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Here we present evidence for the ubiquity of fine spike timing and temporal coding broadly observed across sensory systems and widely conserved across diverse phyla, spanning invertebrates and vertebrates. A taxonomy of basic neural coding types includes channel activation patterns, temporal patterns of spikes, and patterns of spike latencies. Various examples and types of combination temporal-channel codes are discussed, including firing sequence codes. Multiplexing of temporal codes and mixed channel-temporal codes are considered. Neurophysiological and perceptual evidence for temporal coding in many sensory modalities is surveyed: audition, mechanoreception, electroreception, vision, gustation, olfaction, cutaneous senses, proprioception, and the vestibular sense. Precise phase-locked, phase-triggered, and spike latency codes can be found in many sensory systems. Temporal resolutions on millisecond and submillisecond scales are common. General correlation-based representations and operations are discussed. In almost every modality, there is some role for temporal coding, often in surprising places, such as color vision and taste. More investigations into temporal coding are well-warranted.

Time is essential for understanding the brain. A temporal theory for realizing major brain functions (e.g., sensation, cognition, motivation, attention, memory, learning, and motor action) is proposed that uses temporal codes, time-domain neural networks, correlation-based binding processes and signal dynamics. It adopts a signal-centric perspective in which neural assemblies produce circulating and propagating characteristic temporally patterned signals for each attribute (feature). Temporal precision is essential for temporal coding and processing. The characteristic spike patterns that constitute the signals enable general-purpose, multimodal, multidimensional vectorial representations of objects, events, situations, and procedures. Signals are broadcast and interact with each other in spreading activation time-delay networks to mutually reinforce, compete, and create new composite patterns. Sequences of events are directly encoded in the relative timings of event onsets. New temporal patterns are created through nonlinear multiplicative and thresholding signal interactions, such as mixing operations found in radio communications systems and wave interference patterns. The newly created patterns then become markers for bindings of specific combinations of signals and attributes (e.g., perceptual symbols, semantic pointers, and tags for cognitive nodes). Correlation operations enable both bottom-up productions of new composite signals and top-down recovery of constituent signals. Memory operates using the same principles: nonlocal, distributed, temporally coded memory traces, signal interactions and amplifications, and content-addressable access and retrieval. A short-term temporary store is based on circulating temporal spike patterns in reverberatory, spike-timing-facilitated circuits. A long-term store is based on synaptic modifications and neural resonances that select specific delay-paths to produce temporally patterned signals. Holographic principles of nonlocal representation, storage, and retrieval can be applied to temporal patterns as well as spatial patterns. These can automatically generate pattern recognition (wavefront reconstruction) capabilities, ranging from objects to concepts, for distributed associative memory applications. The evolution of proposed neural implementations of holograph-like signal processing and associative content-addressable memory mechanisms is discussed. These can be based on temporal correlations, convolutions, simple linear and nonlinear operations, wave interference patterns, and oscillatory interactions. The proposed mechanisms preserve high resolution temporal, phase, and amplitude information. These are essential for establishing high phase coherency and determining phase relationships, for binding/coupling, synchronization, and other operations. Interacting waves can sum constructively for amplification, or destructively, for suppression, or partially. Temporal precision, phase-locking, phase-dependent coding, phase-coherence, synchrony are discussed within the context of wave interference patterns and oscillatory interactions. Sequences of mixed neural oscillations are compared with a cascade of sequential mixing stages in a single-sideband carrier suppressed (SSBCS) radio communications system model. This mechanism suggests a manner by which multiple neural oscillation bands could interact to produce new emergent information-bearing oscillation bands, as well as to abolish previously generated bands. A hypothetical example illustrates how a succession of different oscillation carriers (gamma, beta, alpha, theta, and delta) could communicate and propagate (broadcast) information sequentially through a neural hierarchy of speech and language processing stages. Based on standard signal mixing principles, each stage emergently generates the next. The sequence of oscillatory bands generated in the mixing cascade model is consistent with neurophysiological observations. This sequence corresponds to stages of speech-language processing (sound/speech detection, acoustic-phonetics, phone/clusters, syllables, words/phrases, word sequences/sentences, and concepts/understanding). The oscillatory SSBCS cascade model makes specific predictions for oscillatory band frequencies that can be empirically tested. The principles postulated here may apply broadly for local and global oscillation interactions across the cortex. Sequences of oscillatory interactions can serve many functions, e.g., to regulate the flow and interaction of bottom-up, gamma-mediated and top-down, beta-mediated neural signals, to enable cross-frequency coupling. Some specific guidelines are offered as to how the general time-domain theory might be empirically tested. Neural signals need to be sampled and analyzed with high temporal resolution, without destructive windowing or filtering. Our intent is to suggest what we think is possible, and to widen both the scope of brain theory and experimental inquiry into brain mechanisms, functions, and behaviors.

Time is of the essence in how neural codes, synchronies, and oscillations might function in encoding, representation, transmission, integration, storage, and retrieval of information in brains. This Hypothesis and Theory article examines observed and possible relations between codes, synchronies, oscillations, and types of neural networks they require. Towards reverse-engineering informational functions in brains, prospective, alternative neural architectures incorporating principles from radio modulation and demodulation, active reverberant circuits, distributed content-addressable memory, signal-signal time-domain correlation and convolution operations, spike-correlation-based holography, and self-organizing, autoencoding anticipatory systems are outlined. Synchronies and oscillations are thought to subserve many possible functions: sensation, perception, action, cognition, motivation, affect, memory, attention, anticipation, and imagination. These include direct involvement in coding attributes of events and objects through phase-locking as well as characteristic patterns of spike latency and oscillatory response. They are thought to be involved in segmentation and binding, working memory, attention, gating and routing of signals, temporal reset mechanisms, inter-regional coordination, time discretization, time-warping transformations, and support for temporal wave-interference based operations. A high level, partial taxonomy of neural codes consists of channel, temporal pattern, and spike latency codes. The functional roles of synchronies and oscillations in prospective neural codes, including oscillatory phase-offset codes, are outlined. Various forms of multiplexing neural signals are considered: time-division, frequency-division, code-division, oscillatory-phase, synchronized channels, oscillatory hierarchies, polychronous ensembles. An expandable, annotative neural spike train framework for encoding low- and high-level attributes of events and objects is proposed. Coding schemes require appropriate neural architectures for their interpretation. Time-delay, oscillatory, wave-interference, synfire chain, polychronous, and neural timing networks are discussed. Some novel concepts for formulating an alternative, more time-centric theory of brain function are discussed. As in radio communication systems, brains can be regarded as networks of dynamic, adaptive transceivers that broadcast and selectively receive multiplexed temporally-patterned pulse signals. These signals enable complex signal interactions that select, reinforce, and bind common subpatterns and create emergent lower dimensional signals that propagate through spreading activation interference networks. If memory traces share the same kind of temporal pattern forms as do active neuronal representations, then distributed, holograph-like content-addressable memories are made possible via temporal pattern resonances.

The study uses organizational theory to analyze the historical event of Pennsylvania's normal school transition to undergraduate teachers college status, from 1919 to 1937. Analysis is framed within organizational change theories that focus on the relationship between an organization and its environment. Although little is known about how U.S. normal schools made the transition to college status, the historical literature on teacher education points to the changing educational environment as a key factor, which, in turn, supports the choice of an environmental perspective for an initial organizational analysis of the event. The purpose of the investigation is to determine how the Pennsylvania normal schools reorganized to attain college status. The following questions guided the research: (1) What changes were made in the schools' missions, curricula, and administrative structures during the transition, from 1920 to 1937? (2) How were these changes made--through environmental pressures, administrative decisions, or negotiation between school administrators and other groups? Two Pennsylvania schools, Indiana State Normal School and Clarion State Normal School, are used as examples of how changes in goals, curricula, and administration occurred as all of the state's normals achieved teachers college status. State and institutional documents were examined to trace the changes in the schools and their environment. Results of the investigation indicate that although state officials dominated the initial reorganizational phase, between 1919 and 1937 the transformation into teachers colleges reflected a negotiated change process in which both environmental and school forces shaped organizational behavior. Throughout this period, the schools' administrative leadership and organizational processes influenced the way in which plans were formed, revised, and implemented. The schools' dramatic change from local control and relative autonomy and the introduction of a narrowly vocationalized curriculum distinguished the Pennsylvania transition. Ultimately, however, Pennsylvania's unique story ended like that of other U.S. teachers colleges. Increased interdependence, competition from liberal arts colleges, and a normative network of educational professionals promoted similarity. By 1937, the state's teachers colleges offered the combination of academics, educational courses, and vocational specialties found at most teachers colleges across the nation.

BACKGROUNDPediatric SARS-CoV-2 infection can be complicated by a dangerous hyperinflammatory condition termed multisystem inflammatory syndrome in children (MIS-C). The clinical and immunologic spectrum of MIS-C and its relationship to other inflammatory conditions of childhood have not been studied in detail.METHODSWe retrospectively studied confirmed cases of MIS-C at our institution from March to June 2020. The clinical characteristics, laboratory studies, and treatment response were collected. Data were compared with historic cohorts of Kawasaki disease (KD) and macrophage activation syndrome (MAS).RESULTSTwenty-eight patients fulfilled the case definition of MIS-C. Median age at presentation was 9 years (range: 1 month to 17 years); 50% of patients had preexisting conditions. All patients had laboratory confirmation of SARS-CoV-2 infection. Seventeen patients (61%) required intensive care, including 7 patients (25%) who required inotrope support. Seven patients (25%) met criteria for complete or incomplete KD, and coronary abnormalities were found in 6 cases. Lymphopenia, thrombocytopenia, and elevation in inflammatory markers, D-dimer, B-type natriuretic peptide, IL-6, and IL-10 levels were common but not ubiquitous. Cytopenias distinguished MIS-C from KD and the degree of hyperferritinemia and pattern of cytokine production differed between MIS-C and MAS. Immunomodulatory therapy given to patients with MIS-C included intravenous immune globulin (IVIG) (71%), corticosteroids (61%), and anakinra (18%). Clinical and laboratory improvement were observed in all cases, including 6 cases that did not require immunomodulatory therapy. No mortality was recorded in this cohort.CONCLUSIONMIS-C encompasses a broad phenotypic spectrum with clinical and laboratory features distinct from KD and MAS.FUNDINGThis work was supported by the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Allergy and Infectious Diseases; Rheumatology Research Foundation Investigator Awards and Medical Education Award; Boston Children's Hospital Faculty Career Development Awards; the McCance Family Foundation; and the Samara Jan Turkel Center.

Insulin is considered to be a key antigenic target of T cells in Type 1 Diabetes (T1D) and autoimmune diabetes in the NOD mouse with particular focus on the B-chain amino acid sequence B:9-23 as the primary epitope. Our lab previously discovered that hybrid insulin peptides (HIPs), comprised of insulin C-peptide fragments fused to other β-cell granule peptides, are ligands for several pathogenic CD4 T cell clones derived from NOD mice and for autoreactive CD4 T cells from T1D patients. A subset of CD4 T cell clones from our panel react to insulin and B:9-23 but only at high concentrations of antigen. We hypothesized that HIPs might also be formed from insulin B-chain sequences covalently bound to other endogenously cleaved ß-cell proteins. We report here on the identification of a B-chain HIP, termed the 6.3HIP, containing a fragment of B:9-23 joined to an endogenously processed peptide of ProSAAS, as a strong neo-epitope for the insulin-reactive CD4 T cell clone BDC-6.3. Using an I-A g7 tetramer loaded with the 6.3HIP, we demonstrate that T cells reactive to this B-chain HIP can be readily detected in NOD mouse islet infiltrates. This work suggests that some portion of autoreactive T cells stimulated by insulin B:9-23 may be responding to B-chain HIPs as peptide ligands.

Background. Group A rotaviruses (RVA) are a significant cause of pediatric gastroenteritis worldwide. The New Vaccine Surveillance Network (NVSN) has conducted active surveillance for RVA at pediatrie hospitals and emergency departments at 3-7 geographically diverse sites in the United States since 2006. Methods. Over 6 consecutive years, from 2008 to 2013, 1523 samples from NVSN sites that were tested positive by a Rotaclone enzyme immunoassay were submitted to the Centers for Disease Control and Prevention for genotyping. Results. In the 2009, 2010, and 2011 seasons, genotype G3P[8] was the predominant genotype throughout the network, with a 46%-84% prevalence. In the 2012 season, G12P[8] replaced G3P[8] as the most common genotype, with a 70% prevalence, and this trend persisted in 2013 (68.0% prevalence). Vaccine (RotaTeq; Rotarix) strains were detected in 0.6%-3.4% of genotyped samples each season. Uncommon and unusual strains (eg, G8P[4], G3P[24], G2P[8], G3P[4], G3P[6], G24P[14], G4P[6], and G9P[4]) were detected sporadically over the study period. Year, study site, and race were found to be significant predictors of genotype. Conclusions. Continued active surveillance is needed to monitor RVA genotypes in the United States and to detect potential changes since vaccine licensure.

Mortality is a crucial indicator of well-being, and recent mortality trends have been a subject of public debate in many Western countries. This paper compares mortality inequality in Canada and the United States over the period 1990/91 through 2010/11. In Canada, mortality inequality remained constant among the youngest but increased for men over 24 and women over 14. In contrast, in the United States, mortality inequality fell for children and youth and either modestly increased or held steady at older ages. By 2010/11, the initially higher US rates of infant and child mortality had almost converged to their Canadian counterparts.

The Mars Atmosphere and Volatile Evolution (MAVEN) mission, during the second of its Deep Dip campaigns, made comprehensive measurements of martian thermosphere and ionosphere composition, structure, and variability at altitudes down to ~130 kilometers in the subsolar region. This altitude range contains the diffusively separated upper atmosphere just above the well-mixed atmosphere, the layer of peak extreme ultraviolet heating and primary reservoir for atmospheric escape. In situ measurements of the upper atmosphere reveal previously unmeasured populations of neutral and charged particles, the homopause altitude at approximately 130 kilometers, and an unexpected level of variability both on an orbit-to-orbit basis and within individual orbits. These observations help constrain volatile escape processes controlled by thermosphere and ionosphere structure and variability.

The obstetrical conditions placenta accreta spectrum (PAS) and placenta previa are a significant source of pregnancy-associated morbidity and mortality, yet the specific molecular and cellular underpinnings of these conditions are not known. In this study, we identified misregulated gene expression patterns in tissues from placenta previa and percreta (the most extreme form of PAS) compared with control cases. By comparing this gene set with existing placental single-cell and bulk RNA-Seq datasets, we show that the upregulated genes predominantly mark extravillous trophoblasts. We performed immunofluorescence on several candidate molecules and found that PRG2 and AQPEP protein levels are upregulated in both the fetal membranes and the placental disk in both conditions. While this increased AQPEP expression remains restricted to trophoblasts, PRG2 is mislocalized and is found throughout the fetal membranes. Using a larger patient cohort with a diverse set of gestationally aged-matched controls, we validated PRG2 as a marker for both previa and PAS and AQPEP as a marker for only previa in the fetal membranes. Our findings suggest that the extraembryonic tissues surrounding the conceptus, including both the fetal membranes and the placental disk, harbor a signature of previa and PAS that is characteristic of EVTs and that may reflect increased trophoblast invasiveness. Summary sentence 3SEQ and immunofluorescence reveal that extravillous trophoblast factors, most notably PRG2 and AQPEP, define the diseases placenta previa and placenta accreta spectrum in both the chorioamniotic membranes and the placental disk.