Summary
Autoregulation of nodulation (AON), a systemic signaling pathway in legumes, limits the number of nodules formed by the legume in its symbiosis with rhizobia. Recent research suggests a model ...for the systemic regulation in Medicago truncatula in which root signaling peptides are translocated to the shoot where they bind to a shoot receptor complex containing the leucine‐rich repeat receptor‐like kinase SUNN, triggering signal transduction which terminates nodule formation in roots. Here we show that a tagged SUNN protein capable of rescuing the sunn‐4 phenotype is localized to the plasma membrane and is associated with the plasmodesmata. Using bimolecular fluorescence complementation analysis we show that, like its sequence ortholog Arabidopsis CLV1, SUNN interacts with homologous CLV1‐interacting proteins MtCLAVATA2 and MtCORYNE. All three proteins were also able to form homomers and MtCRN and MtCLV2 also interact with each other. A crn Tnt1 insertion mutant of M. truncatula displayed a shoot controlled increased nodulation phenotype, similar to the clv2 mutants of pea and Lotus japonicus. Together these data suggest that legume AON signaling could occur through a multi‐protein complex and that both MtCRN and MtCLV2 may play roles in AON together with SUNN.
Significance Statement
Control of nodule number in legume roots is mediated by a receptor kinase that acts in the shoot, but how the signal is perceived in the shoot and transmitted to the roots is still unclear. Proteins that interact in local meristem signaling in Arabidopsis are shown here to interact with a kinase in the systemic nodulation signaling pathway in M. truncatula, suggesting that like the local pathway, the systemic pathway may coordinate multiple signals with different receptor/ligand combinations.
Cell division is often regulated by extracellular signaling networks to ensure correct patterning during development. In Arabidopsis, the SHORT-ROOT (SHR)/SCARECROW (SCR) transcription factor dimer ...activates CYCLIND6;1 (CYCD6;1) to drive formative divisions during root ground tissue development. Here, we show plasma-membrane-localized BARELY ANY MERISTEM1/2 (BAM1/2) family receptor kinases are required for SHR-dependent formative divisions and CYCD6;1 expression, but not SHR-dependent ground tissue specification. Root-enriched CLE ligands bind the BAM1 extracellular domain and are necessary and sufficient to activate SHR-mediated divisions and CYCD6;1 expression. Correspondingly, BAM-CLE signaling contributes to the restriction of formative divisions to the distal root region. Additionally, genetic analysis reveals that BAM-CLE and SHR converge to regulate additional cell divisions outside of the ground tissues. Our work identifies an extracellular signaling pathway regulating formative root divisions and provides a framework to explore this pathway in patterning and evolution.
Summary
Autoregulation of nodulation (
AON
), a systemic signaling pathway in legumes, limits the number of nodules formed by the legume in its symbiosis with rhizobia. Recent research suggests a ...model for the systemic regulation in
Medicago truncatula
in which root signaling peptides are translocated to the shoot where they bind to a shoot receptor complex containing the leucine‐rich repeat receptor‐like kinase
SUNN
, triggering signal transduction which terminates nodule formation in roots. Here we show that a tagged
SUNN
protein capable of rescuing the
sunn‐4
phenotype is localized to the plasma membrane and is associated with the plasmodesmata. Using bimolecular fluorescence complementation analysis we show that, like its sequence ortholog Arabidopsis
CLV
1,
SUNN
interacts with homologous
CLV
1‐interacting proteins Mt
CLAVATA
2 and Mt
CORYNE
. All three proteins were also able to form homomers and Mt
CRN
and Mt
CLV
2 also interact with each other. A
crn Tnt
1 insertion mutant of
M. truncatula
displayed a shoot controlled increased nodulation phenotype, similar to the
clv2
mutants of pea and
Lotus japonicus
. Together these data suggest that legume
AON
signaling could occur through a multi‐protein complex and that both Mt
CRN
and Mt
CLV
2 may play roles in
AON
together with
SUNN
.
Significance Statement
Control of nodule number in legume roots is mediated by a receptor kinase that acts in the shoot, but how the signal is perceived in the shoot and transmitted to the roots is still unclear. Proteins that interact in local meristem signaling in Arabidopsis are shown here to interact with a kinase in the systemic nodulation signaling pathway in
M. truncatula,
suggesting that like the local pathway, the systemic pathway may coordinate multiple signals with different receptor/ligand combinations.
We explored moderating effects of situational content on associations between Big Five expressions and behavioral effectiveness judgments within-jobs. Critical incidents were rated for effectiveness ...and personality expression and sorted by whether they represented task or interpersonal situations. We computed experts' implicit trait policies (
Motowidlo, Hooper, & Jackson, 2006b
) to assess the effectiveness of behavioral manifestations of personality and whether their effectiveness differed by situation type. Emotionally stable and conscientious actions were more effective in task situations and open and agreeable actions were more effective in interpersonal situations. Findings lead us to hypothesize that the validity coefficients of personality tests may vary by situation within-jobs.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Carbapenem-resistant
(CRE) represent a health threat, but effective control interventions remain unclear. Hospital wastewater sites are increasingly being highlighted as important potential ...reservoirs. We investigated a large
carbapenemase (KPC)-producing
outbreak and wider CRE incidence trends in the Central Manchester University Hospital NHS Foundation Trust (CMFT) (United Kingdom) over 8 years, to determine the impact of infection prevention and control measures. Bacteriology and patient administration data (2009 to 2017) were linked, and a subset of CMFT or regional hospital KPC-producing
isolates (
= 268) were sequenced. Control interventions followed international guidelines and included cohorting, rectal screening (
= 184,539 screens), environmental sampling, enhanced cleaning, and ward closure and plumbing replacement. Segmented regression of time trends for CRE detections was used to evaluate the impact of interventions on CRE incidence. Genomic analysis (
= 268 isolates) identified the spread of a KPC-producing
outbreak clone (strain A, sequence type 216 ST216;
= 125) among patients and in the environment, particularly on 2 cardiac wards (wards 3 and 4), despite control measures. ST216 strain A had caused an antecedent outbreak and shared its KPC plasmids with other
lineages and
species. CRE acquisition incidence declined after closure of wards 3 and 4 and plumbing replacement, suggesting an environmental contribution. However, ward 3/ward 4 wastewater sites were rapidly recolonized with CRE and patient CRE acquisitions recurred, albeit at lower rates. Patient relocation and plumbing replacement were associated with control of a clonal KPC-producing
outbreak; however, environmental contamination with CRE and patient CRE acquisitions recurred rapidly following this intervention. The large numbers of cases and the persistence of
in
, including pathogenic lineages, are of concern.
BRAFV600E mutation in microsatellite-unstable (MSI) colorectal carcinomas (CRCs) virtually excludes Lynch syndrome (LS). In microsatellite-stable (MSS) CRCs it predicts poor prognosis. We propose a ...universal CRC LS screening algorithm using concurrent reflex immunohistochemistry (IHC) for BRAFV600E and mismatch-repair (MMR) proteins. We compared BRAFV600E IHC with multiplex polymerase chain reaction (PCR) and matrix-assisted laser desorption/ionization-time of flight mass spectrometry in 216 consecutive CRCs from 2011. Discordant cases were resolved with real-time PCR. BRAFV600E IHC was performed on 51 CRCs from the Australasian Colorectal Cancer Family Registry (ACCFR), which were fully characterized for BRAF mutation by allele-specific PCR, MMR status (MMR IHC and MSI), MLH1 promoter methylation, and germline MLH1 mutation. We then assessed MMR and BRAFV600E IHC on 1403 consecutive CRCs. By matrix-assisted laser desorption/ionization-time of flight mass spectrometry 15 cases did not yield a BRAF result, whereas 38/201 (19%) were positive. By IHC 45/216 (20%) were positive. Of the 7 discordant cases, real-time PCR confirmed the IHC result in 6. In the 51 CRCs from the ACCFR, IHC was concordant with allele-specific PCR in 50 cases. BRAFV600E and MSI IHC on 1403 CRCs demonstrated the following phenotypesBRAF/MSS (1029 cases, 73%), BRAF/MSS (98, 7%), BRAF/MSI (183, 13%), and BRAF/MSI (93, 7%). All 11/1403 cancers associated with proven LS were BRAF/MSI. We conclude that BRAF IHC is highly concordant with 2 commonly used PCR-based BRAFV600E assays; it performed well in identifying MLH1 mutation carriers from the ACCFR and identified all cases of proven LS among the 1403 CRCs. Reflex BRAFV600E and MMR IHC are simple cheap tests that facilitate universal LS screening and identify the poor prognosis of the BRAFV600E-mutant MSS CRC phenotype.
IMPORTANCE: Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial ...activation considerations in therapeutic advancement. OBJECTIVES: To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses. MAIN OUTCOMES AND MEASURES: Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET). RESULTS: Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median range age at death, 81 54-96 years) and 728 were female (53%; median range age at death, 81 53-102 years). A younger symptomatic onset (Spearman ρ = 0.39, P < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median IQR, 13 9-18) vs not (median IQR, 21 15-27; P < .001). Hippocampal MRI volume (Spearman ρ = −0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = −0.74; P < .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median IQR, 0.46% 0.32%-0.75%) compared with cases with a CLix score of 10 to 30 (median IQR, 0.75% 0.51%-0.98%) and on par with a CLix score of 30 or greater (median IQR, 0.40% 0.32%-0.57%; P = .02). CONCLUSIONS AND RELEVANCE: Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.
Resistance to paclitaxel chemotherapy frequently develops in ovarian cancer. Oncolytic adenoviruses are a novel therapy for human malignancies that are being evaluated in early phase trials. However, ...there are no reliable predictive biomarkers for oncolytic adenovirus activity in ovarian cancer. We investigated the link between paclitaxel resistance and oncolytic adenovirus activity using established ovarian cancer cell line models, xenografts with de novo paclitaxel resistance and tumour samples from two separate trials. The activity of multiple Ad5 vectors, including dl922-947 (E1A CR2-deleted), dl1520 (E1B-55K deleted) and Ad5 WT, was significantly increased in paclitaxel resistant ovarian cancer in vitro and in vivo. This was associated with greater infectivity resulting from increased expression of the primary receptor for Ad5, CAR (coxsackie adenovirus receptor). This, in turn, resulted from increased CAR transcription secondary to histone modification in resistant cells. There was increased CAR expression in intraperitoneal tumours with de novo paclitaxel resistance and in tumours from patients with clinical resistance to paclitaxel. Increased CAR expression did not cause paclitaxel resistance, but did increase inflammatory cytokine expression. Finally, we identified dysregulated cell cycle control as a second mechanism of increased adenovirus efficacy in paclitaxel-resistant ovarian cancer. Ad11 and Ad35, both group B adenoviruses that utilise non-CAR receptors to infect cells, are also significantly more effective in paclitaxel-resistant ovarian cell models. Inhibition of CDK4/6 using PD-0332991 was able both to reverse paclitaxel resistance and reduce adenovirus efficacy. Thus, paclitaxel resistance increases oncolytic adenovirus efficacy via at least two separate mechanisms – if validated further, this information could have future clinical utility to aid patient selection for clinical trials.
•Oncolytic adenoviruses are more effective in paclitaxel-resistant ovarian cancer, via multiple mechanisms.•Paclitaxel increases expression of coxsackie adenovirus receptor (CAR) through altered histone modification.•Increased CAR expression can increase inflammatory cytokine expression.•Paclitaxel resistance also increases adenovirus activity via dysregulated cell cycle control.
A new regional coupled modelling framework is introduced – the Regional
Coupled Suite (RCS). This provides a flexible research capability with which
to study the interactions between atmosphere, ...land, ocean, and wave processes
resolved at kilometre scale, and the effect of environmental feedbacks on the
evolution and impacts of multi-hazard weather events. A configuration of the
RCS focussed on the Indian region, termed RCS-IND1, is introduced. RCS-IND1
includes a regional configuration of the Unified Model (UM) atmosphere,
directly coupled to the JULES land surface model, on a grid with horizontal
spacing of 4.4 km, enabling convection to be explicitly simulated. These are
coupled through OASIS3-MCT libraries to 2.2 km grid NEMO ocean and WAVEWATCH
III wave model configurations. To examine a potential approach to reduce
computation cost and simplify ocean initialization, the RCS includes an
alternative approach to couple the atmosphere to a lower resolution
Multi-Column K-Profile Parameterization (KPP) for the ocean. Through
development of a flexible modelling framework, a variety of fully and
partially coupled experiments can be defined, along with traceable uncoupled
simulations and options to use external input forcing in place of missing
coupled components. This offers a wide scope to researchers designing
sensitivity and case study assessments. Case study results are presented and
assessed to demonstrate the application of RCS-IND1 to simulate two tropical
cyclone cases which developed in the Bay of Bengal, namely Titli in October
2018 and Fani in April 2019. Results show realistic cyclone simulations, and
that coupling can improve the cyclone track and produces more realistic
intensification than uncoupled simulations for Titli but prevents sufficient
intensification for Fani. Atmosphere-only UM regional simulations omit the
influence of frictional heating on the boundary layer to prevent cyclone
over-intensification. However, it is shown that this term can improve
coupled simulations, enabling a more rigorous treatment of the near-surface
energy budget to be represented. For these cases, a 1D mixed layer scheme
shows similar first-order SST cooling and feedback on the cyclones to a 3D
ocean. Nevertheless, the 3D ocean generally shows stronger localized cooling
than the 1D ocean. Coupling with the waves has limited feedback on the
atmosphere for these cases. Priorities for future model development are
discussed.
To date, only the H1
MAPT haplotype has been consistently associated with risk of developing the neurodegenerative disease progressive supranuclear palsy (PSP). We hypothesized that additional ...genetic loci may be involved in conferring risk of PSP that could be identified through a pooling-based genomewide association study of >500,000 SNPs. Candidate SNPs with large differences in allelic frequency were identified by ranking all SNPs by their probe-intensity difference between cohorts. The
MAPT H1 haplotype was strongly detected by this methodology, as was a second major locus on chromosome 11p12-p11 that showed evidence of association at allelic (
P<.001), genotypic (
P<.001), and haplotypic (
P<.001) levels and was narrowed to a single haplotype block containing the DNA damage-binding protein 2 (
DDB2) and lysosomal acid phosphatase 2 (
ACP2) genes. Since DNA damage and lysosomal dysfunction have been implicated in aging and neurodegenerative processes, both genes are viable candidates for conferring risk of disease.
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