A novel plant actin-microtubule bridging complex regulates cytoskeletal and ER structure at ER-PM contact sites

In plants, the cortical endoplasmic reticulum (ER) network is connected to the plasma membrane (PM) through the ER-PM contact sites (EPCSs), whose structures are maintained by EPCS resident proteins and the cytoskeleton.1, 2, 3, 4, 5, 6, 7 Strong co-alignment between EPCSs and the cytoskeleton is observed in plants,1,8 but little is known of how the cytoskeleton is maintained and regulated at the EPCS. Here, we have used a yeast-two-hybrid screen and subsequent in vivo interaction studies in plants by fluorescence resonance energy transfer (FRET)-fluorescence lifetime imaging microscopy (FLIM) analysis to identify two microtubule binding proteins, KLCR1 (kinesin-light-chain-related protein 1) and IQD2 (IQ67-domain 2), that interact with the actin binding protein NET3C and form a component of plant EPCS that mediates the link between the actin and microtubule networks. The NET3C-KLCR1-IQD2 module, acting as an actin-microtubule bridging complex, has a direct influence on ER morphology and EPCS structure. Their loss-of-function mutants, net3a/NET3C RNAi, klcr1, or iqd2, exhibit defects in pavement cell morphology, which we suggest is linked to the disorganization of both actin filaments and microtubules. In conclusion, our results reveal a novel cytoskeletal-associated complex, which is essential for the maintenance and organization of cytoskeletal structure and ER morphology at the EPCS and for normal plant cell morphogenesis

Application of super absorbent polymers (SAP) in concrete construction—update of RILEM state-of-the-art report

Superabsorbent polymers (SAP) are a new, promising class of chemical admixtures which offer new possibilities in respect of influencing the properties of cement-based materials in the fresh, hardening, and hardened states. Much research work has been done in the last two decades to set the stage for introducing this truly multipurpose agent into the practice of construction. In particular, three RILEM Technical Committees: 196-ICC, 225-SAP and 260-RSC contributed considerably to the related progress by coordinating and combining the efforts of international experts in the field. The major product of the RILEM TC 225-SAP work was the State-of-the-Art Report published in 2012. This comprehensive document covered all topics relevant to the application of SAP as a concrete admixture. Since then further important progress has been made in understanding the working mechanisms of SAP in concrete and the effects of SAP-addition on various concrete properties. The article at hand presents an update on the state-of-the-art and is the concluding document delivered by the RILEM TC 260-RSC

Small molecule inhibition of CBP/catenin interactions eliminates drug resistant clones in acute lymphoblastic leukemia

Drug resistance in acute lymphoblastic leukemia (ALL) remains a major problem warranting new treatment strategies. Wnt/catenin signaling is critical for the self-renewal of normal hematopoietic progenitor cells. Deregulated Wnt signaling is evident in chronic and acute myeloid leukemia, however little is known about ALL. Differential interaction of catenin with either the Kat3 coactivator CREBBP (CBP) or the highly homologous EP300 (p300) is critical to determine divergent cellular responses and provides a rationale for the regulation of both proliferation and differentiation by the Wnt signaling pathway. Usage of the coactivator CBP by catenin leads to transcriptional activation of cassettes of genes that are involved in maintenance of progenitor cell self-renewal. However, the use of the coactivator p300, leads to activation of genes involved in the initiation of differentiation. ICG-001 is a novel small molecule modulator of Wnt/catenin signaling, which specifically binds to the N-terminus of CBP and not p300, within amino acids 1–110, thereby disrupting the interaction between CBP and catenin. Here, we report that selective disruption of the CBP/β- and γ-catenin interactions using ICG-001 leads to differentiation of pre-B ALL cells and loss of self-renewal capacity. Survivin, an inhibitor-of-apoptosis protein, was also downregulated in primary ALL after treatment with ICG-001. Using ChIP assay, we demonstrate occupancy by CBP of the survivin promoter, which is decreased by ICG-001 in primary ALL. CBP-mutations have been recently identified in a significant percentage of ALL patients, however, almost all of the identified mutations reported occur C-terminal to the binding site for ICG-001. Importantly, ICG-001, regardless of CBP mutational status and chromosomal aberration, leads to eradication of drug-resistant primary leukemia in combination with conventional therapy in vitro and significantly prolongs the survival of NOD/SCID mice engrafted with primary ALL. Therefore, specifically inhibiting CBP/catenin transcription represents a novel approach to overcome relapse in ALL

An African Salmonella Typhimurium ST313 sublineage with extensive drug-resistance and signatures of host adaptation

Abstract: Bloodstream infections by Salmonella enterica serovar Typhimurium constitute a major health burden in sub-Saharan Africa (SSA). These invasive non-typhoidal (iNTS) infections are dominated by isolates of the antibiotic resistance-associated sequence type (ST) 313. Here, we report emergence of ST313 sublineage II.1 in the Democratic Republic of the Congo. Sublineage II.1 exhibits extensive drug resistance, involving a combination of multidrug resistance, extended spectrum β-lactamase production and azithromycin resistance. ST313 lineage II.1 isolates harbour an IncHI2 plasmid we name pSTm-ST313-II.1, with one isolate also exhibiting decreased ciprofloxacin susceptibility. Whole genome sequencing reveals that ST313 II.1 isolates have accumulated genetic signatures potentially associated with altered pathogenicity and host adaptation, related to changes observed in biofilm formation and metabolic capacity. Sublineage II.1 emerged at the beginning of the 21st century and is involved in on-going outbreaks. Our data provide evidence of further evolution within the ST313 clade associated with iNTS in SSA

Infection with the Persistent Murine Norovirus Strain MNV-S99 Suppresses IFN-Beta Release and Activation of Stat1 In Vitro

Norovirus infection is the main cause of epidemic non-bacterial gastroenteritis in humans. Although human norovirus (HuNoV) infection is self-limiting, it can persist for extended periods of time in immune deficient patients. Due to the lack of robust cell culture and small animal systems, little is known about HuNoV pathogenicity. However, murine norovirus (MNV) can be propagated in cell culture and is used as a model to study norovirus infection. Several MNV are known to persist in mice. In this study, we show that the MNV strain MNV-S99 persists in wild type inbred (C57BL/6J) mice over a period of at least 5 weeks post infection. Viral RNA was detectable in the jejunum, ileum, cecum, and colon, with the highest titers in the colon and cecum. To characterize the effect of MNV-S99 on the innate immune response, Stat1 phosphorylation and IFN-β production were analyzed and compared to the non-persistent strain MNV-1.CW3. While MNV-S99 and MNV-1.CW3 showed comparable growth characteristics in vitro, Stat1 phosphorylation and IFN-β release is strongly decreased after infection with MNV-S99 compared to MNV-1.CW3. In conclusion, our results show that unlike MNV-1.CW3, MNV-S99 establishes a persistent infection in mice, possibly due to interfering with the innate immune response

Diversity and biogeography of planktonic diatoms in Svalbard fjords: The role of dispersal and Arctic endemism in phytoplankton community structuring

International audienceUnderstanding the processes that shape the community structure of Arctic phytoplankton is crucial for predicting responses of Arctic ecosystems to the ongoing ocean warming. In particular, little is known about the importance of phytoplankton dispersal by the North Atlantic Current and the prevalence and maintenance of Arctic endemism. We investigated the diversity and biogeography of diatoms from five Svalbard fjords and the Hausgarten observatory (Fram Strait) by combining diatom cultivation and 18S rRNA gene metabarcoding. In total, 50 diatom strains were isolated from the area during the HE492 cruise in August 2017. The strains were identified taxonomically using molecular and morphological approaches, and their biogeographic distribution was mapped using the local metabarcoding dataset and a global compilation of published metabarcoding datasets. Biogeographic analysis was also conducted for the locally most abundant diatom metabarcoding amplicon sequence variants. The biogeographic analyses demonstrated that Arctic diatoms exhibit three general biogeographic distribution types: Arctic, Arctic-temperate, and cosmopolitan. At Hausgarten and in outer Isfjorden on the west coast of Svalbard, the communities were dominated by genotypes with Arctic-temperate and cosmopolitan distribution. Diatom communities in nearby Van Mijenfjorden, inner Isfjorden and Kongsfjorden were dominated by genotypes with Arctic-temperate distribution, and cosmopolitan species were less abundant. The genotypes endemic to the Arctic had lower abundance on the west coast of Svalbard. The two northernmost fjords (Woodfjorden and Wijdefjorden) had a higher abundance of genotypes endemic to the Arctic. Our results demonstrate that the diatom communities in the Svalbard area consist of genotypes endemic to the Arctic, and genotypes with broader biogeographic distribution, all of which are further structured by local environmental gradients. Finer biogeographic patterns observed within Arctic-temperate and cosmopolitan genotypes suggest that certain genotypes can be used as indicators of increasing influence of Atlantic waters on the phytoplankton community structure in the Svalbard area

Prophylactic nimodipine treatment for hearing preservation after vestibular schwannoma surgery: study protocol of a randomized multi-center phase III trial—AkniPro 2

Background!#!A previously performed phase III trial on 112 subjects investigating prophylactic nimodipine treatment in vestibular schwannoma (VS) surgery showed no clear beneficial effects on preservation of facial and cochlear nerve functions, though it should be considered that protection of facial nerve function was the primary outcome. However, the risk for postoperative hearing loss was halved in the nimodipine group compared to the control group (OR 0.49; 95% CI 0.18-1.30; p = 0.15). Accordingly, this phase III extension trial investigates the efficacy and safety of prophylactic nimodipine for hearing preservation in VS surgery.!##!Methods!#!This is a randomized, multi-center, two-armed, open-label phase III trial with blinded expert review and two-stage with interim analysis. Three hundred thirty-six adults with the indication for microsurgical removal of VS (Koos I-IV) and serviceable preoperative hearing (Gardner-Robertson scale (GR) 1-3) are assigned to either the therapy (intravenous nimodipine 1-2 mg/h from the day before surgery until the fifth postoperative day and standard of care) or the control group (surgery only and standard of care). The primary endpoint of the trial is postoperative cochlear nerve function measured before discharge according to GR 1-3 versus GR 4-5 (binary). Hearing function will be determined by pre- and postoperative audiometry with speech discrimination, which will be evaluated by a blinded expert reviewer. Furthermore, patient-reported outcomes using standardized questionnaires will be analyzed.!##!Discussion!#!Prophylactic parenteral nimodipine treatment may have a positive effect on hearing preservation in VS surgery and would improve patient's quality of life. Further secondary analyses are planned. Except for dose-depending hypotension, nimodipine is known as a safe drug. In the future, prophylactic nimodipine treatment may be recommended as a routine medication in VS surgery. VS can be considered as an ideal model for clinical evaluation of neuroprotection, since hearing outcome can be classified by well-recognized criteria. The beneficial effect of nimodipine may be transferable to other surgical procedures with nerves at risk and may have impact on basic research.!##!Trial registration!#!EudraCT 2019-002317-19, DRKS00019107 . 8th May 2020

Early childhood professionals' perceptions of children's school readiness characteristics in six countries

The opinions of early years educators and primary school teachers regarding the school readiness characteristics (SRC) that best support a child's positive transition to school differ. The aims of our study were to determine key elements of perceived SRC and to identify the priorities of pre-service and in-service early years professionals in six countries: Australia, Austria, Colombia, Germany, Nicaragua, and Slovenia. In total, 1198 early years professionals responded to a survey that investigated perceptions of child school readiness characteristics. Independence, social skills and concentration were reported to be very important. Academic precursors and physical development were reported to be the least important SRC. Findings for the total sample and specific subgroups are presented and discussed