Les larmes de la mémoire, un déchirement infini vu par les yeux d’Élie Wiesel

The aim of this article is to consider the perfect complementarity and the heterogeneous structure of two of Elie Wiesel’s works, which formulate a constant questioning on the fault of the uprooted man: L’Oublié, published by Éditions du Seuil in 1989 and Un désir fou de danser, a novel published by the same editions in 2006. In this works, the Romanian author Elie Wiesel gives his voice to characters constantly persecuted by demons from their past. Hyper lucid and attentive to the noise of his time, Wiesel celebrates, in his novels, a present loaded with memories so as not to abdicate before the sore Jewish memory that seems to haunt him. Madness, freedom, Judaic mysticism, an intimate understanding of Kabbalah, the memory of suffering are all themes that nourish Élie Wiesel and testify to his almost exclusive interest in the open wounds of Jewish history.

CRISPR/Cas13 effectors have differing extents of off-target effects that limit their utility in eukaryotic cells

CRISPR/Cas13 effectors have garnered increasing attention as easily customizable tools for detecting and depleting RNAs of interest. Near perfect complementarity between a target RNA and the Cas13-associated guide RNA is required for activation of Cas13 ribonuclease activity. Nonetheless, the specificity of Cas13 effectors in eukaryotic cells has been debated as the Cas13 nuclease domains can be exposed on the enzyme surface, providing the potential for promiscuous cleavage of nearby RNAs (so-called collateral damage). Here, using co-transfection assays in Drosophila and human cells, we found that the off-target effects of RxCas13d, a commonly used Cas13 effector, can be as strong as the level of on-target RNA knockdown. The extent of off-target effects is positively correlated with target RNA expression levels, and collateral damage can be observed even after reducing RxCas13d/guide RNA levels. The PspCas13b effector showed improved specificity and, unlike RxCas13d, can be used to deplete a Drosophila circular RNA without affecting the expression of the associated linear RNA. PspCas13b nonetheless still can have off-target effects and we notably found that the extent of off-target effects for Cas13 effectors differs depending on the cell type and target RNA examined. In total, these results highlight the need for caution when designing and interpreting Cas13-based knockdown experiments.

Format chain exchange (FORCE) for high-throughput generation of bispecific antibodies in combinatorial binder-format matrices

Generation of bispecific antibodies (bsAbs) requires a combination of compatible binders in formats that support desired functionalities. Here, we report that bsAb-matrices can be generated by Format Chain Exchange (FORCE), enabling screening of combinatorial binder/format spaces. Input molecules for generation of bi/multi-valent bsAbs are monospecific entities similar to knob-into-hole half-antibodies, yet with complementary CH3-interface-modulated and affinity-tagged dummy-chains. These contain mutations that lead to limited interface repulsions without compromising expression or biophysical properties of educts. Mild reduction of combinations of educts triggers spontaneous chain-exchange reactions driven by partially flawed CH3-educt interfaces resolving to perfect complementarity. This generates large bsAb matrices harboring different binders in multiple formats. Benign biophysical properties and good expression yields of educts, combined with simplicity of purification enables process automation. Examples that demonstrate the relevance of screening binder/format combinations are provided as a matrix of bsAbs that simultaneously bind Her1/Her2 and DR5 without encountering binder or format-inflicted interferences.

A Flexible Demand Model for Complements Using Household Production Theory

According to household production theory, consumers buy inputs and combine them to produce final goods from which they derive utility. We use this idea to build a micro-level model for the quantity demanded by a consumer across product categories. Our model proposes an intuitive explanation for the existence of negative cross-price effects across categories and can be estimated on purchase data in the presence of corner solutions and indivisible packages. We find that, even when reusing the same functional form as some previous models of demand for substitutes, our model can accommodate very different patterns of consumer preferences from perfect complementarity to no complementarity between goods. We estimate the model on purchase data from a panel of consumers and find that it yields a better fit than a set of benchmark models. We then show how the demand system estimated can be used to increase the profitability of couponing strategies by taking into account the spillover effect of coupons on demand for complementary categories and by manufacturers to make decisions regarding the size of packages by taking into account cross-category consumption. We also use the model to simulate demand under a shift in the proportions used in joint consumption, which could be stimulated via marketing efforts.

A putative miRNA in the spike gene of SARS-CoV-2 has perfect sequence identity to both the forward and reverse complementary strands of hsa-mir-8055 involved in T-cell response to antigen

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), also known as COVID-19, encodes for a spike protein that is responsible for both attachment and membrane fusion, thereby being critical in the pathogenicity of this virus. Here, I report that a putative miRNA localized in the spike gene of SARS-CoV-2 matches to the forward strand of hsa-miR-8055, a miRNA expressed during T-cell response to antigen, and also binds with perfect complementarity to its seed region

Expressions of miR-155 and miR-181 and predictions of their structures and targets in pigs (Sus scrofa)

Background and Aim: MicroRNAs (miRNAs) are responsible for gene expression control at the post-transcription level in many species. Several miRNAs are required in the regulation of immune responses, such as B-cell differentiation, T-cell receptor signaling pathway, CD4+ T cell selection, and so on. Studies on miRNAs have been extensively conducted in humans and mice; however, reports relevant to miRNAs, especially miR-155 and miR-181, in pigs are limited. Consequently, the present study aimed to investigate the structures, target genes, and expressions of miR-155 and miR-181 in various porcine cells and tissues. Materials and Methods: Five healthy male pigs from a porcine reproductive and respiratory syndrome virus-negative farm were studied. Before slaughter, blood samples were collected for peripheral blood mononuclear cell isolation. After slaughter, samples of spleen, lymph nodes, and forelimb muscles were collected. Both miR-155 and miR-181 were investigated for their structures with RNAfold web server, for their target genes from three online web servers, and for their expressions using polymerase chain reaction (PCR). Results: The structures of miR-155 and miR-181 contained hairpins with free energies of –35.27 and –35.29 kcal/mole, respectively. Target gene prediction revealed that miR-155 had perfect complementarity with Socs1 and Mapk3k14, while miR-181 had perfect complementarity with Ddx3x, Nfat5, Foxp1, and Mpp5. PCR showed that both miRNAs were detectable from all investigated cells and tissues. Moreover, the highest expression of both miRNAs was found from the lymph node of the pigs. Conclusion: Both miR-155 and miR-181 might be involved with the regulation of porcine immune functions as both miRNAs were detected in several cells and tissues of the pigs. In addition, they had very high complementarities with the seed regions of several immune-related genes.

Polypentagonal ice-like water networks emerge solely in an activity-improved variant of ice-binding protein

Polypentagonal water networks were recently observed in a protein capable of binding to ice crystals, or ice-binding protein (IBP). To examine such water networks and clarify their role in ice-binding, we determined X-ray crystal structures of a 65-residue defective isoform of a Zoarcidae-derived IBP (wild type, WT) and its five single mutants (A20L, A20G, A20T, A20V, and A20I). Polypentagonal water networks composed of ∼50 semiclathrate waters were observed solely on the strongest A20I mutant, which appeared to include a tetrahedral water cluster exhibiting a perfect position match to the (101¯0) first prism plane of a single ice crystal. Inclusion of another symmetrical water cluster in the polypentagonal network showed a perfect complementarity to the waters constructing the (202¯1) pyramidal ice plane. The order of ice-binding strength was A20L < A20G < WT < A20T < A20V < A20I, where the top three mutants capable of binding to the first prism and the pyramidal ice planes commonly contained a bifurcated γ-CH3 group. These results suggest that a fine-tuning of the surface of Zoarcidae-derived IBP assisted by a side-chain group regulates the holding property of its polypentagonal water network, the function of which is to freeze the host protein to specific ice planes.

Selective targeting of point-mutated KRAS through artificial microRNAs

Mutated protein-coding genes drive the molecular pathogenesis of many diseases, including cancer. Specifically, mutated KRAS is a documented driver for malignant transformation, occurring early during the pathogenesis of cancers such as lung and pancreatic adenocarcinomas. Therapeutically, the indiscriminate targeting of wild-type and point-mutated transcripts represents an important limitation. Here, we leveraged on the design of miRNA-like artificial molecules (amiRNAs) to specifically target point-mutated genes, such as KRAS, without affecting their wild-type counterparts. Compared with an siRNA-like approach, the requirement of perfect complementarity of the microRNA seed region to a given target sequence in the microRNA/target model has proven to be a more efficient strategy, accomplishing the selective targeting of point-mutated KRAS in vitro and in vivo.

A New Double Stranded RNA Suppresses Bladder Cancer Development by Upregulating p21Waf1/CIP1Expression

We have previously demonstrated that miR-1180-5p has potent ability to upregulate p21 expression by targeting promoter and inhibit bladder cancer. This prompted us to conjecture that a candidate dsRNA (dsP21-397) with perfect complementarity to the miR-1180-5p target site of p21 promoter may also trigger p21 expression. Transfection of dsP21-397 into T24 and EJ cells significantly activated p21 expression at 72 h and the activation presented in a time-course and dose-dependent manner. Moreover, the p21-activated activities of dsP21-397 and miR-1180-5p are not significantly different. Overexpression of p21 downregulated Cyclin D1, CDK4/6, and Cyclin A2 expression, and thereby induced cell cycle arrest and inhibited proliferation. Moreover, dsP21-397 suppressed bladder cancer largely depended on manipulating p21. In conclusion, our study identifies a pair of miRNA-dsRNA mediating endogenous p21 overexpression.

In search of symbiosis: the Security Council in the humanitarian domain

While the Security Council's incursion into the protection of individuals or groups could appear necessary – or even praiseworthy – it should be viewed with caution. The author argue that the search for perfect complementarity between the powers of the Security Council and humanitarian action should not overlook the political nature of the Council, the omissions and inconsistencies in its decisions regarding grave offences against human dignity and the effects of coercive action – including armed force – on the provision of neutral and impartial assistance to the victims of an armed conflict.