The Great Contribution of Engels to <i>Capital</i>

Marx and Engels were close confidants and had the same beliefs and aspirations. Both of them devoted a great deal of effort to Capital. Although Engels did not claim co-authorship of Capital, he was a genuine collaborator in ensuring it would appear, making major contributions to its creation and publication. Together with Marx, he helped lay the foundations for Capital in the 1840s, establishing the basic elements of practice, method, and politics that would bring the work into being. From the 1850s to 1867 he devoted enormous energies to supporting the creation of Capital. During the 1870s he worked to promote Capital, and from 1883 to 1894 he toiled at preparing the final two volumes for publication. All in all, Engels was a legendary writer who devoted himself to Capital over a period of half a century. </p

A genome-wide association study based on the China Kadoorie Biobank identifies genetic associations between snoring and cardiometabolic traits

Despite the high prevalence of snoring in Asia, little is known about the genetic etiology of snoring and its causal relationships with cardiometabolic traits. Based on 100,626 Chinese individuals, a genome-wide association study on snoring was conducted. Four novel loci were identified for snoring traits mapped on SLC25A21, the intergenic region of WDR11 and FGFR, NAA25, ALDH2, and VTI1A, respectively. The novel loci highlighted the roles of structural abnormality of the upper airway and craniofacial region and dysfunction of metabolic and transport systems in the development of snoring. In the two-sample bi-directional Mendelian randomization analysis, higher body mass index, weight, and elevated blood pressure were causal for snoring, and a reverse causal effect was observed between snoring and diastolic blood pressure. Altogether, our results revealed the possible etiology of snoring in China and indicated that managing cardiometabolic health was essential to snoring prevention, and hypertension should be considered among snorers

Analysis of AgoshRNA maturation and loading into Ago2

The RNA interference (RNAi) pathway was recently expanded by the discovery of multiple alternative pathways for processing of natural microRNA (miRNA) and man-made short hairpin RNA (shRNA) molecules. One non-canonical pathway bypasses Dicer cleavage and requires instead processing by Argonaute2 (Ago2), which also executes the subsequent silencing step. We named these molecules AgoshRNA, which generate only a single active RNA strand and thus avoid off-target effects that can be induced by the passenger strand of a regular shRNA. Previously, we characterized AgoshRNA processing by deep sequencing and demonstrated that-after Ago2 cleavage-AgoshRNAs acquire a short 3' tail of 1-3 A-nucleotides and are subsequently trimmed, likely by the poly(A)-specific ribonuclease (PARN). As a result, the mature single-stranded AgoshRNA may dock more stably into Ago2. Here we set out to analyze the activity of different synthetic AgoshRNA processing intermediates. Ago2 was found to bind preferentially to partially single-stranded AgoshRNA in vitro. In contrast, only the double-stranded AgoshRNA precursor associated with Ago2 in cells, correlating with efficient intracellular processing and reporter knockdown activity. These results suggest the presence of a cellular co-factor involved in AgoshRNA loading into Ago2 in vivo. We also demonstrate specific AgoshRNA loading in Ago2, but not Ago1/3/4, thus further reducing unwanted side effect

<i>In vivo</i> complex formation of the AgoshRNA set and Ago2.

<p><b>(A)</b> Northern blot analysis of immunoprecipitated AgoshRNAs with Ago2-FLAG. Both bound and depleted (unbound) fractions are shown for all synthetic RNA molecules. A size marker is included on the left hand side. Ethidium bromide staining of 5.8S rRNA and tRNAs was included as loading control below the blots. <b>(B)</b> Western blot analysis of the Ago2-bound and unbound fractions using antibodies against FLAG and α-Actin.</p

Chemical interaction dictated energy level alignment at the N,N'-dipentyl-3,4,9,10-perylenedicarboximide/CH3NH3PbI3 interface

Here, we report the electronic structures at the N, N′-dipentyl-3,4,9,10-perylenedicarboximide (PTCDI-C5)/CH3NH3PbI3 interface identified in-situ by X-ray photoemission spectroscopy and ultraviolet photoemission spectroscopy. Strong chemical reactions are found to occur upon the deposition of PTCDI-C5 molecules on CH3NH3PbI3. Electron donation from PTCDI-C5 molecules to CH3NH3PbI3 leads to the filling of surface states and the emergence of an interfacial gap state with its onset tailed to the Fermi level. As a consequence, the downward surface band bending resulting from surface states acting as donor states at the pristine perovskite surface is reduced by 0.2 eV. After the energy level alignment at the interface is established, the perovskite conduction band minimum is found to be in line with the lowest unoccupied molecular orbital favoring the electron extraction with a moderate valence band maximum-highest occupied molecular orbital offset of ∼0.7 eV. The present results demonstrate that interfacial chemical reactions can dictate energetics at organic/perovskite interfaces. Understanding the chemical interaction and resultant electronic structures at those interfaces is crucial for efficient and long-term stable perovskite-based devices when passivation of chemical active sites and matched energy level could be readily reached

Processing and Ago2 loading of shRNA and AgoshRNA molecules.

<p>Illustration of the processing options for the Dicer-dependent shRNA and Dicer-independent AgoshRNA. Short hairpin RNAs are cleaved by Dicer resulting in a ds siRNA molecule. One of the strands is selected to be loaded into Ago2. It is however unknown whether the siRNA enters Ago as duplex, after which the passenger strand is degraded (duplex loading model), or whether one of the strands is selected prior to Ago loading by an unknown helicase (helicase model). On the other hand, the Dicer-independent AgoshRNA (and miR-451) are too small to be cleaved by Dicer and are loaded in Ago2 in their precursor form (pre-Agosh). The 5’ end can dock into the Ago2 MID-domain (closed circle), but the 3’ end is not in the vicinity of the Ago2 PAZ-domain and thus unable to dock (open circle). The hairpin is subsequently cleaved by Ago2 (Agosh^cleave), tailed (Agosh^A) and finally trimmed by PARN (Agosh^trim). The resulting single-stranded molecule can dock both 5’ and 3’ ends to facilitate stable loading in Ago2.</p

<i>In vivo</i> complex formation of the AgoshRNA set with Ago1-4 proteins.

<p>Northern blot analysis of immunoprecipitated pre-Agosh with all four human Ago proteins. Both the bound and depleted (unbound) fractions are shown. A size marker is included on the right hand side. Ago2* was expressed from a different vector as the other four Argonaute proteins. Fold enrichment of bound over unbound is indicated underneath lane. Ethidium bromide staining of 5.8S rRNA and tRNAs is shown as loading control below the blot.</p

Sequences of Ago2-associated RNA.

<p>Sequences of Ago2-associated RNA.</p

<i>In vivo</i> processing of the synthetic AgoshRNA molecules.

<p><b>(A)</b> 100 pmol of the synthetic RNAs was analyzed on a 15% polyacrylamide gel and stained with ethidium bromide. <b>(B)</b> HEK 293T were transfected with 100 pmol of the synthetic RNA molecules. Total cellular RNA was isolated after 48 h and analyzed by northern blot. An LNA probe targeting the 5’ side of the hairpin was used. A size marker is included on the right hand side. Ethidium bromide staining of 5.8S rRNA and tRNAs is included below the blot as loading control. <b>(C)</b> As B, but now using an LNA probe targeting the 3’ side of the hairpin.</p

Integrating genome-wide CRISPR immune screen with multi-omic clinical data reveals distinct classes of tumor intrinsic immune regulators

Background Despite approval of immunotherapy for a wide range of cancers, the majority of patients fail to respond to immunotherapy or relapse following initial response. These failures may be attributed to immunosuppressive mechanisms co-opted by tumor cells. However, it is challenging to use conventional methods to systematically evaluate the potential of tumor intrinsic factors to act as immune regulators in patients with cancer.Methods To identify immunosuppressive mechanisms in non-responders to cancer immunotherapy in an unbiased manner, we performed genome-wide CRISPR immune screens and integrated our results with multi-omics clinical data to evaluate the role of tumor intrinsic factors in regulating two rate-limiting steps of cancer immunotherapy, namely, T cell tumor infiltration and T cell-mediated tumor killing.Results Our studies revealed two distinct types of immune resistance regulators and demonstrated their potential as therapeutic targets to improve the efficacy of immunotherapy. Among them, PRMT1 and RIPK1 were identified as a dual immune resistance regulator and a cytotoxicity resistance regulator, respectively. Although the magnitude varied between different types of immunotherapy, genetically targeting PRMT1 and RIPK1 sensitized tumors to T-cell killing and anti-PD-1/OX40 treatment. Interestingly, a RIPK1-specific inhibitor enhanced the antitumor activity of T cell-based and anti-OX40 therapy, despite limited impact on T cell tumor infiltration.Conclusions Collectively, the data provide a rich resource of novel targets for rational immuno-oncology combinations