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.

     

As the number falls,alternatives to the Hagberg–Perten falling number method: A review

This review examines the application, limitations, and potential alternatives to the Hagberg–Perten falling number (FN) method used in the global wheat industry for detecting the risk of poor end-product quality mainly due to starch degradation by the enzyme α-amylase. By viscometry, the FN test indirectly detects the presence of α-amylase, the primary enzyme that digests starch. Elevated α-amylase results in low FN and damages wheat product quality resulting in cakes that fall, and sticky bread and noodles. Low FN can occur from preharvest sprouting (PHS) and late maturity α-amylase (LMA). Moist or rainy conditions before harvest cause PHS on the mother plant. Continuously cool or fluctuating temperatures during the grain filling stage cause LMA. Due to the expression of additional hydrolytic enzymes, PHS has a stronger negative impact than LMA. Wheat grain with low FN/high α-amylase results in serious losses for farmers, traders, millers, and bakers worldwide. Although blending of low FN grain with sound wheat may be used as a means of moving affected grain through the marketplace, care must be taken to avoid grain lots from falling below contract-specified FN. A large amount of sound wheat can be ruined if mixed with a small amount of sprouted wheat. The FN method is widely employed to detect α-amylase after harvest. However, it has several limitations, including sampling variability, high cost, labor intensiveness, the destructive nature of the test, and an inability to differentiate between LMA and PHS. Faster, cheaper, and more accurate alternatives could improve breeding for resistance to PHS and LMA and could preserve the value of wheat grain by avoiding inadvertent mixing of high- and low-FN grain by enabling testing at more stages of the value stream including at harvest, delivery, transport, storage, and milling. Alternatives to the FN method explored here include the Rapid Visco Analyzer, enzyme assays, immunoassays, near-infrared spectroscopy, and hyperspectral imaging.     

Novel TTLL5 Variants Associated with Cone-Rod Dystrophy and Early-Onset Severe Retinal Dystrophy

Variants of the TTLL5 gene, which encodes tubulin tyrosine ligase-like family member five, are a rare cause of cone dystrophy (COD) or cone-rod dystrophy (CORD). To date, only a few TTLL5 patients have been clinically and genetically described. In this study, we report five patients harbouring biallelic variants of TTLL5. Four adult patients presented either COD or CORD with onset in the late teenage years. The youngest patient had a phenotype of early onset severe retinal dystrophy (EOSRD). Genetic analysis was performed by targeted next generation sequencing of gene panels and assessment of copy number variants (CNV). We identified eight variants, of which six were novel, including two large multiexon deletions in patients with COD or CORD, while the EOSRD patient harboured the novel homozygous p.(Trp640*) variant and three distinct USH2A variants, which might explain the observed rod involvement. Our study highlights the role of TTLL5 in COD/CORD and the importance of large deletions. These findings suggest that COD or CORD patients lacking variants in known genes may harbour CNVs to be discovered in TTLL5, previously undetected by classical sequencing methods. In addition, variable phenotypes in TTLL5-associated patients might be due to the presence of additional gene defects.     

Translesion Synthesis or Repair by Specialized DNA Polymerases Limits Excessive Genomic Instability upon Replication Stress

DNA can experience “replication stress”, an important source of genome instability, induced by various external or endogenous impediments that slow down or stall DNA synthesis. While genome instability is largely documented to favor both tumor formation and heterogeneity, as well as drug resistance, conversely, excessive instability appears to suppress tumorigenesis and is associated with improved prognosis. These findings support the view that karyotypic diversity, necessary to adapt to selective pressures, may be limited in tumors so as to reduce the risk of excessive instability. This review aims to highlight the contribution of specialized DNA polymerases in limiting extreme genetic instability by allowing DNA replication to occur even in the presence of DNA damage, to either avoid broken forks or favor their repair after collapse. These mechanisms and their key regulators Rad18 and Polθ not only offer diversity and evolutionary advantage by increasing mutagenic events, but also provide cancer cells with a way to escape anti-cancer therapies that target replication forks.     

A Practical Method for Animating Anisotropic Elastoplastic Materials

This paper introduces a simple method for simulating highly anisotropic elastoplastic material behaviors like the dissolution of fibrous phenomena (splintering wood, shredding bales of hay) and materials composed of large numbers of irregularly-shaped bodies (piles of twigs, pencils, or cards). We introduce a simple transformation of the anisotropic problem into an equivalent isotropic one, and we solve this new “fictitious” isotropic problem using an existing simulator based on the material point method. Our approach results in minimal changes to existing simulators, and it allows us to re-use popular isotropic plasticity models like the Drucker-Prager yield criterion instead of inventing new anisotropic plasticity models for every phenomenon we wish to simulate.     

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.     

Emotional expression and physical heath: Revising traumatic memories or fostering self-regulation?

Health benefits derived from personal trauma disclosure are well established. This study examined whether disclosing emotions generated by imaginative immersion in a novel traumatic event would similarly enhance health and adjustment. College women, preselected for trauma presence, were randomly assigned to write about real traumas, imaginary traumas, or trivial events. Yoked real-trauma and imaginary-trauma participants wrote about real-trauma participants' experiences. Imaginary-trauma participants were significantly less depressed than real-trauma participants at immediate posttest, but they were similarly angry, fearful, and happy. Compared with control group participants, both trauma groups made significantly fewer illness visits at 1-month follow-up: however, real-trauma participants reported more fatigue and avoidance than did the other groups. Imaginary-trauma group effects could reflect catharsis, emotional regulation, or construction of resilient possible selves. (PsycINFO Database Record (c) 2010 APA, all rights reserved)