Cutaneous adverse reactions associated with COVID-19 vaccines: Current evidence and potential immune mechanisms.

As the number of vaccinated individuals has increased, there have been increasing reports of cutaneous hypersensitivity reactions. The main COVID-19 vaccines administered include messenger ribonucleic acid vaccines, non-replicating viral vector vaccines, inactivated whole-virus vaccines, and protein-based vaccines. These vaccines contain active components such as polyethylene glycol, polysorbate 80, aluminum, tromethamine, and disodium edetate dihydrate. Recent advances in understanding the coordination of inflammatory responses by specific subsets of lymphocytes have led to a new classification based on immune response patterns. We categorize these responses into four patterns: T helper (Th)1-, Th2-, Th17/22-, and Treg-polarized cutaneous inflammation after stimulation of COVID-19 vaccines. Although the association between COVID-19 vaccination and these cutaneous adverse reactions remains controversial, the occurrence of rare dermatoses and their short intervals suggest a possible relationship. Despite the potential adverse reactions, the administration of COVID-19 vaccines is crucial in the ongoing battle against severe acute respiratory syndrome coronavirus 2.

Experimental biology can inform our understanding of food insecurity.

Food insecurity is a major public health issue. Millions of households worldwide have intermittent and unpredictable access to food and this experience is associated with greater risk for a host of negative health outcomes. While food insecurity is a contemporary concern, we can understand its effects better if we acknowledge that there are ancient biological programs that evolved to respond to the experience of food scarcity and uncertainty, and they may be particularly sensitive to food insecurity during development. Support for this conjecture comes from common findings in several recent animal studies that have modeled insecurity by manipulating predictability of food access in various ways. Using different experimental paradigms in different species, these studies have shown that experience of insecure access to food can lead to changes in weight, motivation and cognition. Some of these studies account for changes in weight through changes in metabolism, while others observe increases in feeding and motivation to work for food. It has been proposed that weight gain is an adaptive response to the experience of food insecurity as 'insurance' in an uncertain future, while changes in motivation and cognition may reflect strategic adjustments in foraging behavior. Animal studies also offer the opportunity to make in-depth controlled studies of mechanisms and behavior. So far, there is evidence that the experience of food insecurity can impact metabolic efficiency, reproductive capacity and dopamine neuron synapses. Further work on behavior, the central and peripheral nervous system, the gut and liver, along with variation in age of exposure, will be needed to better understand the full body impacts of food insecurity at different stages of development.

Metabolomic differences of exhaled breath condensate among children with and without asthma.

BACKGROUND: There remains an unmet need in objective tests for diagnosing asthma in children. The objective of this study was to investigate the potential of metabolomic profiles of exhaled breath condensate (EBC) to discriminate stable asthma in Asian children in the community. METHODS: One hundred and sixty-five Asian children (92 stable asthma and 73 non-asthmatic controls) participating in a population-based cohort were enrolled and divided into training and validation sets. Nuclear magnetic resonance-based metabolomic profiles of EBC samples were analyzed by using orthogonal partial least squares discriminant analysis. RESULTS: EBC metabolomic signature (lactate, formate, butyrate, and isobutyrate) had an area under the receiver operator characteristic curve (AUC) of 0.826 in discriminating children with and without asthma in the training set, which significantly outperformed FeNO (AUC = 0.574; P < .001) and FEV1 /FVC % predicted (AUC = 0.569; P < .001). The AUC for EBC metabolomic signature was 0.745 in the validation set, which was slightly but not significantly lower than in the testing set (P = .282). We further extrapolated two potentially involved metabolic pathways, including pyruvate (P = 1.67 × 10-3 ; impact: 0.14) and methane (P = 1.89 × 10-3 ; impact: 0.15), as the most likely divergent metabolisms between children with and without asthma. CONCLUSION: This study provided evidence supporting the role of EBC metabolomic signature to discriminate stable asthma in Asian children in the community, with a discriminative property outperforming conventional clinical tests such as FeNO or spirometry.

Phosphotyrosine-mediated LAT assembly on membranes drives kinetic bifurcation in recruitment dynamics of the Ras activator SOS.

The assembly of cell surface receptors with downstream signaling molecules is a commonly occurring theme in multiple signaling systems. However, little is known about how these assemblies modulate reaction kinetics and the ultimate propagation of signals. Here, we reconstitute phosphotyrosine-mediated assembly of extended linker for the activation of T cells (LAT):growth factor receptor-bound protein 2 (Grb2):Son of Sevenless (SOS) networks, derived from the T-cell receptor signaling system, on supported membranes. Single-molecule dwell time distributions reveal two, well-differentiated kinetic species for both Grb2 and SOS on the LAT assemblies. The majority fraction of membrane-recruited Grb2 and SOS both exhibit fast kinetics and single exponential dwell time distributions, with average dwell times of hundreds of milliseconds. The minor fraction exhibits much slower kinetics, extending the dwell times to tens of seconds. Considering this result in the context of the multistep process by which the Ras GEF (guanine nucleotide exchange factor) activity of SOS is activated indicates that kinetic stabilization from the LAT assembly may be important. This kinetic proofreading effect would additionally serve as a stochastic noise filter by reducing the relative probability of spontaneous SOS activation in the absence of receptor triggering. The generality of receptor-mediated assembly suggests that such effects may play a role in multiple receptor proximal signaling processes.

Design of a Highly Bistable Photoswitchable Tethered Ligand for Rapid and Sustained Manipulation of Neurotransmission.

Photoswitchable neurotransmitter receptors are powerful tools for precise manipulation of neural signaling. However, their applications for slow or long-lasting biological events are constrained by fast thermal relaxation of cis-azobenzene. We address this issue by modifying the ortho positions of azobenzene used in the tethered ligand. In cultured cells and intact brain tissue, conjugating inhibitory neurotransmitter receptors with one of the derivatives, dMPC1, allows bidirectional receptor control with 380 and 500 nm light. Moreover, the receptors can be locked in either an active or an inactive state in darkness after a brief pulse of light. This strategy thus enables both rapid and sustained manipulation of neurotransmission, allowing optogenetic interrogation of neural functions over a broad range of time scales.

Light-Switchable Ion Channels and Receptors for Optogenetic Interrogation of Neuronal Signaling.

Optogenetics is an emerging technique that enables precise and specific control of biological activities in defined space and time. This technique employs naturally occurring or engineered light-responsive proteins to manipulate the physiological processes of the target cells. To better elucidate the molecular bases of neural functions, substantial efforts have been made to confer light sensitivity onto ion channels and neurotransmitter receptors that mediate signaling events within and between neurons. The chemical strategies for engineering light-switchable channels/receptors and the neuronal implementation of these tools are discussed.

E-cadherin junction formation involves an active kinetic nucleation process.

Epithelial (E)-cadherin-mediated cell-cell junctions play important roles in the development and maintenance of tissue structure in multicellular organisms. E-cadherin adhesion is thus a key element of the cellular microenvironment that provides both mechanical and biochemical signaling inputs. Here, we report in vitro reconstitution of junction-like structures between native E-cadherin in living cells and the extracellular domain of E-cadherin (E-cad-ECD) in a supported membrane. Junction formation in this hybrid live cell-supported membrane configuration requires both active processes within the living cell and a supported membrane with low E-cad-ECD mobility. The hybrid junctions recruit α-catenin and exhibit remodeled cortical actin. Observations suggest that the initial stages of junction formation in this hybrid system depend on the trans but not the cis interactions between E-cadherin molecules, and proceed via a nucleation process in which protrusion and retraction of filopodia play a key role.

H-Ras forms dimers on membrane surfaces via a protein-protein interface.

The lipid-anchored small GTPase Ras is an important signaling node in mammalian cells. A number of observations suggest that Ras is laterally organized within the cell membrane, and this may play a regulatory role in its activation. Lipid anchors composed of palmitoyl and farnesyl moieties in H-, N-, and K-Ras are widely suspected to be responsible for guiding protein organization in membranes. Here, we report that H-Ras forms a dimer on membrane surfaces through a protein-protein binding interface. A Y64A point mutation in the switch II region, known to prevent Son of sevenless and PI3K effector interactions, abolishes dimer formation. This suggests that the switch II region, near the nucleotide binding cleft, is either part of, or allosterically coupled to, the dimer interface. By tethering H-Ras to bilayers via a membrane-miscible lipid tail, we show that dimer formation is mediated by protein interactions and does not require lipid anchor clustering. We quantitatively characterize H-Ras dimerization in supported membranes using a combination of fluorescence correlation spectroscopy, photon counting histogram analysis, time-resolved fluorescence anisotropy, single-molecule tracking, and step photobleaching analysis. The 2D dimerization Kd is measured to be ∼1 × 10(3) molecules/µm(2), and no higher-order oligomers were observed. Dimerization only occurs on the membrane surface; H-Ras is strictly monomeric at comparable densities in solution. Analysis of a number of H-Ras constructs, including key changes to the lipidation pattern of the hypervariable region, suggest that dimerization is a general property of native H-Ras on membrane surfaces.

Membrane-protein binding measured with solution-phase plasmonic nanocube sensors.

We describe a solution-phase sensor of lipid-protein binding based on localized surface plasmon resonance (LSPR) of silver nanocubes. When silica-coated nanocubes are mixed in a suspension of lipid vesicles, supported membranes spontaneously assemble on their surfaces. Using a standard laboratory spectrophotometer, we calibrated the LSPR peak shift due to protein binding to the membrane surface and then characterized the lipid-binding specificity of a pleckstrin homology domain protein.

Nucleus accumbens dopamine release reflects Bayesian inference during instrumental learning.

Dopamine release in the nucleus accumbens has been hypothesized to signal reward prediction error, the difference between observed and predicted reward, suggesting a biological implementation for reinforcement learning. Rigorous tests of this hypothesis require assumptions about how the brain maps sensory signals to reward predictions, yet this mapping is still poorly understood. In particular, the mapping is non-trivial when sensory signals provide ambiguous information about the hidden state of the environment. Previous work using classical conditioning tasks has suggested that reward predictions are generated conditional on probabilistic beliefs about the hidden state, such that dopamine implicitly reflects these beliefs. Here we test this hypothesis in the context of an instrumental task (a two-armed bandit), where the hidden state switches repeatedly. We measured choice behavior and recorded dLight signals reflecting dopamine release in the nucleus accumbens core. Model comparison based on the behavioral data favored models that used Bayesian updating of probabilistic beliefs. These same models also quantitatively matched the dopamine measurements better than non-Bayesian alternatives. We conclude that probabilistic belief computation plays a fundamental role in instrumental performance and associated mesolimbic dopamine signaling.

Transcriptome analysis of age-related gain of callus-forming capacity in Arabidopsis hypocotyls.

Callus-forming capacity is enhanced with hypocotyl maturity in Arabidopsis. However, the genetic regulation of age-related gain in capacity for callus formation is unclear. We used a gene expression microarray assay to characterize the underlying mechanisms during callus formation in young and mature hypocotyl explants of Arabidopsis. As expected, genes involved in photosynthesis and cell wall thickening showed altered expression during hypocotyl maturation. In addition, genes involved in cytokinin perception were enriched in mature hypocotyl tissues. Phytohormone-induced callus formation in hypocotyl explants was accompanied by increased expression of genes mainly related to the cell cycle, histones and epigenetics. The induction level of these genes was higher in mature hypocotyl explants than young explants during callus formation. We identified a number of genes, including those with unknown function, potentially involved in age-related gain in callus formation. Our results provide insight into the effect of hypocotyl age on callus formation. Altered cytokinin signaling components, cell cycle regulation and epigenetics may work in concert to lead to gain of callus-forming capacity in hypocotyls with age.

Isolation and characterisation of lactic acid bacteria from jiang-gua (fermented cucumbers), a traditional fermented food in Taiwan.

BACKGROUND: Jiang-gua (fermented cucumbers) is a popular traditional fermented food in Taiwan. The microflora of lactic acid bacteria (LAB) in jiang-gua have not been investigated in detail. In this study, LAB from jiang-gua were isolated, characterised and identified. RESULTS: A total of 103 LAB were isolated; 70 cultures were isolated from jiang-gua samples and 33 cultures were isolated from its raw substrate, cucumber. These isolates were mainly characterised phenotypically and then divided into seven groups (A-G) by restriction fragment length polymorphism analysis and sequencing of 16S ribosomal DNA. The isolates were identified as Enterococcus casseliflavus, Leuconostoc lactis, Leuconostoc mesenteroides, Lactobacillus pentosus, Lactobacillus plantarum, Lactobacillus paraplantarum, Lactococcus lactis subsp. lactis, Weissella cibaria and Weissella hellenica. The antibacterial activities of the isolates were determined and 11 Lc. lactis subsp. lactis strains showed inhibitory activity against the indicator strain Lactobacillus sakei JCM 1157(T) . CONCLUSION: Heterofermentative W. cibaria and Leu. lactis were the major LAB found in jiang-gua samples without soy sauce. In soy sauce-added samples, homofermentative L. pentosus and L. plantarum were the most abundant LAB. In addition, the results also suggested that HhaI and RsaI restriction enzymes could be applied to distinguish W. hellenica and Weissella paramesenteroides.

Making sense of strengths and weaknesses observed in adolescent laboratory rodents.

During adolescence, rodents disperse from their natal site, find a new home, and navigate social relationships and threats. Although rats and mice in the laboratory cannot fully express these natural behaviors, they show striking changes in their affective and cognitive behavior across the adolescent period. In some laboratory-based behavior metrics, adolescent rodents fail to show the same behaviors expressed by adults, but in other metrics, adolescent behavioral performance is more robust or more flexible than at other ages. These data are often interpreted in light of proximate level analysis of development of neural circuits. It is also informative to attempt ultimate-level explanations and consider how sex and species-specific adolescent behavioral changes support dispersal, foraging, and social interactions in the wild.

Case report: Development of vanishing bile duct syndrome in Stevens-Johnson syndrome complicated by hemophagocytic lymphohistiocytosis.

Background: Vanishing bile duct syndrome is a rare drug-induced disease characterized by cholestasis and ensuing ductopenia. Dermatological manifestations of drug hypersensitivity such as Stevens-Johnson syndrome and toxic epidermal necrolysis may also present in such cases. Hemophagocytic lymphohistiocytosis is a hyperimmune response caused by unchecked stimulation of macrophages, natural killer cells, and cytotoxic T lymphocytes. Case presentation: We report a severe case who presented with concurrent Stevens-Johnson syndrome and vanishing bile duct syndrome complicated by hemophagocytic lymphohistiocytosis after the ingestion of non-steroidal anti-inflammatory drugs. Despite the fact that improvements in vanishing bile duct syndrome can be assumed when combining the clinical lab data clues, as well as repeated liver biopsies showing recovering ductopenia, the patient developed hypovolemic shock combined with septic shock episodes and died on day 236. Conclusion: To our knowledge, this is the fifteenth report of vanishing bile duct syndrome associated with Stevens-Johnson disease or toxic epidermal necrolysis. Mortality rate remains high without treatment guidelines established due to the rarity and heterogenicity of the population. Further studies are needed to identify possible risk factors, prognostic indicators, and the standard of care for vanishing bile duct syndrome associated with Stevens-Johnson disease or toxic epidermal necrolysis.

Activation, but not inhibition, of the indirect pathway disrupts choice rejection in a freely moving, multiple-choice foraging task.

The dorsomedial striatum (DMS) plays a key role in action selection, but less is known about how direct and indirect pathway spiny projection neurons (dSPNs and iSPNs, respectively) contribute to choice rejection in freely moving animals. Here, we use pathway-specific chemogenetic manipulation during a serial choice foraging task to test the role of dSPNs and iSPNs in learned choice rejection. We find that chemogenetic activation, but not inhibition, of iSPNs disrupts rejection of nonrewarded choices, contrary to predictions of a simple "select/suppress" heuristic. Our findings suggest that iSPNs' role in stopping and freezing does not extend in a simple fashion to choice rejection in an ethological, freely moving context. These data may provide insights critical for the successful design of interventions for addiction or other conditions in which it is desirable to strengthen choice rejection.

The maturation of exploratory behavior in adolescent Mus spicilegus on two photoperiods.

Dispersal from the natal site or familial group is a core milestone of adolescent development in many species. A wild species of mouse, Mus spicilegus, presents an exciting model in which to study adolescent development and dispersal because it shows different life history trajectory depending on season of birth. M. spicilegus born in spring and summer on long days (LD) disperse in the first 3 months of life, while M. spicilegus born on shorter autumnal days (SD) delay dispersal through the wintertime. We were interested in using these mice in a laboratory context to compare age-matched mice with differential motivation to disperse. To first test if we could find a proxy for dispersal related behavior in the laboratory environment, we measured open field and novel object investigation across development in M. spicilegus raised on a LD 12 h:12 h light:dark cycle. We found that between the first and second month of life, distance traveled and time in center of the open field increased significantly with age in M. spicilegus. Robust novel object investigation was observed in all age groups and decreased between the 2nd and 3rd month of life in LD males. Compared to male C57BL/6 mice, male M. spicilegus traveled significantly longer distances in the open field but spent less time in the center of the field. However, when a novel object was placed in the center of the open field, Male M. spicilegus, were significantly more willing to contact and mount it. To test if autumnal photoperiod affects exploratory behavior in M. spicilegus in a laboratory environment, we reared a cohort of M. spicilegus on a SD 10 h:14 h photoperiod and tested their exploratory behavior at P60-70. At this timepoint, we found SD rearing had no effect on open field metrics, but led to reduced novel object investigation. We also observed that in P60-70 males, SD reared M. spicilegus weighed less than LD reared M. spicilegus. These observations establish that SD photoperiod can delay weight gain and blunt some, but not all forms of exploratory behavior in adolescent M. spicilegus.

Transient food insecurity during the juvenile-adolescent period affects adult weight, cognitive flexibility, and dopamine neurobiology.

A major challenge for neuroscience, public health, and evolutionary biology is to understand the effects of scarcity and uncertainty on the developing brain. Currently, a significant fraction of children and adolescents worldwide experience insecure access to food. The goal of our work was to test in mice whether the transient experience of insecure versus secure access to food during the juvenile-adolescent period produced lasting differences in learning, decision-making, and the dopamine system in adulthood. We manipulated feeding schedules in mice from postnatal day (P)21 to P40 as food insecure or ad libitum and found that when tested in adulthood (after P60), males with different developmental feeding history showed significant differences in multiple metrics of cognitive flexibility in learning and decision-making. Adult females with different developmental feeding history showed no differences in cognitive flexibility but did show significant differences in adult weight. We next applied reinforcement learning models to these behavioral data. The best fit models suggested that in males, developmental feeding history altered how mice updated their behavior after negative outcomes. This effect was sensitive to task context and reward contingencies. Consistent with these results, in males, we found that the two feeding history groups showed significant differences in the AMPAR/NMDAR ratio of excitatory synapses on nucleus-accumbens-projecting midbrain dopamine neurons and evoked dopamine release in dorsal striatal targets. Together, these data show in a rodent model that transient differences in feeding history in the juvenile-adolescent period can have significant impacts on adult weight, learning, decision-making, and dopamine neurobiology.

EphA2 receptor activation by monomeric Ephrin-A1 on supported membranes.

The receptor tyrosine kinase EphA2 interacts with its glycosylphosphatidylinositol (GPI)-linked ephrin-A1 ligand in a juxtacrine configuration. The soluble ephrin-A1 protein, without its GPI membrane linker, fails to activate EphA2. However, preclustered ephrin-A1 protein is active in solution and has been frequently used to trigger the EphA2 receptor. Although this approach has yielded insights into EphA2 signaling, preclustered ligands bypass natural receptor clustering processes and thus mask any role of clustering as a signal regulatory mechanism. Here, we present EphA2-expressing cells with a fusion protein of monomeric ephrin-A1 (mEA1) and enhanced monomeric yellow fluorescent protein that is linked to a supported lipid bilayer via a nickel-decahistidine anchor. The mEA1 is homogeneously dispersed, laterally mobile, and monomeric as measured by fluorescence imaging, correlation spectroscopy, and photon counting histogram analysis, respectively. Ephrin-A1 presented in this manner activates EphA2 on the surface of MDA-MB-231 human breast cancer cells, as measured by EphA2 phosphorylation and degradation. Spatial mutation experiments in which nanopatterns on the underlying substrate restrict mEA1 movement in the supported lipid bilayer reveal spatio-mechanical regulation of this signaling pathway, consistent with recently reported observations using a synthetically cross-linked ephrin-A1 dimer.

The effect of social marketing communication on safe driving.

Processing of cognition, affect, and intention was investigated in viewers of advertisements to prevent speeding while driving. Results indicated that anchoring-point messages had greater effects on viewers' cognition, attitude, and behavioral intention than did messages without anchoring points. Further, the changes in message anchoring points altered participants' perceptions of acceptable and unacceptable judgments: a higher anchoring point in the form of speeding mortality was more persuasive in promoting the idea of reducing driving speed. Implications for creation of effective safe driving communications are discussed.

Bioelectronic Measurement of Target Engagement to a Membrane-Bound Transporter.

The ability to detect and characterize drug binding to a target protein is of high priority in drug discovery research. However, there are inherent challenges when the target of interest is an integral membrane protein (IMP). Assuming successful purification of the IMP, traditional approaches for measuring binding such as surface plasmon resonance (SPR) and fluorescence resonance energy transfer (FRET) have been proven valuable. However, the mass dependence of SPR signals may preclude the detection of binding events when the ligand has a significantly smaller mass than the target protein. In FRET-based experiments, protein labeling through modification may inadvertently alter protein dynamics. Graphene Bio-Electronic Sensing Technology (GBEST) aims to overcome these challenges. Label-free characterization takes place in a microfluidic chamber wherein a fluid lipid membrane is reconstituted directly above the GBEST sensor surface. By leveraging the high conductivity, sensitivity, and electrical properties of monolayer graphene, minute changes in electrostatic charges arising from the binding and unbinding of a ligand to a native IMP target can be detected in real time and in a mass-independent manner. Using crude membrane fractions prepared from cells overexpressing monocarboxylate transporter 1 (MCT1), we demonstrate the ability to (1) form a fluid lipid bilayer enriched with MCT1 directly on top of the GBEST sensor and (2) obtain kinetic binding data for an anti-MCT1 antibody. Further development of this novel technology will enable characterization of target engagement by both low- and high-molecular-weight drug candidates to native IMP targets in a physiologically relevant membrane environment.