The management of lupus nephritis as proposed by EULAR/ERA 2019 versus KDIGO 2021

In 2019 and 2021, the European League for Rheumatism (EULAR) jointly with the European Renal Association (ERA) and the Kidney Disease Improving Global Outcomes (KDIGO), respectively, released updated guidelines on the management of lupus nephritis. The Immunology Working Group of the ERA reviewed and compared both updates. Recommendations were either consistent or differences were of negligible clinical relevance for: Indication for kidney biopsy, kidney biopsy interpretation, treatment targets, hydroxychloroquine dosing, first line initial immunosuppressive therapy for active class III, IV (±V) LN, pregnancy in LN, LN in paediatric patients, and LN patients with kidney failure. Relevant differences in the recommended management relate to the recognition of lupus podocytopathies, uncertainties in steroid dosing, drug preferences in specific populations and maintenance therapy, treatment of pure class V LN, therapy of recurrent LN, evolving alternative drug options, and diagnostic work-up of thrombotic microangiopathy. Altogether, both documents provide an excellent guidance to the growing complexity of LN management. This article endeavours to prevent confusion by identifying differences and clarifying discrepancies.

High Systemic Type I Interferon Activity is Associated with Active Class III/IV Lupus Nephritis

Objective Previous studies suggest a link between high serum type I interferon (IFN) and lupus nephritis (LN). We determined whether serum IFN activity is associated with subtypes of LN and studied renal tissues and cells to understand the impact of IFN in LN. Methods 221 systemic lupus erythematosus (SLE) patients were studied. Serum IFN activity was measured by WISH bioassay. mRNA in-situ hybridization was used in renal tissue to measure expression of the representative IFN-induced gene, interferon-induced protein with tetratricopeptide repeats-1 (IFIT1), and the plasmacytoid dendritic cell (pDC) marker gene C-type lectin domain family-4 member C (CLEC4C or BDCA2). Podocyte cell line gene expression was measured by real-time PCR. Results Class III/IV LN prevalence was significantly increased in patients with high serum IFN compared with those with low IFN (OR=5.48, p=4.0x10-7). In multivariate regression models, type I IFN was a stronger predictor of class III/IV LN than complement C3 or anti-dsDNA antibody, and could account for the association of these variables with LN. IFIT1 expression was increased in all classes of LN, but most in the glomerular areas of active class III/IV LN kidneys. IFIT1 expression was not closely co-localized with pDCs. IFN directly activated podocyte cell lines to induce chemokines and proapoptotic molecules. Conclusion Systemic high IFN is involved in the pathogenesis of severe LN. We do not find co-localization of pDCs with IFN signature in renal tissue, and instead observe the greatest intensity of IFN signature in glomerular areas, which could suggest a blood source of IFN.

Increase of activation efficiency of hardening backfilling mixture components by application mining and metallurgical wastes

The main operation associated with the preparation of mining and metallurgical wastes for use as a hardening mixture and backfilling of mined-out space is their crushing and activation. Improving the activation processes is an urgent task, since their use can significantly increase the strength of the filling mass or reduce the consumption of the binder while maintaining its strength characteristics. For the efficient operation of mining enterprises, including ferrous metallurgy mines, it is necessary to provide highquality binders for the preparation of hardening mixtures for filling man-made voids formed during underground mining of solid mineral deposits. It has been established that the use of vibration, mechanical and electrical activation of the components of the hardening backfill mixture at mining enterprises leads to an increase in the activity of substandard materials by up to 10–40% for each apparatus. In particular, the enrichment of inert materials on a vibrating screen ГВ-1,2/3,2, Ukraine, increases the activity by 15– 20%. It has been substantiated that the activation of binders (blast-furnace granular slags) in a vertical vibrating mill МВВ-0,7, Ukraine, and a disintegrator ДУ-65 company “Disintegrator”, Estonia, increases the activity of the binder by 20–25%, when the active class of fractions 0.074 mm – by 55% is released versus 40% in ball mills. The recommended vibratory conveying installations increase the activity of the components of the hardening backfill mixture by 10–15%. The use of vibro-gravity transport installations ensures the supply of the filling mixture at a distance 15–20 times higher than the height of the vertical stack.

The Rhox gene cluster suppresses germline LINE1 transposition

Transposable elements (TEs) are mobile sequences that engender widespread mutations and thus are a major hazard that must be silenced. The most abundant active class of TEs in mammalian genomes is long interspersed element class 1 (LINE1). Here, we report that LINE1 transposition is suppressed in the male germline by transcription factors encoded by a rapidly evolving X-linked homeobox gene cluster. LINE1 transposition is repressed by many members of this RHOX transcription factor family, including those with different patterns of expression during spermatogenesis. One family member—RHOX10—suppresses LINE1 transposition during fetal development in vivo when the germline would otherwise be susceptible to LINE1 activation because of epigenetic reprogramming. We provide evidence that RHOX10 suppresses LINE transposition by inducing Piwil2, which encodes a key component in the Piwi-interacting RNA pathway that protects against TEs. The ability of RHOX transcription factors to suppress LINE1 is conserved in humans but is lost in RHOXF2 mutants from several infertile human patients, raising the possibility that loss of RHOXF2 causes human infertility by allowing uncontrolled LINE1 expression in the germline. Together, our results support a model in which the Rhox gene cluster is in an evolutionary arms race with TEs, resulting in expansion of the Rhox gene cluster to suppress TEs in different biological contexts.

Exploring Methodology for Sharia Subject in Accordance with Dini Integrated Curriculum

Ensuring teaching objectives to be achieved among pupils is not an easy task, especially if the subject is newly introduced to them. Sharia subject in this research, is using Dini Integrated Curriculum (DIC) which was introduced not long ago in 2015. It is unique that this subject is taught in the Arabic Language and not the mother tongue of Malaysians. This research applied quantitative method. Data was collected through interviews with 8 research respondents and then triangulated by observations and document analysis. Research findings showed that teachers used methods connected to games and active class participations. The implications of this research revealed that teaching techniques for this subject can be varied and not mundane.

From Virtual to Physical Problem Solving in Coding

Using coding education to promote computational thinking and nurture problem-solving skills in children has become an emerging global trend. However, how different input and output modalities in coding tools affect coding as a problem-solving process remains unclear. Of interest are the advantages and disadvantages of graphical and tangible interfaces for teaching coding to children. We conducted four kids coding workshops to study how different input and output methods in coding affected the problem-solving process and class dynamics. Results revealed that graphical input could keep children focused on problem solving better than tangible input, but it was less provocative for class discussion. Tangible output supported better schema construction and casual reasoning and promoted more active class engagement than graphical output but offered less affordance for analogical comparison among problems. We also derived insights for designing new tools and teaching methods for kids coding.

Inhibition of RAF dimers: it takes two to tango

The RAS-regulated RAF–MEK1/2–ERK1/2 pathway promotes cell proliferation and survival and RAS and BRAF proteins are commonly mutated in cancer. This has fuelled the development of small molecule kinase inhibitors including ATP-competitive RAF inhibitors. Type I and type I½ ATP-competitive RAF inhibitors are effective in BRAFV600E/K-mutant cancer cells. However, in RAS-mutant cells these compounds instead promote RAS-dependent dimerisation and paradoxical activation of wild-type RAF proteins. RAF dimerisation is mediated by two key regions within each RAF protein; the RKTR motif of the αC-helix and the NtA-region of the dimer partner. Dimer formation requires the adoption of a closed, active kinase conformation which can be induced by RAS-dependent activation of RAF or by the binding of type I and I½ RAF inhibitors. Binding of type I or I½ RAF inhibitors to one dimer partner reduces the binding affinity of the other, thereby leaving a single dimer partner uninhibited and able to activate MEK. To overcome this paradox two classes of drug are currently under development; type II pan-RAF inhibitors that induce RAF dimer formation but bind both dimer partners thus allowing effective inhibition of both wild-type RAF dimer partners and monomeric active class I mutant RAF, and the recently developed “paradox breakers” which interrupt BRAF dimerisation through disruption of the αC-helix. Here we review the regulation of RAF proteins, including RAF dimers, and the progress towards effective targeting of the wild-type RAF proteins

Cognitive Benefits of Activity Engagement among 12,093 Adults Aged over 65 Years

Objective: The present study includes two aims: (1) to understand patterns of activity engagement among older Chinese adults; (2) to further investigate associations between activity engagement and cognitive abilities in this population. Methods: Latent class analysis was applied to answer the aforementioned research questions across different age ranges while controlling for confounding variables (age, health, socioeconomic status (SES), and living alone). Specifically, five latent classes (non-active, working-active, comprehensive-active, physical-active, and less-active) were identified. Furthermore, associations between the classes of activity engagement and cognition were examined separately in three age groups: less than 80 years (young-old group), 80–99.5 years (old-old group) and more than 100 years (oldest-old group) of age. Results: Compared with Non-active older individuals, the other classes with a higher probability of engagement in various activities generally showed higher cognitive abilities (including general cognition, orientation, calculation, recall, and language), but not all patterns of active engagement in daily life were positively associated with better cognitive status across different age ranges. In particular, differences in the individuals’ cognitive abilities across the four active latent classes were especially obvious in the old-old group as follows: the Comprehensive-active class had higher general cognitive and recall abilities than the other three active classes and higher calculation and language abilities than the Working-active class. In addition, significant sex differences were observed in activity patterns, cognition, and their associations in the young-old and old-old groups. Culture-specific programs should be customized to subgroups of different ages and genders by providing different training or activity modules based on their related dimensions of cognitive decline.