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Summary Proper immune cell development at early ontogenic stages is critical for life-long health. How resident immune cells are established in barrier tissues at neonatal stages to provide early protection is an important but still poorly understood question. We herein report that a developmentally programmed preferential generation of skin-homing group 1 innate lymphoid cells (ILC1s) at perinatal stages helps regulate early skin microbiota colonization. We found that a population of skin-homing NK1.1+ ILC1s was preferentially generated in the perinatal thymi of mice. Unique thymic environments and progenitor cells are responsible for the preferential generation of skin-homing NK1.1+ ILC1s at perinatal stages. In the skin, NK1.1+ ILC1s regulate proper microbiota colonization and control the opportunistic pathogen Pseudomonas aeruginosa in neonatal mice. These findings provide insight into the development and function of tissue-specific immune cells at neonatal stages, a critical temporal window for establishment of local tissue immune homeostasis., Graphical Abstract, Highlights • Perinatal thymi support preferential generation of skin-homing CCR10+ NK1.1+ ILC1s • PLZF is crucial for the perinatal thymic development of CCR10+ NK1.1+ ILC1s • Perinatally derived NK1.1+ ILC1s contribute to skin immune system until adulthood • NK1.1+ ILC1s control skin commensal bacterial colonization during neonatal stages, Immunology; Microbiology

Through the method of Z N -KP hierarchy, we propose a new ( 3 + 1 )-dimensional weakly coupled B-KP equation. Based on the bilinear form, we obtain the lump and rational solutions to the dimensionally reduced cases by constructing a symmetric positive semidefinite matrix. Then, we do numerical analysis on the rational solutions and fit the trajectory equation of the crest. Furthermore, we verify the accuracy of the trajectory equation by numerical analysis. This method of solving the lump and rational solutions can also be applied to other nonlinear evolution equations.

We report 301 dengue virus infections among cross-border travelers entering Yunnan Province, China, from Myanmar during 2017. Phylogenetic analysis of 99 strains found all 4 serotypes co-circulating; genetic characteristics have also changed. This finding highlights the urgent need for monitoring dengue virus cross-border transmission as early warning of severe dengue fever.

OBJECTIVES: Enteropathogenic Escherichia coli (EPEC) poses a great threat to developing countries, as EPEC can result in diarrhea and colitis in children. Interestingly, the effect of trace element nutritional deficiencies as well as their supplementation on disease pathogenesis is increasingly being recognized. We have previously reported that supplementation of mice with selenium (Se), a trace element that is incorporated into selenoproteins as the 21(st) amino acid, resulted in the amelioration of chemically induced colitis through the downregulation of pro-inflammatory mediators of the arachidonic acid pathway, including prostaglandin E2 (PGE2). Here we examined the effects of Se supplementation on immune responses during an enteric infection with Citrobacter rodentium, a natural murine enteropathogen. METHODS: C57BL/6 mice placed on Se-deficient (0.01 ppm Se), Se-adequate (0.08 ppm Se), or Se-supplemented (0.4 ppm Se) diets for 8 weeks were infected with Citrobacter rodentium, the murine equivalent of EPEC with a shared core set of virulence factors. Mice were euthanized, and colons were collected for further analysis including western blots and flow cytometry. RESULTS: Se-deficient mice experienced increased bacterial burden, mortality, and decreased colon length following infection, compared to Se-adequate and Se-supplemented mice. Studies revealed that there was an increase type 3 innate-lymphoid cells (ILC3s) and IL-22 producing T helper 17 (Th17) cells, but a decrease in regulatory T- cells (Tregs) and 15-prostaglandin dehydrogenase (15-PGDH), the enzyme that preferentially oxidizes PGE2, in the colon of Se-deficient mice compared to Se-adequate and Se-supplemented mice. Treatment of Se-adequate mice with CAY10397, an inhibitor of 15-PGDH, increased the bacterial burden following infection. Infection of mice that lack expression of selenoproteins in macrophages (Trsp(fl/fl) LysM(Cre)) showed increased mortality despite being fed diets replete with Se. CONCLUSIONS: Adequate to supplemental levels of dietary Se is required to maximize the expression of selenoproteins to effectively mediate resolution of enteric infections. Selenoproteins act through diverse mechanisms, including modulation of immune responses and inflammation through the oxidative metabolism of PGE(2). FUNDING SOURCES: National Institute of Health.

Men who have sex with men (MSM) have differences in immune activation and gut microbiome composition compared with men who have sex with women (MSW), even in the absence of HIV infection. Gut microbiome differences associated with HIV itself when controlling for MSM, as assessed by 16S rRNA sequencing, are relatively subtle. Understanding whether gut microbiome composition impacts immune activation in HIV-negative and HIV-positive MSM has important implications since immune activation has been associated with HIV acquisition risk and disease progression. To investigate the effects of MSM and HIV-associated gut microbiota on immune activation, we transplanted feces from HIV-negative MSW, HIV-negative MSM, and HIV-positive untreated MSM to gnotobiotic mice. Following transplant, 16S rRNA gene sequencing determined that the microbiomes of MSM and MSW maintained distinct compositions in mice and that specific microbial differences between MSM and MSW were replicated. Immunologically, HIV-negative MSM donors had higher frequencies of blood CD38+ HLADR+ and CD103+ T cells and their fecal recipients had higher frequencies of gut CD69+ and CD103+ T cells, compared with HIV-negative MSW donors and recipients, respectively. Significant microbiome differences were not detected between HIV-negative and HIV-positive MSM in this small donor cohort, and immune differences between their recipients were trending but not statistically significant. A larger donor cohort may therefore be needed to detect immune-modulating microbes associated with HIV. To investigate whether our findings in mice could have implications for HIV replication, we infected primary human lamina propria cells stimulated with isolated fecal microbiota, and found that microbiota from MSM stimulated higher frequencies of HIV-infected cells than microbiota from MSW. Finally, we identified several microbes that correlated with immune readouts in both fecal recipients and donors, and with in vitro HIV infection, which suggests a role for gut microbiota in immune activation and potentially HIV acquisition in MSM., Author summary The communities of commensal microbes that colonize the human gut comprise the gut microbiome, which has been shown to play a significant role in shaping the immune system. Recent studies have reported a distinct gut microbiome composition in men who have sex with men (MSM) exhibiting HIV-risk behaviors when compared with low-risk men who have sex with women (MSW), regardless of their HIV infection status. Whether these gut microbiome differences in high-risk MSM directly impact immune activation is important to understand since increased T cell activation is associated with increased HIV transmission risk and more severe disease. To test the immunological effect of the gut microbiome in MSM, we transplanted stool from HIV-negative MSW, HIV-negative high-risk MSM, and HIV-positive MSM to germ-free mice. DNA sequencing showed that specific microbiome differences associated with MSM were successfully engrafted in mice, and that these differences were associated with increased CD4+ and CD8+ T cell activation in the mice. These results provide evidence for a direct link between microbiome composition and immune activation in HIV-negative and HIV-positive MSM, and rationale for investigating the gut microbiome as a risk factor for HIV transmission.

Macromolecular assembly has been studied for various applications. However, while macromolecules can recognize one another for assembly, their assembled structures usually lack the function of specific molecular recognition. We hypothesized that bifunctional aptamer-protein macromers would possess dual functions of molecular assembly and recognition. The data show that hybrid aptamer-fibrinogen macromers can assemble to form hydrogels. Moreover, the assembled hydrogels can recognize vascular endothelial growth factor (VEGF) for sustained release. When the VEGF-loaded hydrogels are implanted in vivo, they can promote angiogenesis and skin wound healing. Thus, this work has successfully demonstrated a promising macromolecular system for broad applications such as drug delivery and regenerative medicine.

By requiring B=P^sT^dA and substituting u=A+B into the b-family equation and Novikov equation, we can obtain Alice-Bob peakon systems, where P^s and T^d are the arbitrary shifted parity transformation and delayed time reversal transformation, respectively. The nonlocal integrable Camassa-Holm equation and Degasperis-Procesi equation can be derived from the Alice-Bob b-family equations by choosing different parameters. Some new types of interesting solutions are solved including explicit one-peakons, two-peakons, and N-peakons solutions.

Innate lymphoid cells (ILCs) 'preferentially' localize into barrier tissues, where they function in tissue protection but can also contribute to inflammatory diseases. The mechanisms that regulate the establishment of ILCs in barrier tissues are poorly understood. Here we found that under steady-state conditions, ILCs in skin-draining lymph nodes (sLNs) were continuously activated to acquire regulatory properties and high expression of the chemokine receptor CCR10 for localization into the skin. CCR10(+) ILCs promoted the homeostasis of skin-resident T cells and, reciprocally, their establishment in the skin required T cell-regulated homeostatic environments. CD207(+) dendritic cells expressing the transcription factor Foxn1 were required for the proper generation of CCR10(+) ILCs. These observations reveal mechanisms that underlie the specific programming and priming of skin-homing CCR10(+) ILCs in the sLNs.

Versatile controllability of interactions and magnetic field in ultracold atomic gases ha now reached an era where spin mixing dynamics and spin-nematic squeezing can be studied. Recent experiments have realized spin-nematic squeezed vacuum and dynamic stabilization following a quench through a quantum phase transition. Here we propose a scheme for storage of maximal spin-nematic squeezing, with its squeezing angle maintained in a fixed direction, in a dipolar spin-1 condensate by applying a microwave pulse at a time that maximal squeezing occurs. The dynamic stabilization of the system is achieved by manipulating the external periodic microwave pulses. The stability diagram for the range of pulse periods and phase shifts that stabilize the dynamics is numerical simulated and agrees with a stability analysis. Moreover, the stability range coincides well with the spin-nematic vacuum squeezed region which indicates that the spin-nematic squeezed vacuum will never disappear as long as the spin dynamics are stabilized.

Low molecular weight polycyclic aromatic hydrocarbons (LMW PAHs; < 206.3 g/mol) are prevalent and ubiquitous environmental contaminants, presenting a human health concern, and have not been as thoroughly studied as the high MW PAHs. LMW PAHs exert their pulmonary effects, in part, through P38-dependent and -independent mechanisms involving cell-cell communication and the production of pro-inflammatory mediators known to contribute to lung disease. Specifically, we determined the effects of two representative LMW PAHs, 1-methylanthracene (1-MeA) and fluoranthene (Flthn), individually and as a binary PAH mixture on the dysregulation of gap junctional intercellular communication (GJIC) and connexin 43 (Cx43), activation of mitogen activated protein kinases (MAPK), and induction of inflammatory mediators in a mouse non-tumorigenic alveolar type II cell line (C10). Both 1-MeA, Flthn, and the binary PAH mixture of 1-MeA and Flthn dysregulated GJIC in a dose and time-dependent manner, reduced Cx43 protein, and activated the following MAPKs: P38, ERK1/2, and JNK. Inhibition of P38 MAPK prevented PAH-induced dysregulation of GJIC, whereas inhibiting ERK and JNK did not prevent these PAHs from dysregulating GJIC indicating a P38-dependent mechanism. A toxicogenomic approach revealed significant P38-dependent and -independent pathways involved in inflammation, steroid synthesis, metabolism, and oxidative responses. Genes in these pathways were significantly altered by the binary PAH mixture when compared with 1-MeA and Flthn alone suggesting interactive effects. Exposure to the binary PAH mixture induced the production and release of cytokines and metalloproteinases from the C10 cells. Our findings with a binary mixture of PAHs suggest that combinations of LMW PAHs may elicit synergistic or additive inflammatory responses which warrant further investigation and confirmation.

Neutrophils trap and kill bacteria by forming highly decondensed chromatin structures, termed neutrophil extracellular traps (NETs). We previously reported that histone hypercitrullination catalyzed by peptidylarginine deiminase 4 (PAD4) correlates with chromatin decondensation during NET formation. However, the role of PAD4 in NET-mediated bacterial trapping and killing has not been tested. Here, we use PAD4 knockout mice to show that PAD4 is essential for NET-mediated antibacterial function. Unlike PAD4+/+ neutrophils, PAD4−/− neutrophils cannot form NETs after stimulation with chemokines or incubation with bacteria, and are deficient in bacterial killing by NETs. In a mouse infectious disease model of necrotizing fasciitis, PAD4−/− mice are more susceptible to bacterial infection than PAD4+/+ mice due to a lack of NET formation. Moreover, we found that citrullination decreased the bacterial killing activity of histones and nucleosomes, which suggests that PAD4 mainly plays a role in chromatin decondensation to form NETs instead of increasing histone-mediated bacterial killing. Our results define a role for histone hypercitrullination in innate immunity during bacterial infection.

The production of distinct sets of T cell receptor (TCR) gammadelta(+) T cells occurs in an ordered fashion in thymic development. The Vgamma3 and Vgamma4 genes, located downstream in the TCRgamma Cgamma1 gene cluster, are expressed by the earliest waves of developing TCRgammadelta(+) T cells in the fetal thymus, destined for intraepithelial locations. Upstream Vgamma2 and Vgamma5 genes are expressed in later waves in the adult and constitute most TCRgammadelta(+) T cells in secondary lymphoid tissue. This developmental pattern is caused in part by a preference for rearrangements of the downstream Vgamma3 and Vgamma4 genes in the early fetal stage, which switches to a preference for rearrangements of the upstream Vgamma2 and Vgamma5 gene rearrangements in the adult. Our gene targeting studies show that the downstream Vgamma genes rearrange preferentially in the early fetal thymus because of their downstream location, independent of promoter or recombination signal sequences and unrelated to the extent of germline transcription. Remarkably, gene deletion studies show that the downstream Vgamma genes competitively inhibit upstream Vgamma rearrangements at the fetal stage. These data provide a mechanism for specialization of the fetal thymus for the production of T cells expressing specific Vgamma genes.

Quantum Fisher information is a key concept in the field of quantum metrology, which aims to enhance the parameter accuracy by using quantum resources. In this paper, utilizing a representation of quantum Fisher information for a general unitary parametrization process, we study unitary parametrization processes governed by su(2) dynamics. We obtain the analytical expression for the Hermitian operator of the parametrization and the maximal quantum Fisher information. We find that the maximal quantum Fisher information over the parameter space consists of two parts, one is quadratic in the time and the other oscillates with the time. We apply our result to the estimation of a magnetic field and obtained the maximal quantum Fisher information. We further discuss a driving field with a time-dependent Hamiltonian and find the maximal quantum Fisher information of the driving frequency attains optimum when it is in resonance with the atomic frequency., 6 pages, 2 figures, published version

Immunoglobulin E (IgE) activates mast cells (MCs). It remains unknown whether IgE also activates other inflammatory cells, and contributes to the pathogenesis of abdominal aortic aneurysms (AAAs). This study demonstrates that CD4+ T cells express IgE receptor FcεR1, at much higher levels than do CD8+ T cells. IgE induces CD4+ T-cell production of IL6 and IFN-γ, but reduces their production of IL10. FcεR1 deficiency (Fcer1a-/-) protects apolipoprotein E-deficient (Apoe-/-) mice from angiotensin-II infusion-induced AAAs and reduces plasma IL6 levels. Adoptive transfer of CD4+ T cells (but not CD8+ T cells), MCs, and macrophages from Apoe-/- mice, but not those from Apoe-/- Fcer1a-/- mice, increases AAA size and plasma IL6 in Apoe-/- Fcer1a-/- recipient mice. Biweekly intravenous administration of an anti-IgE monoclonal antibody ablated plasma IgE and reduced AAAs in Apoe-/- mice. Patients with AAAs had significantly higher plasma IgE levels than those without AAAs. This study establishes an important role of IgE in AAA pathogenesis by activating CD4+ T cells, MCs, and macrophages and supports consideration of neutralizing plasma IgE in the therapeutics of human AAAs.

Background CCR10 and CCL27 make up the most skin-specific chemokine receptor/ligand pair implicated in skin allergy and inflammatory diseases, including atopic dermatitis and psoriasis. This pair is thought to regulate the migration, maintenance, or both of skin T cells and is suggested to be therapeutic targets for treatment of skin diseases. However, the functional importance of CCR10/CCL27 in vivo remains elusive. Objective We sought to determine the expression and function of CCR10 in different subsets of skin T cells under both homeostatic and inflammatory conditions to gain a mechanistic insight into the potential roles of CCR10 during skin inflammation. Methods Using heterozygous and homozygous CCR10 knockout/enhanced green fluorescent protein knockin mice, we assessed the expression of CCR10 on regulatory and effector T cells of healthy and inflamed skin induced by chemicals, pathogens, and autoreactive T cells. In addition, we assessed the effect of CCR10 knockout on the maintenance and functions of different T cells and inflammatory status in the skin during different phases of the immune response. Results CCR10 expression is preferentially induced on memory-like skin-resident T cells and their progenitors for their maintenance in homeostatic skin but not expressed on most skin-infiltrating effector T cells during inflammation. In CCR10 knockout mice the imbalanced presence and dysregulated function of resident regulatory and effector T cells result in over-reactive and prolonged innate and memory responses in the skin, leading to increased clearance of Leishmania species infection in the skin. Conclusion CCR10 is a critical regulator of skin immune homeostasis.

Decoherence-free subspaces (DFSs) provide a strategy for protecting the dynamics of an open system from decoherence induced by the system-environment interaction. So far, DFSs have been primarily studied in the framework of Markovian master equations. In this work, we study decoherence-free (DF) states in the general setting of a non-Markovian fermionic environment. We identify the DF states by diagonalizing the non-unitary evolution operator for a two-level fermionic system attached to an electron reservoir. By solving the exact master equation, we show that DF states can be stabilized dynamically., Comment: 11 pages, 3 figures. Any comments are welcome

Chemokine receptor CCR10 is expressed by all intestinal IgA-producing plasma cells and is suggested to play an important role in positioning these cells in the lamina propria for proper IgA production to maintain intestinal homeostasis and protect against infection. However, interfering with CCR10 or its ligand did not impair intestinal IgA production under homeostatic conditions or during infection, and the in vivo function of CCR10 in the intestinal IgA response remains unknown. We found that an enhanced generation of IgA + cells in isolated lymphoid follicles of intestines offset defective intestinal migration of IgA + cells in CCR10-KO mice, resulting in the apparently normal IgA production under homeostatic conditions and in primary response to pathogen infection. However, the compensatorily generated IgA + cells in CCR10-KO mice carried fewer hypermutations in their Ig heavy chain alleles than those of WT mice, indicating that their IgA repertoires are qualitatively different, which might impact the intestinal homeostasis of microflora. In addition, CCR10-deficient long-lived IgA-producing plasma cells and IgA + memory B cells generated against the pathogen infection could not be maintained properly in intestines. Consequently, IgA memory responses to the pathogen reinfection were severely impaired in CCR10-KO mice. These findings elucidate critical roles of CCR10 in regulating the intestinal IgA response and memory maintenance and could help in design of vaccines against intestinal and possibly other mucosal pathogens.

Objective— Cathepsin K (CatK) is one of the most potent mammalian elastases. We have previously shown increased expression of CatK in human abdominal aortic aneurysm (AAA) lesions. Whether this protease participates directly in AAA formation, however, remains unknown. Methods and Results— Mouse experimental AAA was induced with aortic perfusion of a porcine pancreatic elastase. Using this experimental model, we demonstrated that absence of CatK prevented AAA formation in mice 14 days postperfusion. CatK deficiency significantly reduced lesion CD4 + T-cell content, total lesion and medial cell proliferation and apoptosis, medial smooth muscle cell (SMC) loss, elastinolytic CatL and CatS expression, and elastin fragmentation, but it did not affect AAA lesion Mac-3 + macrophage accumulation or CD31 + microvessel numbers. In vitro studies revealed that CatK contributed importantly to CD4 + T-cell proliferation, SMC apoptosis, and other cysteinyl cathepsin and matrix metalloproteinase expression and activities in SMCs and endothelial cells but played negligible roles in microvessel growth and monocyte migration. AAA lesions from CatK-deficient mice showed reduced elastinolytic cathepsin activities compared with those from wild-type control mice. Conclusion— This study demonstrates that CatK plays an essential role in AAA formation by promoting T-cell proliferation, vascular SMC apoptosis, and elastin degradation and by affecting vascular cell protease expression and activities.

Unlike conventional αβ T cells, which preferentially reside in secondary lymphoid organs for adaptive immune responses, various subsets of unconventional T cells, such as the γδ T cells with innate properties, preferentially reside in epithelial tissues as the first line of defense. However, mechanisms underlying their tissue-specific development are not well understood. We report in this paper that among different thymic T cell subsets fetal thymic precursors of the prototypic skin intraepithelial Vγ3+ T lymphocytes (sIELs) were selected to display a unique pattern of homing molecules, including a high level of CCR10 expression that was important for their development into sIELs. In fetal CCR10-knockout mice, the Vγ3+ sIEL precursors developed normally in the thymus but were defective in migrating into the skin. Although the earlier defect in skin-seeding by sIEL precursors was partially compensated for by their normal expansion in the skin of adult CCR10-knockout mice, the Vγ3+ sIELs displayed abnormal morphology and increasingly accumulated in the dermal region of the skin. These findings provide definite evidence that CCR10 is important in sIEL development by regulating the migration of sIEL precursors and their maintenance in proper regions of the skin and support the notion that unique homing properties of different thymic T cell subsets play an important role in their peripheral location.

The exact non-Markovian dynamics of a microcavity strongly coupled to a general reservoir at arbitrary temperature is studied. With the exact master equation for the reduced density operator of the cavity system, we analytically solve the time evolution of the cavity state and the associated physical observables. We show that the non-Markovian dynamics is completely determined by the propagating (retarded) and correlation Green functions. Compare the non-Markovian behavior at finite temperature with those at zero-temperature limit or Born-Markov limit, we find that the non-Markovian memory effect can dramatically change the coherent and thermal dynamics of the cavity. We also numerically study the dissipation dynamics of the cavity through the mean mode amplitude decay and the average photon number decay in the microwave regime. It is shown that the strong coupling between the cavity and the reservoir results in a long-time dissipationless evolution to the cavity field amplitude, and its noise dynamics undergoes a critical transition from the weak to strong coupling due to the non-Markovian memory effect., 12 pages, 6 figures

Assembly of TCRalpha and TCRdelta genes from the TCRalpha/delta locus is tightly controlled for the proper generation of alphabeta and gammadelta T cells. Of100 shared variable gene segments in the TCRalpha/delta locus, only a few are predominantly used for the TCRdelta gene assembly, while most are for TCRalpha. However, the importance and mechanisms of the selective variable gene rearrangement for T cell development are not fully understood. We report herein that the development of a tissue-specific gammadelta T cell population is critically affected by recombination signal sequence-associated restriction on the variable gene usage for TCRdelta assembly. We found that the development of substitute skin gammadelta T cells in mice deficient of the TCRgamma3 gene, which is used in wild-type skin gammadelta T cells, was drastically affected by the strain background. A Vgamma2(+) skin gammadelta T cell population developed in mice of the B6 but not the 129 strain backgrounds, due to a difference in the rearrangement of endogenous Vdelta7(+) TCRdelta genes, which paired with the Vgamma2(+) TCRgamma gene to generate the Vgamma2/Vdelta7(+) skin gammadelta T cell precursors in fetal thymi of the B6 background mice. The defective TCRdelta rearrangement of the 129-"Vdelta7" gene was associated with specific variations in its recombination signal sequence, which renders it poorly compatible for rearrangement to Ddelta genes. These findings provide the first direct evidence that recombination signal sequence-associated restriction on the variable gene usage for TCRalpha/delta gene assembly plays an important role in T cell development.