Acute myocarditis is an inflammatory condition that may herald the onset of dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). We investigated the frequency and clinical ...consequences of DCM and ACM genetic variants in a population-based cohort of patients with acute myocarditis.
This was a population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterized cardiomyopathy-associated genes with comparison to healthy controls (n=1053) sequenced on the same platform. Case ascertainment in England was assessed against national hospital admission data. The primary outcome was all-cause mortality.
Variants that would be considered pathogenic if found in a patient with DCM or ACM were identified in 8% of myocarditis cases compared with <1% of healthy controls (
=0.0097). In the London cohort (n=230; median age, 33 years; 84% men), patients were representative of national myocarditis admissions (median age, 32 years; 71% men; 66% case ascertainment), and there was enrichment of rare truncating variants (tv) in ACM-associated genes (3.1% of cases versus 0.4% of controls; odds ratio, 8.2;
=0.001). This was driven predominantly by
-tv in patients with normal LV ejection fraction and ventricular arrhythmia. In Maastricht (n=106; median age, 54 years; 61% men), there was enrichment of rare truncating variants in DCM-associated genes, particularly
-tv, found in 7% (all with left ventricular ejection fraction <50%) compared with 1% in controls (odds ratio, 3.6;
=0.0116). Across both cohorts over a median of 5.0 years (interquartile range, 3.9-7.8 years), all-cause mortality was 5.4%. Two-thirds of deaths were cardiovascular, attributable to worsening heart failure (92%) or sudden cardiac death (8%). The 5-year mortality risk was 3.3% in genotype-negative patients versus 11.1% for genotype-positive patients (
=0.08).
We identified DCM- or ACM-associated genetic variants in 8% of patients with acute myocarditis. This was dominated by the identification of
-tv in those with normal left ventricular ejection fraction and
-tv in those with reduced left ventricular ejection fraction. Despite differences between cohorts, these variants have clinical implications for treatment, risk stratification, and family screening. Genetic counseling and testing should be considered in patients with acute myocarditis to help reassure the majority while improving the management of those with an underlying genetic variant.
Background
Difficulty in preoperatively assessing the risk for occult invasion or surgery that precludes future accurate axillary mapping in patients with ductal cancer in situ (DCIS) account for ...overutilization of SLND.
Methods
Prospective, multicenter, cohort study, including women with any DCIS planned for mastectomy or DCIS grade 2 and > 20 mm, any DCIS grade 3, any mass-forming DCIS and any planned surgery. Patients received an interstitial SPIO injection during breast surgery, but no upfront SLND was performed. If invasion was identified on final pathology, delayed SLND (d-SLND) was performed separately with the coadministration of isotope ± blue dye (BD). Study outcomes were proportion of upfront SLNDs that were avoided, detection rates during d-SLND, and impact on healthcare costs.
Results
In total, 78.7% of study participants (
N
= 254, mean age 60 years, mean DCIS size 37.8 mm) avoided upfront SLND. On d-SLND (median 28 days, range 9–46), SPIO outperformed Tc
99
with (98.2% vs. 63.6%,
p
< 0.001) or without BD (92.7% vs. 50.9%,
p
< 0.001) and had higher nodal detection rate (86.9% vs. 32.3%,
p
< 0.001) and with BD (93.9% vs. 41.4%,
p
< 0.001). Only 27.9% of all SLNs retrieved were concordant for Tc
99
and SPIO. Type of breast procedure (WLE vs. oncoplastic BCT vs. mastectomy) affected these outcomes and accounted for the low performance of Tc
99
(
p
< 0.001). d-SLND resulted in a 28.1% total cost containment for women with pure DCIS on final pathology (4190 vs. 5828 USD,
p
< 0.001).
Conclusions
Marking the SLN with SPIO may avoid overtreatment and allow for accurate d-SLND in patients with DCIS.
Early-life antibiotic exposure perturbs the intestinal microbiota and accelerates type 1 diabetes (T1D) development in the NOD mouse model. Here, we found that maternal cecal microbiota transfer ...(CMT) to NOD mice after early-life antibiotic perturbation largely rescued the induced T1D enhancement. Restoration of the intestinal microbiome was significant and persistent, remediating the antibiotic-depleted diversity, relative abundance of particular taxa, and metabolic pathways. CMT also protected against perturbed metabolites and normalized innate and adaptive immune effectors. CMT restored major patterns of ileal microRNA and histone regulation of gene expression. Further experiments suggest a gut-microbiota-regulated T1D protection mechanism centered on Reg3γ, in an innate intestinal immune network involving CD44, TLR2, and Reg3γ. This regulation affects downstream immunological tone, which may lead to protection against tissue-specific T1D injury.
Display omitted
•CMT rescued antibiotic-induced T1D enhancement in NOD mice•CMT restored potential T1D-protective bacterial taxa•CMT restored global patterns of gene expression and modifications in the ileum•The study reveals a regulatory network of the innate immunity-sensing intestinal signals
Using a mouse model in which early-life antibiotics enhance T1D, Zhang et al. show that subsequent maternal cecal microbiota transfer reduces illness. The restorative effects on the intestinal microbiome and metabolism, ileal wall gene expression and regulation, and innate and adaptive immune effectors suggest a gut-microbiota-regulated T1D protective mechanism.
Plant mitochondria represent the largest group of respiring organelles on the planet. Plant mitochondrial messenger RNAs (mRNAs) lack Shine-Dalgarno-like ribosome-binding sites, so it is unknown how ...plant mitoribosomes recognize mRNA. We show that “mitochondrial translation factors” mTRAN1 and mTRAN2 are land plant–specific proteins, required for normal mitochondrial respiration chain biogenesis. Our studies suggest that mTRANs are noncanonical pentatricopeptide repeat (PPR)–like RNA binding proteins of the mitoribosomal “small” subunit. We identified conserved Adenosine (A)/Uridine (U)-rich motifs in the 5′ regions of plant mitochondrial mRNAs. mTRAN1 binds this motif, suggesting that it is a mitoribosome homing factor to identify mRNAs. We demonstrate that mTRANs are likely required for translation of all plant mitochondrial mRNAs. Plant mitochondrial translation initiation thus appears to use a protein-mRNA interaction that is divergent from bacteria or mammalian mitochondria.
Editor’s summary
Mitochondrial protein translation machinery has diverged within groups of eukaryotes, with differing ribosome structures and initiation sites. Tran
et al
. found that two proteins, mTRAN1 and mTRAN2, are required for translation initiation in
Arabidopsis
mitochondria. The mTRAN proteins form part of the ribosome small subunit and bind to motifs in the 5′ untranslated regions of mitochondrial genes, allowing protein translation to begin. This work offers insight into translation initiation in plants and highlights how different mitochondrial translation mechanisms have evolved from a common bacterial ancestor. —Madeleine Seale
Noncanonical pentatricopeptide repeat-like RNA-binding proteins of the mitoribosome initiate plant mitochondrial protein translation.
INTRODUCTION
Mitochondria are eukaryotic organelles required for energy conversion and metabolism. As mitochondria are likely remnants of bacteria that were once incorporated through endosymbiosis, they have retained many features similar to their bacterial ancestors. Mitochondria in most eukaryotes have retained their own genome, which encodes a set of proteins required for mitochondrial operation. During evolution many mitochondrial components have, however, diverged substantially between eukaryotic kingdoms, of which the mitochondrial ribosome (mitoribosome) is a prime example. How mitochondrial mRNAs are recognized by mitoribosomes to initiate protein translation in plants has been an enigma, especially because mitochondrial mRNAs lack bacterial-type Shine-Dalgarno ribosome-binding sequences.
RATIONALE
We characterized two “proteins of unknown function” that were suggested to be part of plant mitoribosomes, using
Arabidopsis thaliana
(Arabidopsis) as a model system. To assess their functions, we produced plants with reduced expression of these proteins and assessed how their loss of function affected mitochondrial biogenesis and proteostasis. In addition, we searched the 5′ regions of mitochondrial mRNAs for conserved motifs that could act as potential mitoribosomal binding sites.
RESULTS
We found that the identified genes, which we named “mitochondrial translation factors”
mTRAN1
and
mTRAN2
, are conserved in land plants but absent in green algae, animals, and fungi. mTRANs were exclusively found inside mitochondria, and when
mTRAN1
and/or
mTRAN2
were impaired in Arabidopsis, the plants showed growth reductions ranging from moderate growth inhibition to embryo lethality, indicating that they are essential for normal plant development. In the
mtran
double mutants, mitochondrial biogenesis and function were impaired, with reduced abundance and activity of all oxidative phosphorylation complexes that contain mitochondrially encoded subunits (Complexes I, III, IV, and V). Using coimmunoprecipitation assays, we found that mTRAN1 and -2 are part of the plant mitoribosomal “small” subunit (mtSSU), in line with previous studies. Transcriptome analysis of
mtran
double mutants showed a rearrangement of nuclear, mitochondrial, and chloroplast gene expression that further suggested mitochondrial translation defects. In agreement, we showed that
mtran
double mutants have reduced mitochondrial protein synthesis rates. A large proportion of mitochondrial mRNAs were not bound by mitoribosomes in
mtran
double mutants, suggesting an important role for mTRANs in translation initiation. Structural modeling indicated that mTRAN proteins are alpha-solenoid proteins related to pentatricopeptide repeat (PPR) proteins and are thus potentially RNA-binding proteins. Because we could not find putative RNA motifs that could be bound by mTRANs using classical “PPR-code” detection tools, we searched the 5′ sequences of thousands of plant mitochondrial genes for conserved motifs. We identified A/U-rich motifs (CUUUxU and AAGAAx/AxAAAG) and showed that mTRAN1 can directly bind these motifs in vitro and in vivo. Finally, using ribosome footprinting (Ribo-seq), we showed that mTRANs are required for binding and translation of likely all plant mitochondrial mRNAs.
CONCLUSION
This study establishes mTRAN proteins as factors required for mitochondrial translation in plants. Our results indicate that mTRANs can bind conserved A/U-rich motifs present in the 5′ regions of plant mitochondrial mRNAs, which may act as ribosome binding sites. mTRANs may thus act as “universal” homing factors to guide the mitoribosome to mitochondrial mRNAs and initiate translation. Plant mitochondrial translation initiation therefore appears to use a protein-mRNA interaction that is divergent from bacteria or mammalian mitochondria.
mTRAN proteins mediate mitochondrial translation in plants.
Plant mitochondria are required for energy metabolism, growth, and survival. Several proteins of the mitochondrial respiration chain and Adenosine triphosphate (ATP)-synthase are encoded by the mitochondrial genome and translated by mitoribosomes. Plant-specific mTRAN proteins are part of the plant mitoribosome “small” subunit (mtSSU). Our results indicate that mTRANs likely recognize A/U-rich sequence motifs in the 5′ regions of mitochondrial mRNAs to mediate translation initiation. After mRNA-binding, the “large” mitoribosomal subunit (mtLSU) joins to start translation. fMet, N-formylmethionine; A, adenosine; U, uridine; G, guanine; C, cytosine.
The water’s edge is a critically important and efficient location to trade with other partners by connecting inland water channels and sea lanes and to obtain food provisions from the biologically ...diverse and productive sea. Human civilization has built around the ports and harbors by constructing fixed structures to support waterborne transport and enhance or sustain city functions for millennia. These artificially fixed structures are not in natural equilibrium with the environment (water and sediment). Access channels and the sea bottom adjacent to piers are often dredged to accommodate larger ships. Bottom sediment dredging is a part of port management. Where to place the dredged material is of primary concern for port authorities because of its sheer volume and the potential to be chemically contaminated. The London Convention and the London Protocol (LC/LP) are international treaties that provide a process in preventing pollution from dumping of contaminated material at sea, and finding sound alternatives such as confined disposal facilities, and using clean dredged material in wetland creation or beach nourishment, based on the precautionary approach. The Anthropocene (Anthropocene refers to the most recent period in Earth’s history when human activity started to impact significantly on the climate and ecosystems.) coast of ports, harbors, wetlands, shorelines, and beaches of the coastal megacities faces tremendous challenges in managing navigational and shoreline infrastructure in view of sea level rise and climate change. Dredged sediments are a resource and are a key to protection of shorelines. The benefits of being members of the LC/LP treaties are that there is a wealth of various national experiences on sediment management available via the network of LC/LP national experts and in the records of the LC/LP’s Meetings of Contracting Parties.
Herein, we describe an organocatalytic living polymerization approach to network and subsequent hydrogel formation. Cyclic carbonate-functionalized macromolecules were ring-opened using an alcoholic ...initiator in the presence of an organic catalyst, amidine 1,8-diazabicyclo5.4.0undec-7-ene. A model reaction for the cross-linking identified monomer concentration-dependent reaction regimes, and enhanced kinetic control was demonstrated by introducing a comonomer, trimethylene carbonate. The addition of the comonomer facilitated near-quantitative conversion of monomer to polymer (>96%). Resulting poly(ethylene glycol) networks swell significantly in water, and an open co-continuous (water−gel) porous structure was observed by scanning electron microscopy. The organocatalytic ring-opening polymerization of cyclic carbonate functional macromonomers using alcoholic initiators provides a simple, efficient, and versatile approach to hydrogel networks.
Purpose
Women with radiographically dense or texturally complex breasts are at increased risk for interval cancer, defined as cancers diagnosed after a normal screening examination. The purpose of ...this study was to create masking measures and apply them to identify interval risk in a population of women who experienced either screen‐detected or interval cancers after controlling for breast density.
Methods
We examined full‐field digital screening mammograms acquired from 2006 to 2015. Examinations associated with 182 interval cancers were matched to 173 screen‐detected cancers on age, race, exam date and time since last imaging examination. Local Image Quality Factor (IQF) values were calculated and used to create IQF maps that represented mammographic masking. We used various statistics to define global masking measures of these maps. Association of these masking measures with interval cancer vs screen‐detected cancer was estimated using conditional logistic regression in a univariate and adjusted model for Breast Imaging‐Reporting and Data System (BI‐RADS) density. Receiver operator curves were calculated in each case to compare specificity vs sensitivity, and area under those curves were generated. Proportion of screen‐detected cancer was estimated for stratifications of IQF features.
Results
Several masking features showed significant association with interval compared to screen‐detected cancers after adjusting for BI‐RADS density (up to P = 2.52E‐6), and the 10th percentile of the IQF value (P = 1.72E‐3) showed the strongest improvement in the area under the receiver operator curve, increasing from 0.65 using only BI‐RADS density to 0.69. The highest masking group had a 32% proportion of screen‐detected cancers while the low masking group had a 69% proportion.
Conclusions
We conclude that computer vision methods using model observers may improve quantifying the probability of breast cancer detection beyond using breast density alone.
Chronic rhinosinusitis display a variety of different phenotypes. The symptoms of disease are characterised by various signs and symptoms such as nasal congestion, nasal discharge, pressure sensation ...in the face and reduced or complete loss of smell.In a patient population undergoing functional endoscopic sinonasal surgery (FESS) for chronic rhinosinusitis, we wanted to investigate the clinical features and explore if the presence of biofilm, nasal polyps or other disease characteristic could serve as predictor for the symptomatic load. A patient group undergoing septoplasty without disease of the sinuses was included as control.
The Sinonasal outcome test (SNOT-20), EPOS visual analogue scale (VAS) and the Lund-Mackey CT score (LM CT score) were used to examine 23 patients with chronic rhinosinusitis without nasal polyps (CRSsNP), 30 patient with nasal polyps (CRSwNP) and 22 patients with septal deviation. Tissue samples were collected prospectively during surgery. The cohort has previously been examined for the presence of biofilm.
Patients with CRSsNP and CRSwNP had significantly higher degree of symptoms compared to the septoplasty group (SNOT-20 scores of 39.8, 43.6 and 29.9, respectively,
= 0.034). There were no significant differences in the total SNOT-20 or VAS symptoms scores between the CRSsNP and CRSwNP subgroups. However patients with nasal polyps showed significantly higher scores of symptoms related to sinonasal discomfort such as cough, runny nose and need to blow nose (
= 0.011,
= 0.046,
= 0.001 respectively). Patients with nasal polyps showed a significantly higher LM CT score compared to patients without polyps (12.06 versus 8.00,
= 0.001). The presence of biofilm did not impact the degree of symptoms.
The presence of nasal polyp formations in CRS patients was associated with a higher symptomatic airway load as compared to patients without polyps. These findings suggest that nasal polyps could be an indicator of more substantial sinonasal disease. The presence of biofilm did not impact the degree of symptoms, however, as biofilm seem to be a common feature of chronic rhinosinusitis (89% in this cohort), it is more likely to be involved in the development of the CRS, rather than being a surrogate marker for increased symptomatic load.
Herein, we describe an organocatalytic living polymerization approach to network and subsequent hydrogel formation. Cyclic carbonate-functionalized macromolecules were ring-opened using an alcoholic ...initiator in the presence of an organic catalyst, amidine 1,8-diazabicyclo5.4.0undec-7-ene. A model reaction for the cross-linking identified monomer concentration-dependent reaction regimes, and enhanced kinetic control was demonstrated by introducing a comonomer, trimethylene carbonate. The addition of the comonomer facilitated near-quantitative conversion of monomer to polymer (>96%). Resulting poly(ethylene glycol) networks swell significantly in water, and an open co-continuous (water-gel) porous structure was observed by scanning electron microscopy. The organocatalytic ring-opening polymerization of cyclic carbonate functional macromonomers using alcoholic initiators provides a simple, efficient, and versatile approach to hydrogel networks.
PDF
