12 or a placebo and then secondary blood samples were obtained 24 h and 7 days post-consumption. Samples were analysed using multi-parametric flow cytometry, to quantify immune cell frequency changes, and by a LEGENDplex assay of human inflammatory cytokines. Consumption of S. salivarius BLIS K12 was associated with increased levels of IL-8 at 24 h. The frequency of Tregs increased in samples taken 7 days after probiotic consumption, and IL-10 concentrations were higher at 7 days than 24 h after consumption. There was no difference in the frequency and/or activation of CD4+ T cells, CD8+ T cells, B cells and NK cells. Interestingly, there was an increase in IL-12, 7 days after the consumption of S. salivarius BLIS K12. Collectively, this research demonstrates that ingestion of the probiotic S. salivarius K12 can induce changes in the systemic immune response. The implications of the generation and type of immune response warrant further study to determine potential health benefits.

Comprehensive phenotyping of erythropoiesis in human bone marrow: Evaluation of normal and ineffective erythropoiesis.

Identification of stage-specific erythroid cells is critical for studies of normal and disordered human erythropoiesis. While immunophenotypic strategies have previously been developed to identify cells at each stage of terminal erythroid differentiation, erythroid progenitors are currently defined very broadly. Refined strategies to identify and characterize BFU-E and CFU-E subsets are critically needed. To address this unmet need, a flow cytometry-based technique was developed that combines the established surface markers CD34 and CD36 with CD117, CD71, and CD105. This combination allowed for the separation of erythroid progenitor cells into four discrete populations along a continuum of progressive maturation, with increasing cell size and decreasing nuclear/cytoplasmic ratio, proliferative capacity and stem cell factor responsiveness. This strategy was validated in uncultured, primary erythroid cells isolated from bone marrow of healthy individuals. Functional colony assays of these progenitor populations revealed enrichment of BFU-E only in the earliest population, transitioning to cells yielding BFU-E and CFU-E, then CFU-E only. Utilizing CD34/CD105 and GPA/CD105 profiles, all four progenitor stages and all five stages of terminal erythroid differentiation could be identified. Applying this immunophenotyping strategy to primary bone marrow cells from patients with myelodysplastic syndrome, identified defects in erythroid progenitors and in terminal erythroid differentiation. This novel immunophenotyping technique will be a valuable tool for studies of normal and perturbed human erythropoiesis. It will allow for the discovery of stage-specific molecular and functional insights into normal erythropoiesis as well as for identification and characterization of stage-specific defects in inherited and acquired disorders of erythropoiesis.

Quantifying Structural and Non-structural Expectations in Relative Clause Processing.

Information-theoretic complexity metrics, such as Surprisal (Hale, 2001; Levy, 2008) and Entropy Reduction (Hale, 2003), are linking hypotheses that bridge theorized expectations about sentences and observed processing difficulty in comprehension. These expectations can be viewed as syntactic derivations constrained by a grammar. However, this expectation-based view is not limited to syntactic information alone. The present study combines structural and non-structural information in unified models of word-by-word sentence processing difficulty. Using probabilistic minimalist grammars (Stabler, 1997), we extend expectation-based models to include frequency information about noun phrase animacy. Entropy reductions derived from these grammars faithfully reflect the asymmetry between subject and object relatives (Staub, 2010; Staub, Dillon, & Clifton, 2017), as well as the effect of animacy on the measured difficulty profile (Lowder & Gordon, 2012; Traxler, Morris, & Seely, 2002). Visualizing probability distributions on the remaining alternatives at particular parser states allows us to explore new, linguistically plausible interpretations for the observed processing asymmetries, including the way that expectations about the relativized argument influence the processing of particular types of relative clauses (Wagers & Pendleton, 2016).

In vitro Inhibition of Clinical Isolates of Otitis Media Pathogens by the Probiotic Streptococcus salivarius BLIS K12.

Otitis media is a common childhood infection, frequently requiring antibiotics. With high rates of antibiotic prescribing and increasing antibiotic resistance, new strategies in otitis media prevention and treatment are needed. The aim of this study was to assess the in vitro inhibitory activity Streptococcus salivarius BLIS K12 against otitis media pathogens. Efficacy of the bacteriocin activity of S. salivarius BLIS K12 against the otitis media isolates was assessed using the deferred antagonism test. Overall, 48% of pathogenic isolates exhibited some growth inhibition by S. salivarius BLIS K12. S. salivarius BLIS K12 can inhibit the in vitro growth of the most common pathogens.

Warm-season annual forages in forage-finishing beef systems: II. Animal performance and carcass characteristics.

More information on expected animal performance and carcass traits of forage-finished steers grazing warm-season annual forages is needed. To achieve this objective, a grazing trial was conducted in 2014, 2015, and 2016 (70, 63, and 56 d, respectively), with variation in length of grazing based on forage availability. Sixteen pastures (0.81 ha) were assigned to 1 of 4 forage treatments in a randomized complete block design. Forage treatments were brown midrib sorghum × sudangrass (BMR; Sorghum bicolor var. bicolor*bicolor var. sudanense), sorghum × sudangrass (SS), pearl millet [PM; Pennisetum glaucum (L.)R.Br.], or pearl millet planted with crabgrass [PMCG; Digitaria sanguinalis (L.) Scop.]. Each year, British-cross beef steers (n = 32; 3 y average: 429 ± 22 kg) were stratified by weight and randomly assigned to 1 of the 16 pastures for forage finishing. Each pasture was subdivided into two 0.405-ha paddocks for rotational stocking and a put-and-take stocking method was used to maintain a forage allowance of 116 kg forage dry matter/100 kg body weight (BW). Shrunk body weight and ultrasonically measured carcass composition were recorded at the initiation, middle, and end of each grazing season. Steers were harvested once forage availability became limited and chilled carcasses (24 h) were evaluated for yield grade and quality grade attributes. Statistical analysis was conducted using the GLIMMIX procedure in SAS 9.4 (Cary, NC) with main effects of treatment, year, and the interaction. Pasture and block were considered random effects while date was assessed as a main effect when applicable. Daily stocking densities were greater (P < 0.04) for SS than PMCG in the first 20 d of 2014 and 2015. Forage treatment did not affect (P > 0.17) total gain, total average daily gain, or body weight at any time point. Ultrasound composition traits of loin muscle area, 12th rib fat thickness, intramuscular fat, and rump fat were impacted (P < 0.01) by scanning date. No differences (P > 0.08) in forage treatments were observed for carcass characteristics associated with yield grade or quality grade. The findings suggest that forage-finished cattle during the summer months on BMR, SS, PM, and PMCG perform similarly, giving producers the option to use the most economical or practical forage type for their production system.

Localizing syntactic predictions using recurrent neural network grammars.

Brain activity in numerous perisylvian brain regions is modulated by the expectedness of linguistic stimuli. We leverage recent advances in computational parsing models to test what representations guide the processes reflected by this activity. Recurrent Neural Network Grammars (RNNGs) are generative models of (tree, string) pairs that use neural networks to drive derivational choices. Parsing with them yields a variety of incremental complexity metrics that we evaluate against a publicly available fMRI data-set recorded while participants simply listen to an audiobook story. Surprisal, which captures a word's un-expectedness, correlates with a wide range of temporal and frontal regions when it is calculated based on word-sequence information using a top-performing LSTM neural network language model. The explicit encoding of hierarchy afforded by the RNNG additionally captures activity in left posterior temporal areas. A separate metric tracking the number of derivational steps taken between words correlates with activity in the left temporal lobe and inferior frontal gyrus. This pattern of results narrows down the kinds of linguistic representations at play during predictive processing across the brain's language network.

Steroid resistance in Diamond Blackfan anemia associates with p57Kip2 dysregulation in erythroid progenitors.

Despite the effective clinical use of steroids for the treatment of Diamond Blackfan anemia (DBA), the mechanisms through which glucocorticoids regulate human erythropoiesis remain poorly understood. We report that the sensitivity of erythroid differentiation to dexamethasone is dependent on the developmental origin of human CD34+ progenitor cells, specifically increasing the expansion of CD34+ progenitors from peripheral blood (PB) but not cord blood (CB). Dexamethasone treatment of erythroid-differentiated PB, but not CB, CD34+ progenitors resulted in the expansion of a newly defined CD34+CD36+CD71hiCD105med immature colony-forming unit-erythroid (CFU-E) population. Furthermore, proteomics analyses revealed the induction of distinct proteins in dexamethasone-treated PB and CB erythroid progenitors. Dexamethasone treatment of PB progenitors resulted in the specific upregulation of p57Kip2, a Cip/Kip cyclin-dependent kinase inhibitor, and we identified this induction as critical; shRNA-mediated downregulation of p57Kip2, but not the related p27Kip1, significantly attenuated the impact of dexamethasone on erythroid differentiation and inhibited the expansion of the immature CFU-E subset. Notably, in the context of DBA, we found that steroid resistance was associated with dysregulated p57Kip2 expression. Altogether, these data identify a unique glucocorticoid-responsive human erythroid progenitor and provide new insights into glucocorticoid-based therapeutic strategies for the treatment of patients with DBA.

A TaqMan™-based quantitative PCR screening assay for the probiotic Streptococcus salivarius K12 based on the specific detection of its megaplasmid-associated salivaricin B locus.

In order to assess the colonization efficacy of the oral probiotic Streptococcus salivarius K12, a rapid method for specific detection and enumeration of the strain was developed. Here, we describe a two-step TaqMan™ quantitative PCR assay using primer-probe combinations targeting genes of the locus encoding the lantibiotic bacteriocin salivaricin B.

Bacterial survival and adhesion for formulating new oral probiotic foods.

Probiotics are defined as live microorganisms, which, when administered in adequate amounts, confer health benefits to the host. Traditionally, probiotic food research has heavily focused on the genera Bifidobacteria and Lactobacilli, along with their benefits for gut health. Recently with the identification of new probiotic strains specifically intended for oral health applications, the development of probiotic foods for oral health benefits has garnered interest, with a renewed focus on identifying new food formats for delivering probiotics. The development of novel oral probiotic foods is highly complex, as the composition of a food matrix dictates: (1) bacterial viability during production and shelf life and (2) how bacteria partition with components within a food matrix and subsequently adhere to oral cavity surfaces. At present, virtually no information is available on oral probiotic strains such as Streptococcus salivarius; specifically, how orally-derived strains survive under different food parameters. Furthermore, limited information exists on the partition behavior of probiotics with food components, governed by physico-chemical interactions and adhesion phenomena. This review aspires to examine this framework by providing a foundation with existing literature related to the common probiotic genera, in order to inform and drive future attempts of designing new oral probiotic food formats.