Friends in Low Places: Intestinal Commensals Limit Colitis through Molecular Mimicry.

Inflammatory bowel disease is thought to arise from inappropriate inflammation to gut bacteria, yet mechanisms preventing these responses remain elusive. In this issue of Cell, Nanjundappa et al. report that Bacteroides share an epitope with a pancreas-specific peptide that induces protective CD8+ T cells, identifying molecular mimicry as a mechanism to enforce tolerance in the gut.

Search for Evidence of Baryogenesis and Dark Matter in B

A new dark sector antibaryon, denoted ψ_{D}, could be produced in decays of B mesons. This Letter presents a search for B^{+}→ψ_{D}+p (and the charge conjugate) decays in e^{+}e^{-} annihilations at 10.58 GeV, using data collected in the BABAR experiment. Data corresponding to an integrated luminosity of 398 fb^{-1} are analyzed. No evidence for a signal is observed. Branching fraction upper limits in the range from 10^{-7}-10^{-5} are obtained at 90% confidence level for masses of 1.0

The Global Task Force for Chronic Pain in People with HIV (PWH): Developing a research agenda in an emerging field.

Chronic pain is a common comorbidity in people with HIV (PWH), with prevalence estimates of 25-85%. Research in this area is growing, but significant gaps remain. A Global Task Force of HIV experts was organized to brainstorm a scientific agenda and identify measurement domains critical to advancing research in this field. Experts were identified through literature searches and snowball sampling. Two online questionnaires were developed by Task Force members. Questionnaire 1 asked participants to identify knowledge gaps in the field of HIV and chronic pain and identify measurement domains in studies of chronic pain in PWH. Responses were ranked in order of importance in Questionnaire 2, which was followed by a group discussion. 29 experts completed Questionnaire 1, 25 completed Questionnaire 2, and 21 participated in the group. Many important clinical and research priorities emerged, including the need to examine etiologies of chronic pain in PWH. Pain-related measurement domains were discussed, with a primary focus on domains that could be assessed in a standardized manner across various cohorts that include PWH in different countries. We collaboratively identified clinical and research priorities, as well as gaps in standardization of measurement domains, that can be used to move the field forward.

CX3CR1 deficiency leads to impairment of immune surveillance in the epididymis.

Mononuclear phagocytes (MPs) play an active role in the immunological homeostasis of the urogenital tract. In the epididymis, a finely tuned balance between tolerance to antigenic sperm and immune activation is required to maintain epididymal function while protecting sperm against pathogens and stressors. We previously characterized a subset of resident MPs that express the CX3CR1 receptor, emphasizing their role in antigen sampling and processing during sperm maturation and storage in the murine epididymis. Bacteria-associated epididymitis is the most common cause of intrascrotal inflammation and frequently leads to reproductive complications. Here, we examined whether the lack of functional CX3CR1 in homozygous mice (CX3CR1EGFP/EGFP, KO) alters the ability of MPs to initiate immune responses during epididymitis induced by LPS intravasal-epididymal injection. Confocal microscopy revealed that CX3CR1-deficient MPs located in the initial segments of the epididymis displayed fewer luminal-reaching membrane projections and impaired antigen capture activity. Moreover, flow cytometry showed a reduction of epididymal KO MPs with a monocytic phenotype under physiological conditions. In contrast, flow cytometry revealed an increase in the abundance of MPs with a monocytic signature in the distal epididymal segments after an LPS challenge. This was accompanied by the accumulation of CD103+ cells in the interstitium, and the prevention or attenuation of epithelial damage in the KO epididymis during epididymitis. Additionally, CX3CR1 deletion induced downregulation of Gja1 (connexin 43) expression in KO MPs. Together, our study provides evidence that MPs are gatekeepers of the immunological blood-epididymis barrier and reveal the role of the CX3CR1 receptor in epididymal mucosal homeostasis by inducing MP luminal protrusions and by regulating the monocyte population in the epididymis at steady state as well as upon infection. We also uncover the interaction between MPs and CD103+ dendritic cells, presumably through connexin 43, that enhance immune responses during epididymitis. Our study may lead to new diagnostics and therapies for male infertility and epididymitis by identifying immune mechanisms in the epididymis.

Comprehensive assessment of germline pathogenic variant detection in tumor-only sequencing.

BACKGROUND: Tumor-only sequencing, implemented for the identification of somatic variants, is oftentimes used for the detection of actionable germline variants. We sought to determine whether tumor-only sequencing assays are suitable for detection of actionable germline variants, given their importance for the delivery of targeted therapies and risk-reducing measures. PATIENTS AND METHODS: The detection of germline variants affecting moderate- and high-penetrance cancer susceptibility genes (CSGs) by tumor-only sequencing was compared to clinical germline testing in 21 333 cancer patients who underwent tumor and germline testing using the Food and Drug Administration (FDA)-authorized Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Targets (MSK-IMPACT) assay. Seven homologous recombination deficiency (HRD), two DNA damage response (DDR) and four mismatch repair (MMR) genes, as well as NF1, RB1 and TP53 were included in the analysis. FDA-authorized and New York State Department of Health-approved sequencing methods for germline, tumor/normal and tumor-only sequencing assays and analytical pipelines were employed. RESULTS: In patients who underwent tumor and germline sequencing, as compared to clinical genetic testing, tumor-only sequencing failed to detect 10.5% of clinically actionable pathogenic germline variants in CSGs, including 18.8%, 12.8% and 7.3% of germline variants in MMR, DDR and HRD genes, respectively. The sensitivity for detection of pathogenic germline variants by tumor-only sequencing was 89.5%. Whilst the vast majority of pathogenic germline exonic single-nucleotide variants (SNVs) and small indels were detected by tumor-only sequencing, large percentages of germline copy number variants, intronic variants and repetitive element insertions were not detected. CONCLUSIONS: Tumor-only sequencing is adequate for the detection of clinically actionable germline variants, particularly for SNVs and small indels; however, a small subset of alterations affecting HRD, DDR and MMR genes may not be detected optimally. Therefore, for high-risk patients with negative tumor-only sequencing results, clinical genetic testing could be considered given the impact of these variants on therapy and genetic counseling.

Genome sequencing reveals underdiagnosis of primary ciliary dyskinesia in bronchiectasis.

BACKGROUND: Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60-80% of cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia (PCD). Diagnosis of PCD has management implications including addressing comorbidities, implementing genetic and fertility counselling and future access to PCD-specific treatments. Diagnostic testing can be complex; however, PCD genetic testing is moving rapidly from research into clinical diagnostics and would confirm the cause of bronchiectasis. METHODS: This observational study used genetic data from severe bronchiectasis patients recruited to the UK 100,000 Genomes Project and patients referred for gene panel testing within a tertiary respiratory hospital. Patients referred for genetic testing due to clinical suspicion of PCD were excluded from both analyses. Data were accessed from the British Thoracic Society audit, to investigate whether motile ciliopathies are underdiagnosed in people with bronchiectasis in the UK. RESULTS: Pathogenic or likely pathogenic variants were identified in motile ciliopathy genes in 17 (12%) out of 142 individuals by whole-genome sequencing. Similarly, in a single centre with access to pathological diagnostic facilities, 5-10% of patients received a PCD diagnosis by gene panel, often linked to normal/inconclusive nasal nitric oxide and cilia functional test results. In 4898 audited patients with bronchiectasis, <2% were tested for PCD and <1% received genetic testing. CONCLUSIONS: PCD is underdiagnosed as a cause of bronchiectasis. Increased uptake of genetic testing may help to identify bronchiectasis due to motile ciliopathies and ensure appropriate management.

Tradeoff between the Brillouin and transverse mode instabilities in Yb-doped fiber amplifiers.

The Brillouin instability (BI) due to stimulated Brillouin scattering (SBS) and the transverse (thermal) mode instability (TMI) due to stimulated thermal Rayleigh scattering (STRS) limit the achievable power in high-power lasers and amplifiers. The pump power threshold for BI increases as the core diameter increases, but the threshold for TMI may decrease as the core diameter increases. In this paper, we use a multi-time-scale approach to simultaneously model BI and TMI, which gives us the ability to find the fiber diameter with the highest power threshold. We formulate the equations to compare the thresholds of the combined and individual TMI and BI models. At the pump power threshold and below, there is a negligible difference between the full and individual models, as BI and TMI are not strong enough to interact with each other. The highest pump threshold occurs at the optimal core size of 43 µm for the simple double-clad geometry that we considered. We found that both effects contribute equally to the threshold, and the full BI and TMI model yields a similar threshold as the BI or TMI model alone. However, once the reflectivity is sufficiently large, we find in the full BI and TMI model that BI may trigger TMI and reduce the TMI threshold to a value lower than is predicted in simulations with TMI alone. This result cannot be predicted by models that consider BI and TMI separately. Our approach can be extended to more complex geometries and used for their optimization.

Search for an Axionlike Particle in B Meson Decays.

Axionlike particles (ALPs) are predicted in many extensions of the standard model, and their masses can naturally be well below the electroweak scale. In the presence of couplings to electroweak bosons, these particles could be emitted in flavor-changing B meson decays. We report herein a search for an ALP, a, in the reaction B^{±}→K^{±}a, a→γγ using data collected by the BABAR experiment at SLAC. No significant signal is observed, and 90% confidence level upper limits on the ALP coupling to electroweak bosons are derived as a function of ALP mass, improving current constraints by several orders of magnitude in the range 0.175 GeV

Search for Darkonium in e

Collider searches for dark sectors, new particles interacting only feebly with ordinary matter, have largely focused on identifying signatures of new mediators, leaving much of dark sector structures unexplored. In particular, the existence of dark matter bound states (darkonia) remains to be investigated. This possibility could arise in a simple model in which a dark photon (A^{'}) is light enough to generate an attractive force between dark fermions. We report herein a search for a J^{PC}=1^{--} darkonium state, the ϒ_{D}, produced in the reaction e^{+}e^{-}→γϒ_{D}, ϒ_{D}→A^{'}A^{'}A^{'}, where the dark photons subsequently decay into pairs of leptons or pions, using 514 fb^{-1} of data collected with the BABAR detector. No significant signal is observed, and we set bounds on the γ-A^{'} kinetic mixing as a function of the dark sector coupling constant for 0.001

Search for Lepton Flavor Violation in ϒ(3S)→e

We report on the first search for electron-muon lepton flavor violation (LFV) in the decay of a b quark and b antiquark bound state. We look for the LFV decay ϒ(3S)→e^{±}µ^{∓} in a sample of 118 million ϒ(3S) mesons from 27 fb^{-1} of data collected with the BABAR detector at the SLAC PEP-II e^{+}e^{-} collider operating with a 10.36 GeV center-of-mass energy. No evidence for a signal is found, and we set a limit on the branching fraction B[ϒ(3S)→e^{±}µ^{∓}]<3.6×10^{-7} at 90% C. L. This result can be interpreted as a limit Λ_{NP}/g_{NP}^{2}>80 TeV on the energy scale Λ_{NP} divided by the coupling-squared g_{NP}^{2} of relevant new physics (NP).

The effect of varying levels of purified condensed tannins on performance, blood profile, meat quality and methane emission in male Bapedi sheep fed grass hay and pellet-based diet.

This study determined the effect of purified condensed tannin inclusion levels in a diet on production, haematological indices, blood biochemical components, meat quality and methane emission by yearling indigenous male Bapedi sheep on a grass hay and sheep pellet-based diet in a 28-day trial. The diets contained similar (P > 0.05) nutrients but with different (P < 0.05) purified condensed tannin supplementation levels. A complete randomized design was used. Twenty-four yearling male Bapedi sheep were assigned to four dietary treatments having different purified condensed tannin levels of 0 (GH80P20PCT0), 30 (GH80P20PCT30), 40 (GH80P20PCT40) and 50 (GH80P20PCT50) g/kg DM. A quadratic type of equation was also used to determine condensed tannin supplementation levels for optimal performance and methane emission reduction by sheep. Supplementing diets with purified condensed tannins did not affect (P > 0.05) diet intake, digestibility and live weight gain of male Bapedi sheep. Supplementing diets with purified condensed tannins did not affect (P > 0.05) blood components of male Bapedi sheep. Inclusion of condensed tannins in the diets did not affect (P > 0.05) Bapedi sheep meat pH and sensory attributes. However, supplementing diets with purified condensed tannins decreased (P < 0.05) methane emission by 51 to 60%. A 49.08 g supplementation level with purified condensed tannins per kg DM diet was calculated, with the use of quadratic equations, to result in the lowest methane emission by male Bapedi sheep. The meat of male Bapedi rams on diets containing 30, 40 or 50 g of purified condensed tannins per kg DM contained higher (P < 0.05) antioxidant activities than those from rams fed a diet without purified condensed tannins. These results indicate that purified condensed tannin supplementation levels of 0, 30, 40 or 50 g/kg DM diet had no adverse effects on growth performance, blood profiles and meat sensory attributes of male Bapedi sheep. However, supplementation levels of 30, 40 or 50 g of purified condensed tannins per kg DM diet reduced methane emission by 51 to 60%, and increased sheep meat antioxidant activity values. Supplementing diets with purified condensed tannins has the potential to reduce methane production and emission by sheep. However, long-term studies are recommended to ascertain the present findings.

Accurate and efficient modeling of the transverse mode instability in high energy laser amplifiers.

We study the transverse mode instability (TMI) in the limit where a single higher-order mode (HOM) is present. We demonstrate that when the beat length between the fundamental mode and the HOM is small compared to the length scales on which the pump amplitude and the optical mode amplitudes vary, TMI is a three-wave mixing process in which the two optical modes beat with the phase-matched component of the index of refraction that is induced by the thermal grating. This limit is the usual limit in applications, and in this limit TMI is identified as a stimulated thermal Rayleigh scattering (STRS) process. We demonstrate that a phase-matched model that is based on the three-wave mixing equations can have a large computational advantage over current coupled mode methods that must use longitudinal step sizes that are small compared to the beat length.

Point Absorber Limits to Future Gravitational-Wave Detectors.

High-quality optical resonant cavities require low optical loss, typically on the scale of parts per million. However, unintended micron-scale contaminants on the resonator mirrors that absorb the light circulating in the cavity can deform the surface thermoelastically and thus increase losses by scattering light out of the resonant mode. The point absorber effect is a limiting factor in some high-power cavity experiments, for example, the Advanced LIGO gravitational-wave detector. In this Letter, we present a general approach to the point absorber effect from first principles and simulate its contribution to the increased scattering. The achievable circulating power in current and future gravitational-wave detectors is calculated statistically given different point absorber configurations. Our formulation is further confirmed experimentally in comparison with the scattered power in the arm cavity of Advanced LIGO measured by in situ photodiodes. The understanding presented here provides an important tool in the global effort to design future gravitational-wave detectors that support high optical power and thus reduce quantum noise.

Accurate detection of Zika virus IgG using a novel immune complex binding ELISA.

OBJECTIVES: Accurate serological assays are urgently needed to support public health responses to Zika virus (ZIKV) infection with its potential to cause foetal damage during pregnancy. Current flavivirus serology for ZIKV infections lacks specificity due to cross-reacting antibodies from closely related other flaviviruses. In this study, we evaluated novel serological tests for accurate ZIKV IgG detection. METHODS: Our ELISAs are based on immune complex binding. The high specificity is achieved by the simultaneous incubation of labelled ZIKV antigen and unlabelled flavivirus homolog protein competitors. Two assays were validated with a panel of 406 human samples from PCR-confirmed ZIKV patients collected in Brazil (n = 154), healthy blood donors and other infections from Brazil, Europe, Canada and Colombia (n = 252). RESULTS: The highest specificity (100% [252/252, 95% confidence interval (CI) 98.5-100.0]) was shown by the ZIKV ED3 ICB ELISA using the ED3 antigen of the ZIKV envelope. A similar test using the NS1 antigen (ZIKV NS1 ICB ELISA) was slightly less specific (92.1% [232/252, 95% CI 88.0-95.1]). The commercial Euroimmun ZIKV ELISA had a specificity of only 82.1% (207/252, 95% CI 76.8-86.7). Sensitivity was high (93-100%) from day 12 after onset of symptoms in all three tests. Seroprevalence of ZIKV IgG was analysed in 87 samples from Laos (Asia) confirming that the ED3 ELISA showed specific reactions in other populations. CONCLUSIONS: The novel ED3 ICB ELISA will be useful for ZIKV-specific IgG detection for seroepidemiological studies and serological diagnosis for case management in travellers and in countries where other flavivirus infections are co-circulating.

Process and Outcome Evaluation of a Mindfulness-Based Cognitive Therapy Intervention for Cisgender and Transgender African American Women Living with HIV/AIDS.

There is a need for evidence-based contextualized mental health interventions for persons living with HIV/AIDS. In the current study, the primary researcher conducted open trials with African American women living with HIV/AIDS (AAWLWHA) to examine the acceptability and feasibility of Project UPLIFT, a mindfulness-based cognitive therapy intervention that has demonstrated effectiveness in persons living with epilepsy. Women were recruited for a tele-delivered phone intervention group separated by gender identity, as well as participated in pre- and post-test assessments. Additionally, data on acceptability was collected. Both cis- and transgender women were highly satisfied with the intervention and demonstrated improvement in depressive and stress symptoms. The intervention seemed to be particularly feasible for cisgender women, though more qualitative mental health research may be warranted with transgender women. The current research has implications for the utility of mindfulness-based interventions such as UPLIFT, with AAWLWHA.

Modeling circulating cavity fields using the discrete linear canonical transform.

Fabry-Perot cavities are central to many optical measurement systems. In high-precision experiments, such as aLIGO and AdVirgo, coupled cavities are often required, leading to complex optical behavior. We show, for the first time to our knowledge, that discrete linear canonical transforms (LCTs) can be used to compute circulating optical fields for cavities in which the optics have arbitrary apertures, reflectance and transmittance profiles, and shape. We compare the predictions of LCT models with those of alternative methods. To further highlight the utility of the LCT, we present a case study of point absorbers on the aLIGO mirrors and compare it with recently published results.

From initial segment to cauda: a regional characterization of mouse epididymal CD11c+ mononuclear phagocytes based on immune phenotype and function.

Successful sperm maturation and storage rely on a unique immunological balance that protects the male reproductive organs from invading pathogens and spermatozoa from a destructive autoimmune response. We previously characterized one subset of mononuclear phagocytes (MPs) in the murine epididymis, CX3CR1+ cells, emphasizing their different functional properties. This population partially overlaps with another subset of understudied heterogeneous MPs, the CD11c+ cells. In the present study, we analyzed the CD11c+ MPs for their immune phenotype, morphology, and antigen capturing and presenting abilities. Epididymides from CD11c-EYFP mice, which express enhanced yellow fluorescent protein (EYFP) in CD11c+ MPs, were divided into initial segment (IS), caput/corpus, and cauda regions. Flow cytometry analysis showed that CD11c+ MPs with a macrophage phenotype (CD64+ and F4/80+) were the most abundant in the IS, whereas those with a dendritic cell signature [CD64- major histocompatibility complex class II (MHCII)+] were more frequent in the cauda. Immunofluorescence revealed morphological and phenotypic differences between CD11c+ MPs in the regions examined. To assess the ability of CD11c+ cells to take up antigens, CD11c-EYFP mice were injected intravenously with ovalbumin. In the IS, MPs expressing macrophage markers were most active in taking up the antigens. A functional antigen-presenting coculture study was performed, whereby CD4+ T cells were activated after ovalbumin presentation by CD11c+ epididymal MPs. The results demonstrated that CD11c+ MPs in all regions were capable of capturing and presenting antigens. Together, this study defines a marked regional variation in epididymal antigen-presenting cells that could help us understand fertility and contraception but also has larger implications in inflammation and disease pathology.

Molecular patterns from a human gut-derived Lactobacillus strain suppress pathogenic infiltration of leukocytes into the central nervous system.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory demyelinating disease that affects 2.5 million people worldwide. Growing evidence suggests that perturbation of the gut microbiota, the dense collection of microorganisms that colonize the gastrointestinal tract, plays a functional role in MS. Indeed, specific gut-resident bacteria are altered in patients with MS compared to healthy individuals, and colonization of gnotobiotic mice with MS-associated microbiota exacerbates preclinical models of MS. However, defining the molecular mechanisms by which gut commensals can remotely affect the neuroinflammatory process remains a critical gap in the field. METHODS: We utilized monophasic experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice and relapse-remitting EAE in SJL/J mice to test the effects of the products from a human gut-derived commensal strain of Lactobacillus paracasei (Lb). RESULTS: We report that Lb can ameliorate preclinical murine models of MS with both prophylactic and therapeutic administrations. Lb ameliorates disease through a Toll-like receptor 2-dependent mechanism via its microbe-associated molecular patterns that can be detected in the systemic circulation, are sufficient to downregulate chemokine production, and can reduce immune cell infiltration into the central nervous system (CNS). In addition, alterations in the gut microbiota mediated by Lb-associated molecular patterns are sufficient to provide partial protection against neuroinflammatory diseases. CONCLUSIONS: Local Lb modulation of the gut microbiota and the shedding of Lb-associated molecular patterns into the circulation may be important physiological signals to prevent aberrant peripheral immune cell infiltration into the CNS and have relevance to the development of new therapeutic strategies for MS.

Precision Measurement of the Ratio B(ϒ(3S)→τ

We report on a precision measurement of the ratio R_{τµ}^{ϒ(3S)}=B(ϒ(3S)→τ^{+}τ^{-})/B(ϒ(3S)→µ^{+}µ^{-}) using data collected with the BABAR detector at the SLAC PEP-II e^{+}e^{-} collider. The measurement is based on a 28 fb^{-1} data sample collected at a center-of-mass energy of 10.355 GeV corresponding to a sample of 122 million ϒ(3S) mesons. The ratio is measured to be R_{τµ}^{ϒ(3S)}=0.966±0.008_{stat}±0.014_{syst} and is in agreement with the standard model prediction of 0.9948 within 2 standard deviations. The uncertainty in R_{τµ}^{ϒ(3S)} is almost an order of magnitude smaller than the only previous measurement.

Search for a Dark Leptophilic Scalar in e

Many scenarios of physics beyond the standard model predict the existence of new gauge singlets, which might be substantially lighter than the weak scale. The experimental constraints on additional scalars with masses in the MeV to GeV range could be significantly weakened if they interact predominantly with leptons rather than quarks. At an e^{+}e^{-} collider, such a leptophilic scalar (ϕ_{L}) would be produced predominantly through radiation from a τ lepton. We report herein a search for e^{+}e^{-}→τ^{+}τ^{-}ϕ_{L}, ϕ_{L}→ℓ^{+}ℓ^{-} (ℓ=e, µ) using data collected by the BABAR experiment at SLAC. No significant signal is observed, and we set limits on the ϕ_{L} coupling to leptons in the range 0.04