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Reich B, Zhou Y, Goldstein E, Srivats SS, Contoreggi NH, Kogan JF, McEwen BS, Kreek MJ, Milner TA, Gray JD
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Chronic immobilization stress primes the hippocampal opioid system for oxycodone-associated learning in female but not male rats

SYNAPSE 2019 MAY; 73(5):? Article e22088
In adult female, but not male, Sprague Dawley rats, chronic immobilization stress (CIS) increases mossy fiber (MF) Leu-Enkephalin levels and redistributes delta- and mu-opioid receptors (DORs and MORs) in hippocampal CA3 pyramidal cells and GABAergic interneurons to promote excitation and learning processes following subsequent opioid exposure. Here, we demonstrate that CIS females, but not males, acquire conditioned place preference (CPP) to oxycodone and that CIS "primes" the hippocampal opioid system in females for oxycodone-associated learning. In CA3b, oxycodone-injected (Oxy) CIS females relative to saline-injected (Sal) CIS females exhibited an increase in the cytoplasmic and total densities of DORs in pyramidal cell dendrites so that they were similar to Sal- and Oxy-CIS males. Consistent with our earlier studies, Sal- and Oxy-CIS females but not CIS males had elevated DOR densities in MF-CA3 dendritic spines, which we have previously shown are important for opioid-mediated long-term potentiation. In the dentate gyrus, Oxy-CIS females had more DOR-labeled interneurons than Sal-CIS females. Moreover, Sal- and Oxy-CIS females compared to both groups of CIS males had elevated levels of DORs and MORs in GABAergic interneuron dendrites, suggesting capacity for greater synthesis or storage of these receptors in circuits important for opioid-mediated disinhibition. However, more plasmalemmal MORs were on large parvalbumin-containing dendrites of Oxy-CIS males compared to Sal-CIS males, suggesting a limited ability for increased granule cell disinhibition. These results suggest that low levels of DORs in MF-CA3 synapses and hilar GABAergic interneurons may contribute to the attenuation of oxycodone CPP in males exposed to CIS.
Nasca C, Watson-Lin K, Bigio B, Robakis TK, Myoraku A, Wroolie TE, McEwen BS, Rasgon N
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Childhood trauma and insulin resistance in patients suffering from depressive disorders

Objective: Insulin resistance (IR) is a metabolic dysfunction often co-morbid with major depressive disorder (MDD). The paths to development of MDD remain largely unspecified, highlighting a need for identification of risk factors. Here, we tested whether specific subscales of childhood trauma as well as family history of type-2 diabetes (Fam-Hx-Dm2) are risk factors for development of metabolic dysfunction and severity of depressive symptoms. Research design and methods: We used a sample of 45 adults suffering from MDD that was well-characterized for insulin resistance and sensitivity as assessed by measures of fasting plasma glucose (FPG) plasma insulin (FPI) levels, body mass index (BMI), weight, homeostasis model assessment of insulin sensitivity (HOMA), Matsuda index as well as both glucose and insulin responses to oral glucose challenges, Severity of depressive symptoms was assessed with the Hamilton Depression Rating Scale (HDRS-21). Physical, sexual and emotional abuse as well as physical and emotional neglect were assessed with the Childhood Trauma Questionnaire. First-or second-degree relatives with type-2 diabetes defined fam-Hx-DM2. Results: Individuals reporting higher rates of emotional abuse were more likely to have greater IR as showed by elevated FPI levels and HOMA. No association was found with any of the other subscales of childhood trauma (e.g., physical abuse). Similarly, Fam-Hx-DM2 was associated with greater degree of IR as shown by elevated FPI, HOMA, but also FPG, weight and BMI. Moreover, we report a relationship and interaction between Fam-Hx-DM2 and emotional abuse on severity of depressive symptoms. Specifically, emotional abuse and Fam-HX-DM2 predicted severity of depressive symptoms at HDRS-21. Also, severity of depressive symptoms was greater with higher reported rates of emotional abuse but only in patients with negative Fam-HX-Dm2. Individuals reporting higher emotional abuse and negative Fam-Hx-Dm2 also showed higher FPG levels. Conversely, individuals reporting higher emotional abuse and positive Fam-Hx-Dm2 showed higher FPI levels. This data suggest that Fam-Hx-Dm2 may define two different metabolic endophenotypes. Conclusions: Our findings suggest that Fam-HX-DM2 and emotional abuse represent separate risk factors for developing metabolic dysfunction (i.e.: IR) in patients suffering from MDD, and that the effects of emotional abuse on psychiatric illness may depend upon the personal characteristics, including Farn-Hx-DM2.
Understanding the genetic and metabolic bases of obesity is helpful in planning and developing health strategies. Therefore, the first family-based joint linkage and linkage disequilibrium study was conducted in Iranian pedigrees to assess the relationship between obesity and single-nucleotide polymorphisms (SNPs) located in the 16q12.2 region. In the present study, a total of 13,344 individuals were included, of whom 12,502 individuals were within 3,109 pedigrees and 842 were unrelated singletons. To investigate the relationship between obesity and genetic variants, a joint model of linkage and linkage disequilibrium was applied. Moreover, a sequence kernel association test (SKAT) was used to evaluate the association of the SNP set with body size and lipid profile measurements. The joint model showed that rs13334070, in the intron 4 of the RPGRIP1L gene, has a significant association with obesity. According to the 4-gamete rule, which is a procedure for constructing SNP sets by considering recombination occurrence between SNPs, this polymorphism has a high correlation with six nearby SNPs that make an SNP set. SKAT showed that this SNP set has a significant association with body size factors, but almost no association with most of the lipid profile measurements. In conclusion, from the result of this study, it might be reasonable to consider RPGRIP1L as an important gene whose variations could be associated with obesity risk factors.
Vibholm LK, Lorenzi JCC, Pai JA, Cohen YZ, Oliveira TY, Barton JP, Noceda MG, Lu CL, Ablanedo-Terrazas Y, Estrada PMD, Reyes-Teran G, Tolstrup M, Denton PW, Damsgaard T, Sogaard OS, Nussenzweig MC
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Characterization of Intact Proviruses in Blood and Lymph Node from HIV-Infected Individuals Undergoing Analytical Treatment Interruption

JOURNAL OF VIROLOGY 2019 APR; 93(8):? Article e01920-18
The role of lymphoid tissue as a potential source of HIV-1 rebound following interruption of antiretroviral therapy (ART) is uncertain. To address this issue, we compared the latent viruses obtained from CD4(+) T cells in peripheral blood and lymph nodes to viruses emerging during treatment interruption. Latent viruses were characterized by sequencing near-full-length (NFL) proviral DNA and env from viral outgrowth assays (VOAs). Five HIV-1-infected individuals on ART were studied, four of whom participated in a clinical trial of a TLR9 agonist that included an analytical treatment interruption. We found that 98% of intact or replication-competent clonal sequences overlapped between blood and lymph node. In contrast, there was no overlap between 205 latent reservoir and 125 rebound sequences in the four individuals who underwent treatment interruption. However, rebound viruses could be accounted for by recombination. The data suggest that CD4(+) T cells carrying latent viruses circulate between blood and lymphoid tissues in individuals on ART and support the idea that recombination may play a role in the emergence of rebound viremia. IMPORTANCE HIV-1 persists as a latent infection in CD4(+) T cells that can be found in lymphoid tissues in infected individuals during ART. However, the importance of this tissue reservoir and its contribution to viral rebound upon ART interruption are not clear. In this study, we sought to compare latent HIV-1 from blood and lymph node CD4(+) T cells from five HIV-1-infected individuals. Further, we analyzed the contribution of lymph node viruses to viral rebound. We observed that the frequencies of intact proviruses were the same in blood and lymph node. Moreover, expanded clones of T cells bearing identical proviruses were found in blood and lymph node. These latent reservoir sequences did not appear to be the direct origin of rebound virus. Instead, latent proviruses were found to contribute to the rebound compartment by recombination.
Hubel P, Urban C, Bergant V, Schneider WM, Knauer B, Stukalov A, Scaturro P, Mann A, Brunotte L, Hoffmann HH, Schoggins JW, Schwemmle M, Mann M, Rice CM, Pichlmair A
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A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape

NATURE IMMUNOLOGY 2019 APR; 20(4):493-502
Interferon-stimulated genes (ISGs) form the backbone of the innate immune system and are important for limiting intra- and intercellular viral replication and spread. We conducted a mass-spectrometry-based survey to understand the fundamental organization of the innate immune system and to explore the molecular functions of individual ISGs. We identified interactions between 104 ISGs and 1,401 cellular binding partners engaging in 2,734 high-confidence interactions. 90% of these interactions are unreported so far, and our survey therefore illuminates a far wider activity spectrum of ISGs than is currently known. Integration of the resulting ISG-interaction network with published datasets and functional studies allowed us to identify regulators of immunity and processes related to the immune system. Given the extraordinary robustness of the innate immune system, this ISG network may serve as a blueprint for therapeutic targeting of cellular systems to efficiently fight viral infections.
Beziat V, Jouanguy E, Puel A
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Dominant negative CARD11 mutations: Beyond atopy

Connaughton DM, Kennedy C, Shrill S, Mann N, Murray SL, Williams PA, Conlon E, Nakayama M, van der Ven AT, Ityel H, Kause F, Kolvenbach CM, Dai RF, Vivante A, Braun DA, Schneider R, Kitzler TM, Moloney B, Moran CP, Smyth JS, Kennedy A, Benson K, Stapleton C, Denton M, Magee C, O'Seaghdha CM, Plant WD, Griffin MD, Awan A, Sweeney C, Mane SM, Lifton RP, Griffin B, Leavey S, Casserly L, de Freitas DG, Holian J, Dorman A, Doyle B, Lavin PJ, Little MA, Conlon PJ, Hildebrandt F
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Monogenic causes of chronic kidney disease in adults

KIDNEY INTERNATIONAL 2019 APR; 95(4):914-928
Approximately 500 monogenic causes of chronic kidney disease (CKD) have been identified, mainly in pediatric populations. The frequency of monogenic causes among adults with CKD has been less extensively studied. To determine the likelihood of detecting monogenic causes of CKD in adults presenting to nephrology services in Ireland, we conducted whole exome sequencing (WES) in a multicentre cohort of 114 families including 138 affected individuals with CKD. Affected adults were recruited from 78 families with a positive family history, 16 families with extra-renal features, and 20 families with neither a family history nor extra-renal features. We detected a pathogenic mutation in a known CKD gene in 42 of 114 families (37%). A monogenic cause was identified in 36% of affected families with a positive family history of CKD, 69% of those with extra-renal features, and only 15% of those without a family history or extra-renal features. There was no difference in the rate of genetic diagnosis in individuals with childhood versus adult onset CKD. Among the 42 families in whom a monogenic cause was identified, WES confirmed the clinical diagnosis in 17 (40%), corrected the clinical diagnosis in 9 (22%), and established a diagnosis for the first time in 16 families referred with CKD of unknown etiology (38%). In this multi-centre study of adults with CKD, a molecular genetic diagnosis was established in over one-third of families. In the evolving era of precision medicine, WES may be an important tool to identify the cause of CKD in adults.
Saxena M, Sabado RL, La Mar M, Mohri H, Salazar AM, Dong HQ, Da Rosa JC, Markowitz M, Bhardwaj N, Miller E
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Poly-ICLC, a TLR3 Agonist, Induces Transient Innate Immune Responses in Patients With Treated HIV-Infection: A Randomized Double-Blinded Placebo Controlled Trial

FRONTIERS IN IMMUNOLOGY 2019 APR 9; 10(?):? Article 725
Objective: Toll-like receptor-3 agonist Poly-ICLC has been known to activate immune cells and induce HIV replication in pre-clinical experiments. In this study we investigated if Poly-ICLC could be used for disrupting HIV latency while simultaneously enhancing innate immune responses. Design: This was a randomized, placebo-controlled, double-blinded trial in aviremic, cART-treated HIV-infected subjects. Participants (n = 15) were randomized 3: 1 to receive two consecutive daily doses of Poly-ICLC (1.4mg subcutaneously) vs. placebo. Subjects were observed for adverse events, immune activation, and viral replication. Methods: Besides primary outcomes of safety and tolerability, several longitudinal immune parameters were evaluated including immune cell phenotype and function via flowcytometry, ELISA, and transcriptional profiling. PCR assays for plasma HIV-1 RNA, CD4+ T cell-associated HIV-1 RNA, and proviral DNA were performed to measure HIV reservoirs and latency. Results: Poly-ICLC was overall safe and well-tolerated. Poly-ICLC-related adverse events were Grade 1/2, with the exception of one Grade 3 neutropenia which was short-lived. Mild Injection site reactions were observed in nearly all participants in the Poly-ICLC arm. Transcriptional analyses revealed upregulation of innate immune pathways in PBMCs following Poly-ICLC treatment, including strong interferon signaling accompanied by transient increases in circulating IP-10 (CXCL10) levels. These responses generally peaked by 24-48 h after the first injection and returned to baseline by day 8. CD4(+) T cell number and phenotype were unchanged, plasma viral control was maintained and no significant effect on HIV reservoirs was observed. Conclusions: These finding suggest that Poly-ICLC could be safely used for inducing transient innate immune responses in treated HIV+ subjects indicating promise as an adjuvant for HIV therapeutic vaccines.
Capoor MN, Lochman J, McDowell A, Schmitz JE, Solansky M, Zapletalova M, Alamin TF, Coscia MF, Garfin SR, Jancalek R, Ruzicka F, Shamie AN, Smrcka M, Wang JC, Birkenmaier C, Slaby O
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Intervertebral disc penetration by antibiotics used prophylactically in spinal surgery: implications for the current standards and treatment of disc infections

EUROPEAN SPINE JOURNAL 2019 APR; 28(4):783-791
PurposeThe presence of Propionibacterium acnes in a substantial component of resected disc specimens obtained from patients undergoing discectomy or microdiscectomy has led to the suggestion that this prominent human skin and oral commensal may exacerbate the pathology of degenerative disc disease. This hypothesis, therefore, raises the exciting possibility that antibiotics could play an important role in treating this debilitating condition. To date, however, little information about antibiotic penetration into the intervertebral disc is available. MethodsIntervertebral disc tissue obtained from 54 microdiscectomy patients given prophylactic cefazolin (n=25), clindamycin (n=17) or vancomycin (n=12) was assayed by high-performance liquid chromatography, with cefaclor as an internal standard, to determine the concentration of antibiotic penetrating into the disc tissue.ResultsIntervertebral disc tissues from patients receiving the positively charged antibiotic clindamycin contained a significantly greater percentage of the antibacterial dose than the tissue from patients receiving negatively charged cefazolin (P<0.0001) and vancomycin, which has a slight positive charge (P<0.0001).ConclusionPositively charged antibiotics appear more appropriate for future studies investigating potential options for the treatment of low-virulence disc infections. [GRAPHICS]
Rostol JT, Marraffini LA
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Non-specific degradation of transcripts promotes plasmid clearance during type III-A CRISPR-Cas immunity

NATURE MICROBIOLOGY 2019 APR; 4(4):656-662
Type III-A CRISPR-Cas systems employ the Cas10-Csm complex to destroy bacteriophages and plasmids, using a guide RNA to locate complementary RNA molecules from the invader and trigger an immune response that eliminates the infecting DNA. In addition, these systems possess the non-specific RNase Csm6, which provides further protection for the host. While the role of Csm6 in immunity during phage infection has been determined, how this RNase is used against plasmids is unclear. Here, we show that Staphylococcus epidermidis Csm6 is required for immunity when transcription across the plasmid target is infrequent, leading to impaired target recognition and inefficient DNA degradation by the Cas10-Csm complex. In these conditions, Csm6 causes growth arrest in the host and prevents further plasmid replication through the indiscriminate degradation of host and plasmid transcripts. In contrast, when plasmid target sequences are efficiently transcribed, Csm6 is dispensable and DNA degradation by Cas10 is sufficient for anti-plasmid immunity. Csm6 therefore provides robustness to the type III-A CRISPR-Cas immune response against difficult targets for the Cas10-Csm complex.