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Aicardi Goutières Syndrome (AGS) is an autoinflammatory disorder resulting in sustained interferon activation through defects in nucleic acid modification and sensing pathways. Thus, mRNA-based vaccination used against SARS-CoV-2, raise disease-specific safety concerns. To assess interferon signaling, we tested mRNA SARS-CoV-2 vaccines in AGS whole blood samples. Interferon activation is measured through quantitation of interferon signaling gene (ISG) expression and is increased in AGS patients. There was no increase in ISG scores from baseline following treatment with the nucleoside modified mRNA formulation compared to an increase with unmodified. A patient-family survey reported that the vaccines were well tolerated. These findings suggest that COVID vaccination using nucleoside-modified forms of mRNA vaccines are unlikely to directly stimulate ISG expression in response to mRNA internalization in AGS tissues. With continued community spread, we recommend vaccination using nucleoside-modified mRNA vaccines in this rare disease group in individuals for whom vaccines were previously well tolerated.

SUMMARYThe CD4 binding site (CD4bs) is a conserved epitope on HIV-1 envelope (Env) that can be targeted by protective broadly neutralizing antibodies (bnAbs). HIV-1 vaccines have not elicited CD4bs bnAbs for many reasons, including the CD4bs is occluded by glycans, immunogen expansion of appropriate naïve B cells, and selection of functional antibody mutations. Here, we demonstrate immunization of macaques with a CD4bs-targeting immunogen elicits neutralizing bnAb precursors with structural and genetic features of CD4-mimicking bnAbs. Structures of the CD4bs nAbs bound to HIV-1 Env demonstrated binding angles similar to human bnAbs and heavy chain second complementarity determining region-dependent binding characteristic of all known human CD4-mimicking bnAbs. Macaque nAbs were derived from variable and joining gene segments orthologous to the genes of human VH1-46-class bnAbs. This vaccine study initiated the B cells from which derive CD4bs bnAbs in primates, accomplishing the key first step in development of an effective HIV-1 vaccine.

Extensive studies have shown that cancer cells have specific nutrient auxotrophy and thus have much a higher demand for certain nutrients than normal cells. Amino acid deprivation has attracted much attention in cancer therapy with positive outcomes from clinical trials. Arginine, as one of the conditionally essential amino acids, plays a pivotal role in cellular division and metabolism. Since many types of cancer cells exhibit decreased expression of argininosuccinate synthetase and/or ornithine transcarbamylase, they are auxotrophic for arginine, which makes arginine deprivation an accessible choice for cancer treatment. Arginine deiminase (ADI) and human arginase (hArg) are the two major protein drugs used for arginine deprivation and are undergoing many clinical trials. However, the clinical application of ADI and hArg is facing some common problems, including their short half-lives, immunogenicity and inconsistent production, which underlines the importance of improving these drugs using protein engineering techniques. Thus, we systematically review the latest studies of protein engineering and anti-cancer studies based on in vitro, in vivo and clinical models of ADI and hArg, and we include the latest studies on drug combinations consisting of ADI/hArg with chemotherapeutic drugs.

Intestinal epithelial cells (IECs) contribute to the regulation of intestinal homeostasis and inflammation through their interactions with the environment and host immune responses. Yet our understanding of IEC-intrinsic regulatory pathways remains incomplete. Here, we identify the guanine nucleotide exchange factor RABGEF1 as a regulator of intestinal homeostasis and innate pathways dependent on IECs. Mice with IEC-specific Rabgef1 deletion (called Rabgef1IEC-KO mice) developed a delayed spontaneous colitis associated with the local upregulation of IEC chemokine expression. In mouse models of colitis based on Interleukin-10 deficiency or dextran sodium sulfate (DSS) exposure, we found that IEC-intrinsic RABGEF1 deficiency exacerbated development of intestinal pathology and dysregulated IEC innate pathways and chemokine expression. Mechanistically, we showed that RABGEF1 deficiency in mouse IECs in vitro was associated with an impairment of early endocytic events, an increased activation of the p38 mitogen-activated protein kinase (MAPK)-dependent pathway, and increased chemokine secretion. Moreover, we provided evidence that the development of spontaneous colitis was dependent on microbiota-derived signals and intrinsic MYD88-dependent pathways in vivo. Our study identifies mouse RABGEF1 as an important regulator of intestinal inflammation, MYD88-dependent IEC-intrinsic signaling, and chemokine production. This suggests that RABGEF1-dependent pathways represent interesting therapeutic targets for inflammatory conditions in the gut.

Mice overexpressing the proallergic cytokine thymic stromal lymphopoietin (TSLP) in the skin develop a pathology resembling atopic dermatitis. RabGEF1, a guanine nucleotide exchange factor for Rab5 GTPase, is a negative regulator of IgE-dependent mast cell activation, and Rabgef1-/- and TSLP transgenic mice share many similar phenotypic characteristics, including elevated serum IgE levels and severe skin inflammation, with infiltrates of both lymphocytes and eosinophils. We report here that Rabgef1-/- mice also develop splenomegaly, lymphadenopathy, myeloid hyperplasia, and high levels of TSLP. Rabgef1-/-TSLPR-/- mice, which lack TSLP/TSLP receptor (TSLPR) signaling, had levels of blood neutrophils, spleen myeloid cells, and serum IL-4, IgG1, and IgE levels that were significantly reduced compared with those in Rabgef1-/-TSLPR+/+ mice. However, Rabgef1-/-TSLPR-/- mice, like Rag1- or eosinophil-deficient Rabgef1-/- mice, developed cutaneous inflammation and epidermal hyperplasia. Therefore, in Rabgef1-/- mice, TSLP/TSLPR interactions are not required for the development of epidermal hyperplasia but contribute to the striking myeloid hyperplasia and overproduction of immunoglobulins observed in these animals. Our study shows that RabGEF1 can negatively regulate TSLP production in vivo and that excessive production of TSLP contributes to many of the phenotypic abnormalities in Rabgef1-/- mice. However, the marked epidermal hyperplasia, cutaneous inflammation, and increased numbers of dermal mast cells associated with RabGEF1 deficiency can develop via a TSLPR-independent pathway, as well as in the absence of Rag1 or eosinophils.

Summary Objectives To assess the efficacy of an aromatic essential oil (1% Zingiber officinale and 0.5% C itrus sinesis ) massage among the elderly with moderate-to-severe knee pain. Method Fifty-nine older persons were enrolled in a double-blind, placebo-controlled experimental study group from the Community Centre for Senior Citizens, Hong Kong. The intervention was six massage sessions with ginger and orange oil over a 3-week period. The placebo control group received the same massage intervention with olive oil only and the control group received no massage. Assessment was done at baseline, post 1-week and post 4 weeks after treatment. Changes from baseline to the end of treatment were assessed on knee pain intensity, stiffness level and physical functioning (by Western Ontario and McMaster Universities Osteoarthritis index) and quality of life (by SF-36). Results There were significant mean changes between the three time-points within the intervention group on three of the outcome measures: knee pain intensity ( p =0.02); stiffness level ( p =0.03); and enhancing physical function ( p =0.04) but these were not apparent with the between-groups comparison ( p =0.48, 0.14 and 0.45 respectively) 4 weeks after the massage. The improvement of physical function and pain were superior in the intervention group compared with both the placebo and the control group at post 1-week time (both p =0.03) but not sustained at post 4 weeks ( p =0.45 and 0.29). The changes in quality of life were not statistically significant for all three groups. Conclusion The aroma-massage therapy seems to have potential as an alternative method for short-term knee pain relief.

The distinct biological effects of neurotrophins are mediated in part through their binding to the high-affinity neurotrophin receptors represented by the Trk family of receptor tyrosine kinases. Using the technique of reverse transcriptase-polymerase chain reaction (RT-PCR), we cloned several partial cDNAs encodingtrkA,trkB, andtrkC from fetal brains of African green monkeys. Southern analysis of PCR products showed that the ventral tegmental area of adult monkey and ventral midbrains of fetal monkeys of E59, E81, E91, and E150 days of gestation expressed all threetrkgene transcripts, whereas onlytrkB andtrkC mRNAs were detectable in the adult substanta nigra. The nucleotide sequences of the cloned monkeytrkcDNAs are highly homologous to their human counterparts, and we detected a splice variant oftrkC that has recently been described in humans, but not in rodents. Moreover, sequencing oftrkC cDNAs derived from four fetal monkey midbrains revealed two novel variants with single nucleotide substitution. A missense mutation (A A _ T to A G _ T) was identified in the codon corresponding to codon 361 of the deduced human TrkC sequence, converting an encoded Asn to Ser. The second variant involves a silent transition at the third nucleotide of the codon Gly 362 (GG C _ to GG A _ ). Furthermore, three of the four potential alleles involving these twotrkC variants were detected in these monkeys, indicating that a segregation of multipletrkC alleles occurs in a geographically contained population of feral monkeys.

Mild footshock stress selectively activates ventral tegmental area dopamine neurons innervating the prefrontal cortex. The same stressor rapidly dissociates ventral tegmental substance P from its preprotachykinin-derived co-transmitter substance K, and preproenkephalin B-derived dynorphin B from preproenkephalin A-derived Met-enkephalin-Arg-Gly-Leu and Leu-enkephalin. Mild footshock stress may provide a paradigm for studying both peptidergic modulation of brain dopaminergic neurons and the dynamic regulation of tachykinin and opioid peptide transcription, processing and utilization.

The newly discovered peptide substance K (SK) is an aliphatic tachykinin structurally related to the aromatic tachykinin substance P (SP). Immunohistochemical examination showed a close association between SK afferents and dopamine (DA) cell bodies. Examination of the possible role of SK in modulating midbrain DA systems revealed that SP, but not SK, is associated with the stress response of the mesocortical system. Ventral tegmental area injections of SK effected locomotor hyperactivity, a mesolimbic-mediated behavior. Ventral tegmental injections of SP, but not SK, activated DA metabolism in the prefrontal cortex, while SK injections altered DA metabolism in the nucleus accumbens, but not the cortical site. These data suggest that SK and SP may differentially modulate the mesolimbic and mesocortical systems.

The effects of stress on dopamine (DA) metabolism in the mesencephalic DA cell body areas and DA terminal field regions were examined. Both mild footshock stress and exposure to a neutral stimulus previously paired with footshock resulted in a selective increase in the levels of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the prefrontal cortex as has been previously reported. Footshock stress also resulted in a slight but significant increase in DOPAC levels in the olfactory tubercles. DOPAC levels were selectively increased in the A10 cell body area (ventral tegmental area) but not A9 region (substantia nigra) by both footshock and the conditioned stress paradigm. These data indicate that the cell bodies of origin of the mesocortical dopaminergic system are activated by stress in contrast to those DA neurons innervating the striatum. It appears that mesocortical dopaminergic neurons exhibit different regulatory features than mesolimbic or nigrostriatal neurons.