Esterase activity and isoenzymes in relation to morphogenesis in Mammillaria gracillis Pfeiff. tissue culture

Cactus Mammillaria gracillis Pfeiff. (Cactaceae), cultivated in vitro, spontaneously switches from an organised to unorganised way of growth, producing a habituated organogenic callus which regenerates normal and hyperhydric shoots without the addition of any growth regulators. Tumour tissues, induced by A. tumefaciens wild strain B6S3 (tumour TW) and rooty mutant GV3101 (tumour TR), do not express any organogenic potential. The esterase (arylesterase EC 3.1.1.2 and carboxylesterase EC 3.1.1.1) activity and isoenzyme pattern of morphologically different cactus tissues: shoot, callus, hyperhydric regenerant, tumours TW and TR, were compared. Tissue samples were frozen at –80 °C and lyophilized before protein extraction. Two esterase substrates, 1- and 2-naphthylacetate, were used. Esterase activity of all tissues varied during the period of one subculture. In shoots and tumours, the highest esterase activity for both substrates was measured on the 21st day, while in the callus and hyperhydric regenerants the highest activity was on the 7th day. Esterases were separated electrophoretically in polyacrylamide gradient gels under non-denaturating conditions. In total, 13 isoesterases, reacting with both substrates, were resolved. No differences in isoenzyme profile were noticed in correlation with the age of tissues, but the esterase activity varied among tissues. The significance of these results is discussed

Esterase activity and isoenzymes in relation to morphogenesis in Mammillaria gracillis Pfeiff. tissue culture

Cactus Mammillaria gracillis Pfeiff. (Cactaceae), cultivated in vitro, spontaneously switches from an organised to unorganised way of growth, producing a habituated organogenic callus which regenerates normal and hyperhydric shoots without the addition of any growth regulators. Tumour tissues, induced by A. tumefaciens wild strain B6S3 (tumour TW) and rooty mutant GV3101 (tumour TR), do not express any organogenic potential. The esterase (arylesterase EC 3.1.1.2 and carboxylesterase EC 3.1.1.1) activity and isoenzyme pattern of morphologically different cactus tissues: shoot, callus, hyperhydric regenerant, tumours TW and TR, were compared. Tissue samples were frozen at –80 °C and lyophilized before protein extraction. Two esterase substrates, 1- and 2-naphthylacetate, were used. Esterase activity of all tissues varied during the period of one subculture. In shoots and tumours, the highest esterase activity for both substrates was measured on the 21st day, while in the callus and hyperhydric regenerants the highest activity was on the 7th day. Esterases were separated electrophoretically in polyacrylamide gradient gels under non-denaturating conditions. In total, 13 isoesterases, reacting with both substrates, were resolved. No differences in isoenzyme profile were noticed in correlation with the age of tissues, but the esterase activity varied among tissues. The significance of these results is discussed

Exact solution of electronic transport in semiconductors dominated by scattering on polaronic impurities

The scattering of electrons on impurities with internal degrees of freedom is bound to produce the signatures of the scatterer's own dynamics and results in nontrivial electronic transport properties. Previous studies of polaronic impurities in low-dimensional structures, like molecular junctions and one-dimensional nanowire models, have shown that perturbative treatments cannot account for a complex energy dependence of the scattering cross section in such systems. Here we derive the exact solution of polaronic impurities shaping the electronic transport in bulk (3D) systems. In the model with a short-ranged electron-phonon interaction, we solve for and sum over all elastic and inelastic partial cross sections, abundant in resonant features. The temperature dependence of the charge mobility shows the power-law dependence, $\mu(T)\propto T^{-\nu}$, with $\nu$ being highly sensitive to impurity parameters. The latter may explain nonuniversal power-law exponents observed experimentally, e.g. in high-quality organic molecular semiconductors.Comment: 5 pages, 6 figure

Translational derepression of Elavl4 isoforms at their alternative 5′ UTRs determines neuronal development

Neurodevelopment requires precise regulation of gene expression, including post-transcriptional regulatory events such as alternative splicing and mRNA translation. However, translational regulation of specific isoforms during neurodevelopment and the mechanisms behind it remain unknown. Using RNA-seq analysis of mouse neocortical polysomes, here we report translationally repressed and derepressed mRNA isoforms during neocortical neurogenesis whose orthologs include risk genes for neurodevelopmental disorders. We demonstrate that the translation of distinct mRNA isoforms of the RNA binding protein (RBP), Elavl4, in radial glia progenitors and early neurons depends on its alternative 5' UTRs. Furthermore, 5' UTR-driven Elavl4 isoform-specific translation depends on upstream control by another RBP, Celf1. Celf1 regulation of Elavl4 translation dictates development of glutamatergic neurons. Our findings reveal a dynamic interplay between distinct RBPs and alternative 5' UTRs in neuronal development and underscore the risk of post-transcriptional dysregulation in co-occurring neurodevelopmental disorders

Minimal residual disease negativity by next-generation flow cytometry is associated with improved organ response in AL amyloidosis

Light chain (AL) amyloidosis is caused by a small B-cell clone producing light chains that form amyloid deposits and cause organ dysfunction. Chemotherapy aims at suppressing the production of the toxic light chain (LC) and restore organ function. However, even complete hematologic response (CR), defined as negative serum and urine immunofixation and normalized free LC ratio, does not always translate into organ response. Next-generation flow (NGF) cytometry is used to detect minimal residual disease (MRD) in multiple myeloma. We evaluated MRD by NGF in 92 AL amyloidosis patients in CR. Fifty-four percent had persistent MRD (median 0.03% abnormal plasma cells). There were no differences in baseline clinical variables in patients with or without detectable MRD. Undetectable MRD was associated with higher rates of renal (90% vs 62%, p = 0.006) and cardiac response (95% vs 75%, p = 0.023). Hematologic progression was more frequent in MRD positive (0 vs 25% at 1 year, p = 0.001). Altogether, NGF can detect MRD in approximately half the AL amyloidosis patients in CR, and persistent MRD can explain persistent organ dysfunction. Thus, this study supports testing MRD in CR patients, especially if not accompanied by organ response. In case MRD persists, further treatment could be considered, carefully balancing residual organ damage, patient frailty, and possible toxicity

Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain

A population of >6 million people worldwide at high risk of Alzheimer’s disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aβ deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome-21-gene BACE2, but prevented by combined chemical β and γ-secretase inhibition. We found that T21-organoids secrete increased proportions of Aβ-preventing (Aβ1-19) and Aβ-degradation products (Aβ1-20 and Aβ1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1-inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ~30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases

Response to Novel Drugs before and after Allogeneic Stem Cell Transplantation in Patients with Relapsed Multiple Myeloma

Multiple myeloma (MM) remains as an incurable disease and, although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative approach, most patients ultimately relapse, and their treatment remains challenging. Because allo-HSCT can modify not only the biology of the disease, but also the immune system and the microenvironment, it can potentially enhance the response to rescue therapies. Information on the efficacy and safety of novel drugs in patients relapsing after allo-HSCT is lacking, however. The objectives of this study were to evaluate the efficacy and toxicity of rescue therapies in patients with MM who relapsed after allo-HSCT, as well as to compare their efficacy before and after allo-HSCT. This retrospective multicenter study included 126 consecutive patients with MM who underwent allo-HSCT between 2000 and 2013 at 8 Spanish centers. All patients engrafted. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 47%, and nonrelapse mortality within the first 100 days post-transplantation was 13%. After a median follow-up of 92 months, overall survival (OS) was 51% at 2 years and 43% at 5 years. The median progression-free survival after allo-HSCT was 7 months, whereas the median OS after relapse was 33 months. Patients relapsing in the first 6 months after transplantation had a dismal prognosis compared with those who relapsed later (median OS, 11 months versus 120 months; P <.001). The absence of chronic GVHD was associated with reduced OS after relapse (hazard ratio, 3.44; P <.001). Most patients responded to rescue therapies, including proteasome inhibitors (PIs; 62%) and immunomodulatory drugs (IMiDs; 77%), with a good toxicity profile. An in-depth evaluation, including the type and intensity of PI- and IMiD-based combinations used before and after allo-HSCT, showed that the overall response rate and duration of response after allo-HSCT were similar to those seen in the pretransplantation period. Patients with MM who relapse after allo-HSCT should be considered candidates for therapy with new drugs, which can achieve similar response rates with similar durability as seen in the pretransplantation period. This pattern does not follow the usual course of the disease outside the transplantation setting, where response rates and time to progression decreases with each consecutive line of treatment

Multiple myeloma and SARS-CoV-2 infection : clinical characteristics and prognostic factors of inpatient mortality

There is limited information on the characteristics, prognostic factors, and outcomes of patients with multiple myeloma (MM) hospitalized with COVID-19. This retrospective case series investigated 167 patients reported from 73 hospitals within the Spanish Myeloma Collaborative Group network in March and April, 2020. Outcomes were compared with 167 randomly selected, contemporary, age-/sex-matched noncancer patients with COVID-19 admitted at six participating hospitals. Among MM and noncancer patients, median age was 71 years, and 57% of patients were male; 75 and 77% of patients, respectively, had at least one comorbidity. COVID-19 clinical severity was moderate-severe in 77 and 89% of patients and critical in 8 and 4%, respectively. Supplemental oxygen was required by 47 and 55% of MM and noncancer patients, respectively, and 21%/9% vs 8%/6% required noninvasive/invasive ventilation. Inpatient mortality was 34 and 23% in MM and noncancer patients, respectively. Among MM patients, inpatient mortality was 41% in males, 42% in patients aged >65 years, 49% in patients with active/progressive MM at hospitalization, and 59% in patients with comorbid renal disease at hospitalization, which were independent prognostic factors on adjusted multivariate analysis. This case series demonstrates the increased risk and identifies predictors of inpatient mortality among MM patients hospitalized with COVID-19