Ultra-Low Dose Cytokines in Rheumatoid Arthritis,Three Birds with One Stone as the Rationale of the 2LARTH® Micro-Immunotherapy Treatment

Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) are two cytokines involved in the perpetuation of the chronic inflammation state characterizing rheumatoid arthritis (RA). Significant advances in the treatment of this pathology have been made over the past ten years, partially through the development of anti-TNF and anti-IL-1 therapies. However, major side effects still persist and new alternative therapies should be considered. The formulation of the micro-immunotherapy medicine (MIM) 2LARTH^® uses ultra-low doses (ULD) of TNF-α, IL-1β, and IL-2, in association with other immune factors, to gently restore the body’s homeostasis. The first part of this review aims at delineating the pivotal roles played by IL-1β and TNF-α in RA physiopathology, leading to the development of anti-TNF and anti-IL-1 therapeutic agents. In a second part, an emphasis will be made on explaining the rationale of using multiple therapeutic targets, including both IL-1β and TNF-α in 2LARTH^® medicine. Particular attention will be paid to the ULD of those two main pro-inflammatory factors in order to counteract their overexpression through the lens of their molecular implication in RA pathogenesis.     

Iminodipropionic acid as the leaving group for DNA polymerization by HIV-1 reverse transcriptase

Previous studies have demonstrated that some selected amino monoacids and amino diacids can function as leaving groups in the polymerase‐catalyzed incorporation of deoxynucleotides into DNA. Among these, the iminodiacetic acid phosphoramidate of deoxyadenosine monophosphate (IDA‐dAMP) represents an interesting example, as it could overcome some of the problems observed when using L ‐aspartic acid as the leaving group, that is, poor chain elongation. We have now synthesized and evaluated a series of IDA‐dAMP analogues that bear either an extended aliphatic chain in the amino acid function, or a phosphonic acid moiety (substituting for the carboxylic acid function). Among these compounds, the nucleotide with an iminodipropionic acid leaving group (IDP‐dAMP) was identified as the best substrate; the excellent single incorporation (91 % conversion to a P+1 strand at 50 μM ) was at a substrate concentration ten times lower than that used for IDA‐dAMP). This nucleotide also presented improved kinetics and elongation capability compared to IDA‐dAMP. The analogues with T, G, and C base moieties were also investigated for their incorporation ability with HIV‐1 RT. The incorporation efficiency was found to decrease in the order A>T>G>C. The properties of the iminodipropionic acid as the leaving group surpass those of previously evaluated leaving groups; this acid will be a prime candidate for in vivo testing.     

Copper(I)/N‐Heterocyclic Carbene (NHC)‐Catalyzed Addition of Terminal Alkynes to Trifluoromethyl Ketones for Use in Continuous Reactors

A copper(I)/N‐heterocyclic carbene complex‐catalyzed addition of terminal alkynes to trifluoromethyl ketones at low loading is described. The developed process functions well using a range of terminal alkynes but functions best when an aryl trifluoromethyl ketone is used. This substrate scope is well‐suited for the production of active pharmaceutical ingredients (APIs) such as efavirenz. In this vein, we demonstrate that the described method can be translated into a flow process laying the framework for a completely continuous synthesis of efavirenz in the future.

     

Fabrication and mechanical analysis of mimosa tannin and commercial flax fibers biocomposites

Composites were prepared by impregnating commercial nonwoven and unidirectional flax fibers mats, with a mimosa tannin/hexamine resin without addition of NaOH as it was described in previous papers and with improved results. The influence of various parameters was observed: the curing cycle including temperature, time, pressure, the moisture content, and the number of fiber mats the composites were made of. A new two-step method was investigated: full drying of the pre-impregnated mats for storage first and then rehydratation just before pressing. The composites obtained gave good modulus of elasticity and tensile strength in traction as well as a good resistance to water swelling for composites prepared with 50% matrix resin/50% natural fibers. Best results appear to be obtained using a slow curing at low temperature (130?°C for 35?min) with moisture content of 20% on dry material.     

Unraveling Membrane Perturbations Caused by the Bacterial Riboregulator Hfq

Hfq is a pleiotropic regulator that mediates several aspects of bacterial RNA metabolism. The protein notably regulates translation efficiency and RNA decay in Gram-negative bacteria, usually via its interaction with small regulatory RNAs. Previously, we showed that the Hfq C-terminal region forms an amyloid-like structure and that these fibrils interact with membranes. The immediate consequence of this interaction is a disruption of the membrane, but the effect on Hfq structure was unknown. To investigate details of the mechanism of interaction, the present work uses different in vitro biophysical approaches. We show that the Hfq C-terminal region influences membrane integrity and, conversely, that the membrane specifically affects the amyloid assembly. The reported effect of this bacterial master regulator on membrane integrity is discussed in light of the possible consequence on small regulatory RNA-based regulation.     

PD-L1 Expression in 65 Conjunctival Melanomas and Its Association with Clinical Outcome

Conjunctival melanoma (CM) iss a rare and aggressive tumour that is increasing in frequency. The prognostic value of PD-L1 expression, alone or in combination with CD8 and PD-1 expression and the BRAF and NRAS status, has not been determined in CM to date. We evaluated the expression of PD-L1, CD8, PD-1 in CM and investigated whether there was an association between the expression of these markers and the BRAF and NRAS molecular profile as well as some clinico-pathological criteria. A total of sixty-five CM were assessed for PD-L1, PD-1, and CD8 expression by immunohistochemistry (IHC) and for BRAF and NRAS genomic alterations using molecular biology techniques and anti-BRAF and anti-NRAS antibodies. PD-L1 expression in tumour cells (TC) was very low or absent but detected in tumour-infiltrating immune cells (IC). A correlation was observed between the expression of PD-L1, CD8, and PD-1 in IC. No correlation between PD-L1 expression (in tumour and/or immune cells) and BRAF or NRAS mutations was observed. PD-L1 expression in IC correlated with a higher pTNM stage and PD-L1 expression in TC with worse disease-specific survival. PD-L1 expression is a potential prognostic biomarker that correlates with poor prognosis in CM patients.     

Social constraints, intrusive thoughts, and depressive symptoms among bereaved mothers.

The study examined how social constraints on discussion of a traumatic experience can interfere with cognitive processing of and recovery from loss. Bereaved mothers were interviewed at 3 weeks (Tl ), 3 months (T2), and 18 months (T3) after their infants' death. Intrusive thoughts at Tl, conceptualized as a marker of cognitive processing, were negatively associated with talking about infant's death at T2 and T3 among socially constrained mothers. The reverse associations were found among unconstrained mothers. Controlling for initial level of distress, there was a positive relation between T1 intrusive thoughts and depressive symptoms over time among socially constrained mothers. However, higher levels of T1 intrusive thoughts were associated with a decrease in T3 depressive symptoms among mothers with unconstrained social relationships. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

CATV in France: Present situation and future directions

Fibre-optic systems have been introduced in France initially in the subscriber loop (fibre to the home) for experimenting switched broadband services (Biarritz opened in 1984) and then, under the Plan Cǎble for CATV/multiservice networks (twelve cities or groups of cities, about 900,000 homes), and as CATV trunks and feeders in 40 other cities or groups of cities (another 4,500,000 homes). This unique experience with fibre in the subscriber loop, albeit slightly premature gives some assurance on the future economic feasibility of the fibre-to-the-home or fibre-to-the-office concepts under development. D2-MAC/packet with smart card access control has been selected as the standard for scrambling/enciphering audiovisual signals on cable and on satellite. The integration of the recent hybrid or fibre broadband TV networks and of their network management systems into the telecommunication networks is still being discussed.