Objective:
Genome-wide association studies (GWASs) of the Alcohol Use Disorders Identification Test (AUDIT), a 10-item screen for alcohol use disorder (AUD), have elucidated novel loci for alcohol ...consumption and misuse. However, these studies also revealed that GWASs can be influenced by numerous biases (e.g., measurement error, selection bias), which may have led to inconsistent genetic correlations between alcohol involvement and AUD, as well as paradoxically negative genetic correlations between alcohol involvement and psychiatric disorders and/or medical conditions. The authors used genomic structural equation modeling to elucidate the genetics of alcohol consumption and problematic consequences of alcohol use as measured by AUDIT.
Methods:
To explore these unexpected differences in genetic correlations, the authors conducted the first item-level and the largest GWAS of AUDIT items (N=160,824) and applied a multivariate framework to mitigate previous biases.
Results:
The authors identified novel patterns of similarity (and dissimilarity) among the AUDIT items and found evidence of a correlated two-factor structure at the genetic level (“consumption” and “problems,” rg=0.80). Moreover, by applying empirically derived weights to each of the AUDIT items, the authors constructed an aggregate measure of alcohol consumption that was strongly associated with alcohol dependence (rg=0.67), moderately associated with several other psychiatric disorders, and no longer positively associated with health and positive socioeconomic outcomes. Lastly, by conducting polygenic analyses in three independent cohorts that differed in their ascertainment and prevalence of AUD, the authors identified novel genetic associations between alcohol consumption, alcohol misuse, and health.
Conclusions:
This work further emphasizes the value of AUDIT for both clinical and genetic studies of AUD and the importance of using multivariate methods to study genetic associations that are more closely related to AUD.
Summary
These guidelines for the management of congenital ichthyoses have been developed by a multidisciplinary group of European experts following a systematic review of the current literature, an ...expert conference held in Toulouse in 2016 and a consensus on the discussions. They summarize evidence and expert‐based recommendations and are intended to help clinicians with the management of these rare and often complex diseases. These guidelines comprise two sections. This is part one, covering topical therapies, systemic therapies, psychosocial management, communicating the diagnosis and genetic counselling.
Linked Comment: Levy. Br J Dermatol 2019; 180:253.
Summary
These guidelines for the management of congenital ichthyoses have been developed by a multidisciplinary group of European experts following a systematic review of the current literature, an ...expert conference held in Toulouse in 2016, and a consensus on the discussions. These guidelines summarize evidence and expert‐based recommendations and intend to help clinicians with the management of these rare and often complex diseases. These guidelines comprise two sections. This is part two, covering the management of complications and the particularities of some forms of congenital ichthyosis.
What's already known about this topic?
Various symptomatic treatment options exist for congenital ichthyoses, but there are no European guidelines.
What does this study add?
These European guidelines for the management of congenital ichthyosis may help to improve outcomes and quality of life for patients.
Linked Comment: Akiyama. Br J Dermatol 2019; 180:449–450.
Plain language summary available online
•Pluto’s nitrogen atmosphere is transported seasonally, forming polar caps.•A climate model has been updated to test against new observations from telescopes.•We predict Pluto’s atmosphere will not ...collapse prior to the 2015 New Horizons flyby.•The range of surface pressures predicted for Pluto in 2015 is 0.3–3.2Pa.•The best match to observations predicts an atmospheric pressure of 2.4Pa.
Pluto has a nitrogen atmosphere in vapor pressure equilibrium with surface ice. N2 is mobile and is transported seasonally even at Pluto’s cold temperatures in the outer Solar System. A thermal model developed by Hansen and Paige in 1996 to model Pluto’s climate has been re-deployed in response to new data and in anticipation of the New Horizons flyby of Pluto in 2015. A number of stellar occultations have been observed in the last 11years as Pluto has crossed the galactic plane. New Hubble Space Telescope images show a variegated surface. These recent observations allow us to model Pluto’s climate with much tighter constraints. Our findings suggest that Pluto’s atmosphere will not collapse prior to the arrival of New Horizons although pressure will be dropping as N2 condenses on the south polar cap. This finding is in contrast to the Olkin et al. (Olkin et al. 2013. arXiv1309.0841O) prediction that permanent volatiles in the northern hemisphere maintain Pluto’s atmospheric pressure throughout its orbit. The range of surface pressures predicted for 2015 for nine cases with very good matches to observables is 0.3–3.2Pa. The best match predicts that New Horizons will detect an atmospheric pressure of 2.4Pa.
PU.1 is a member of the ets family of transcription factors and is expressed exclusively in cells of the hematopoietic lineage. Mice homozygous for a disruption in the PU.1 DNA binding domain are ...born alive but die of severe septicemia within 48 h. The analysis of these neonates revealed a lack of mature macrophages, neutrophils, B cells and T cells, although erythrocytes and megakaryocytes were present. The absence of lymphoid commitment and development in null mice was not absolute, since mice maintained on antibiotics began to develop normal appearing T cells 3–5 days after birth. In contrast, mature B cells remained undetectable in these older mice. Within the myeloid lineage, despite a lack of macrophages in the older antibiotic‐treated animals, a few cells with the characteristics of neutrophils began to appear by day 3. While the PU.1 protein appears not to be essential for myeloid and lymphoid lineage commitment, it is absolutely required for the normal differentiation of B cells and macrophages.
Only mature B lymphocytes can enter the lymphoid follicles of spleen and lymph nodes and thus efficiently participate in the immune response. Mature, long-lived B lymphocytes derive from short-lived ...precursors generated in the bone marrow. We show that selection into the mature pool is an active process and takes place in the spleen. Two populations of splenic B cells were identified as precursors for mature B cells. Transitional B cells of type 1 (T1) are recent immigrants from the bone marrow. They develop into the transitional B cells of type 2 (T2), which are cycling and found exclusively in the primary follicles of the spleen. Mature B cells can be generated from T1 or T2 B cells. Mice with genetic deletions of elements participating in the B cell receptor signaling cascade display developmental arrest at the T1 or T2 stage. The analysis of these defects showed that the development of T2 and mature B cells from T1 precursors requires defined qualitative and quantitative signals derived from the B cell receptor and that the induction of longevity and maturation requires different signals.
Interleukin-7 plays important roles in the B cell developmental pathway including events leading to commitment, survival, proliferation, and maturation. Because of its central role in adult murine B ...lymphopoiesis, IL-7 is frequently used to generate B cell progenitors in vitro. We have shown that differentiation of IL-7-responsive cells in these cultures is influenced by CD45, pre-B cell receptor, and other downstream signaling molecules. A common, but often overlooked aspect of IL-7 containing cultures is the routine maturation of cells to the sIgM
+ stage. The production of B cells in IL-7 containing cultures is balanced by cell death, since such cells fail to survive for long without additional stimulation.
A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million ...people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption
. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein-protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
Studies in mice with targeted deletions of tachykinin genes suggest that tachykinins and their receptors influence emotional behaviors such as aggression, depression and anxiety. Here, we ...investigated whether TAC1‐ and TAC4‐encoded peptides (substance P and hemokinin‐1, respectively) and the neurokinin‐1 receptor (NK‐1R) are involved in the modulation of sexual behaviors. Male mice deficient for the NK‐1R (TACR1 −/−) exhibited decreased exploration of female urine in contrast to C57BL/6 control mice and mice deficient for NK‐1R ligands such as TAC1 −/−, TAC4 −/− and the newly generated TAC1 −/− /TAC4 −/− mice. In comparison to C57BL/6 mice, mounting frequency and duration were decreased in male TACR1 −/− mice, while mounting latency was increased. Decreased preference for sexual pheromones was also seen in female TACR1 −/− mice. Furthermore, administration of the NK‐1R‐antagonist L‐703,606 decreased investigation of female urine by male C57BL/6 mice, suggesting an involvement of NK‐1R in urine sniffing behavior. Our results provide evidence for the NK‐1R in facilitating sexual approach behavior, as male TACR1 −/− mice exhibited blunted approach behavior toward females following the initial interaction compared with C57BL/6 mice. NK‐1R signaling may therefore play an important role in pheromone‐induced sexual behavior.
Persistence of chronic hepatitis B (CHB) is attributed to maintenance of the intrahepatic pool of the viral covalently closed circular DNA (cccDNA), which serves as the transcriptional template for ...all viral gene products required for replication. Current nucleos(t)ide therapies for CHB prevent virus production and spread but have no direct impact on cccDNA or expression of viral genes. We describe a potential curative approach using a highly specific engineered ARCUS nuclease (ARCUS-POL) targeting the hepatitis B virus (HBV) genome. Transient ARCUS-POL expression in HBV-infected primary human hepatocytes produced substantial reductions in both cccDNA and hepatitis B surface antigen (HBsAg). To evaluate ARCUS-POL in vivo, we developed episomal adeno-associated virus (AAV) mouse and non-human primate (NHP) models containing a portion of the HBV genome serving as a surrogate for cccDNA. Clinically relevant delivery was achieved through systemic administration of lipid nanoparticles containing ARCUS-POL mRNA. In both mouse and NHP, we observed a significant decrease in total AAV copy number and high on-target indel frequency. In the case of the mouse model, which supports HBsAg expression, circulating surface antigen was durably reduced by 96%. Together, these data support a gene-editing approach for elimination of cccDNA toward an HBV cure.
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Transient delivery of a highly specific ARCUS gene-editing nuclease (ARCUS-POL) targeting HBV polymerase results in 85% cccDNA reduction and robust HBsAg loss in vitro. Utilizing novel mouse and non-human primate models, LNP delivery of ARCUS-POL mRNA results in high levels of gene editing and >95% reduction of HBsAg.
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