While prokaryotic pan-genomes have been shown to contain many more genes than any individual organism, the prevalence and functional significance of differentially present genes in eukaryotes remains ...poorly understood. Whole-genome de novo assembly and annotation of 54 lines of the grass Brachypodium distachyon yield a pan-genome containing nearly twice the number of genes found in any individual genome. Genes present in all lines are enriched for essential biological functions, while genes present in only some lines are enriched for conditionally beneficial functions (e.g., defense and development), display faster evolutionary rates, lie closer to transposable elements and are less likely to be syntenic with orthologous genes in other grasses. Our data suggest that differentially present genes contribute substantially to phenotypic variation within a eukaryote species, these genes have a major influence in population genetics, and transposable elements play a key role in pan-genome evolution.
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an increasingly recognized cause of end-stage kidney disease, primarily due to mutations in UMOD and MUC1. The lack of clinical ...recognition and the small size of cohorts have slowed the understanding of disease ontology and development of diagnostic algorithms. We analyzed two registries from Europe and the United States to define genetic and clinical characteristics of ADTKD-UMOD and ADTKD-MUC1 and develop a practical score to guide genetic testing. Our study encompassed 726 patients from 585 families with a presumptive diagnosis of ADTKD along with clinical, biochemical, genetic and radiologic data. Collectively, 106 different UMOD mutations were detected in 216/562 (38.4%) of families with ADTKD (303 patients), and 4 different MUC1 mutations in 72/205 (35.1%) of the families that are UMOD-negative (83 patients). The median kidney survival was significantly shorter in patients with ADTKD-MUC1 compared to ADTKD-UMOD (46 vs. 54 years, respectively), whereas the median gout-free survival was dramatically reduced in patients with ADTKD-UMOD compared to ADTKD-MUC1 (30 vs. 67 years, respectively). In contrast to patients with ADTKD-UMOD, patients with ADTKD-MUC1 had normal urinary excretion of uromodulin and distribution of uromodulin in tubular cells. A diagnostic algorithm based on a simple score coupled with urinary uromodulin measurements separated patients with ADTKD-UMOD from those with ADTKD-MUC1 with a sensitivity of 94.1%, a specificity of 74.3% and a positive predictive value of 84.2% for a UMOD mutation. Thus, ADTKD-UMOD is more frequently diagnosed than ADTKD-MUC1, ADTKD subtypes present with distinct clinical features, and a simple score coupled with urine uromodulin measurements may help prioritizing genetic testing.
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Deep RNA sequencing was used to simultaneously analyze vaccinia virus (VACV) and HeLa cell transcriptomes at progressive times following infection. VACV, the prototypic member of the poxvirus family, ...replicates in the cytoplasm and contains a double-stranded DNA genome with ≈200 closely spaced open reading frames (ORFs). The acquisition of a total of nearly 500 million short cDNA sequences allowed construction of temporal strand-specific maps of the entire VACV transcriptome at single-base resolution and analysis of over 14,000 host mRNAs. Before viral DNA replication, transcripts from 118 VACV ORFs were detected; after replication, transcripts from 93 additional ORFs were characterized. The high resolution permitted determination of the precise boundaries of many mRNAs including read-through transcripts and location of mRNA start sites and adjacent promoters. Temporal analysis revealed two clusters of early mRNAs that were synthesized in the presence of inhibitors of protein as well as DNA synthesis, indicating that they do not correspond to separate immediate- and delayed-early classes as defined for other DNA viruses. The proportion of viral RNAs reached 25—55% of the total at 4 h. This rapid change, resulting in a relative decrease of the vast majority of host mRNAs, can contribute to the profound shutdown of host protein synthesis and blunting of antiviral responses. At 2 h, however, a minority of cellular mRNAs was increased. The overrepresented functional categories of the up-regulated RNAs were NF-κB cascade, apoptosis, signal transduction, and ligand-mediated signaling, which likely represent the host response to invasion.
Regulatory T cells (Tregs) are a barrier to anti-tumor immunity. Neuropilin-1 (Nrp1) is required to maintain intratumoral Treg stability and function but is dispensable for peripheral immune ...tolerance. Treg-restricted Nrp1 deletion results in profound tumor resistance due to Treg functional fragility. Thus, identifying the basis for Nrp1 dependency and the key drivers of Treg fragility could help to improve immunotherapy for human cancer. We show that a high percentage of intratumoral NRP1+ Tregs correlates with poor prognosis in melanoma and head and neck squamous cell carcinoma. Using a mouse model of melanoma where Nrp1-deficient (Nrp1–/–) and wild-type (Nrp1+/+) Tregs can be assessed in a competitive environment, we find that a high proportion of intratumoral Nrp1–/– Tregs produce interferon-γ (IFNγ), which drives the fragility of surrounding wild-type Tregs, boosts anti-tumor immunity, and facilitates tumor clearance. We also show that IFNγ-induced Treg fragility is required for response to anti-PD1, suggesting that cancer therapies promoting Treg fragility may be efficacious.
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•Increased percentage of human NRP1+ intratumoral Tregs correlates with poor prognosis•Nrp1-deficient Tregs undermine the function of wild-type Tregs via IFNγ•Hypoxia may drive IFNγ-induced Treg fragility via Hif1α in the tumor microenvironment•IFNγ-mediated Treg functional fragility is required for response to PD1 blockade
Driving Treg fragility in the tumor microenvironment is critical for the efficacy of cancer checkpoint blockade therapy.
Regulatory T cells (T
) are a barrier to anti-tumor immunity. Neuropilin-1 (Nrp1) is required to maintain intratumoral T
stability and function but is dispensable for peripheral immune tolerance. T
...-restricted Nrp1 deletion results in profound tumor resistance due to T
functional fragility. Thus, identifying the basis for Nrp1 dependency and the key drivers of T
fragility could help to improve immunotherapy for human cancer. We show that a high percentage of intratumoral NRP1
T
correlates with poor prognosis in melanoma and head and neck squamous cell carcinoma. Using a mouse model of melanoma where Nrp1-deficient (Nrp1
) and wild-type (Nrp1
) T
can be assessed in a competitive environment, we find that a high proportion of intratumoral Nrp1
T
produce interferon-γ (IFNγ), which drives the fragility of surrounding wild-type T
, boosts anti-tumor immunity, and facilitates tumor clearance. We also show that IFNγ-induced T
fragility is required for response to anti-PD1, suggesting that cancer therapies promoting T
fragility may be efficacious.
3MC syndrome has been proposed as a unifying term encompassing the overlapping Carnevale, Mingarelli, Malpuech and Michels syndromes. These rare autosomal recessive disorders exhibit a spectrum of ...developmental features, including characteristic facial dysmorphism, cleft lip and/or palate, craniosynostosis, learning disability and genital, limb and vesicorenal anomalies. Here we studied 11 families with 3MC syndrome and identified two mutated genes, COLEC11 and MASP1, both of which encode proteins in the lectin complement pathway (collectin kidney 1 (CL-K1) and MASP-1 and MASP-3, respectively). CL-K1 is highly expressed in embryonic murine craniofacial cartilage, heart, bronchi, kidney and vertebral bodies. Zebrafish morphants for either gene develop pigmentary defects and severe craniofacial abnormalities. Finally, we show that CL-K1 serves as a guidance cue for neural crest cell migration. Together, these findings demonstrate a role for complement pathway factors in fundamental developmental processes and in the etiology of 3MC syndrome.
We present emission-line ratios from a sample of 27 Lyman-break galaxies from
z
∼ 5.5 − 9.5 with −17.0 <
M
1500
< −20.4, measured from ultra-deep JWST/NIRSpec multi-object spectroscopy from the ...JWST Advanced Deep Extragalactic Survey (JADES). We used a combination of 28 h deep PRISM/CLEAR and 7 h deep
G
395
M
/
F
290
LP
observations to measure, or place strong constraints on, ratios of widely studied rest-frame optical emission lines including H
α
, H
β
, O
II
λλ
3726, 3729, Ne
III
λ
3869, O
III
λ
4959, O
III
λ
5007, O
I
λ
6300, N
II
λ
6583, and S
II
λλ
6716, 6731 in individual
z
> 5.5 spectra. We find that the emission-line ratios exhibited by these
z
∼ 5.5 − 9.5 galaxies occupy clearly distinct regions of line-ratio space compared to typical
z
∼ 0 − 3 galaxies, instead being more consistent with extreme populations of lower-redshift galaxies. This is best illustrated by the O
III
/O
II
ratio, tracing interstellar medium (ISM) ionisation, in which we observe more than half of our sample to have O
III
/O
II
> 10. Our high signal-to-noise spectra reveal more than an order of magnitude of scatter in line ratios such as O
II
/H
β
and O
III
/O
II
, indicating significant diversity in the ISM conditions within the sample. We find no convincing detections of N
II
λ
6583 in our sample, either in individual galaxies, or a stack of all
G
395
M
/
F
290
LP
spectra. The emission-line ratios observed in our sample are generally consistent with galaxies with extremely high ionisation parameters (log
U
∼ −1.5), and a range of metallicities spanning from ∼0.1 ×
Z
⊙
to higher than ∼0.3 ×
Z
⊙
, suggesting we are probing low-metallicity systems undergoing periods of rapid star formation, driving strong radiation fields. These results highlight the value of deep observations in constraining the properties of individual galaxies, and hence probing diversity within galaxy population.
It has been more than 20 years since the malaria epidemiologic shift to school-aged children was noted. In the meantime, school-aged children (5-15 years) have become increasingly more vulnerable ...with asymptomatic malaria prevalence reaching up to 70%, making them reservoirs for subsequent transmission of malaria in the endemic communities. Intermittent Preventive Treatment of malaria in schoolchildren (IPTsc) has proven to be an effective tool to shrink this reservoir. As of 3
June 2022, the World Health Organization recommends IPTsc in moderate and high endemic areas. Even so, for decision-makers, the adoption of scientific research recommendations has been stifled by real-world implementation challenges. This study presents methodology, challenges faced, and mitigations used in the evaluation of the implementation of IPTsc using dihydroartemisinin-piperaquine (DP) in three councils (Handeni District Council (DC), Handeni Town Council (TC) and Kilindi DC) of Tanga Region, Tanzania so as to understand the operational feasibility and effectiveness of IPTsc on malaria parasitaemia and clinical malaria incidence.
The study deployed an effectiveness-implementation hybrid design to assess feasibility and effectiveness of IPTsc using DP, the interventional drug, against standard of care (control). Wards in the three study councils were the randomization unit (clusters). Each ward was randomized to implement IPTsc or not (control). In all wards in the IPTsc arm, DP was given to schoolchildren three times a year in four-month intervals. In each council, 24 randomly selected wards (12 per study arm, one school per ward) were chosen as representatives for intervention impact evaluation. Mixed design methods were used to assess the feasibility and acceptability of implementing IPTsc as part of a more comprehensive health package for schoolchildren. The study reimagined an existing school health programme for Neglected Tropical Diseases (NTD) control include IPTsc implementation.
The study shows IPTsc can feasibly be implemented by integrating it into existing school health and education systems, paving the way for sustainable programme adoption in a cost-effective manner.
Through this article other interested countries may realise a feasible plan for IPTsc implementation. Mitigation to any challenge can be customized based on local circumstances without jeopardising the gains expected from an IPTsc programme. Trial registration clinicaltrials.gov, NCT04245033. Registered 28 January 2020, https://clinicaltrials.gov/ct2/show/NCT04245033.
The historical contingencies of biological invasions may have important consequences for final invasion outcomes. Here, we characterize the variations in the realized niche during the invasions of ...the bull-headed dung beetle
Onthophagus taurus
(Coleoptera: Scarabaeidae
)
from its native Mediterranean range following accidental (Eastern North America) as well as deliberate (Western North America, Western Australia, and Eastern Australia) releases into novel, exotic ranges approximately 50 years ago. Specifically, we examined whether the climatic responses of exotic
O. taurus
have diverged from those characterizing their native range, and if so, to what degree and in what dimensions. We found that when compared to the native range, all exotic populations exhibited similar overlap proportions regardless of invasion history. However, more detailed analysis of climatic niche features showed that all three deliberately established populations were characterized by overall similar climatic niche features, whereas the accidentally-established Eastern North American populations have undergone significant changes in their climatic niche. Specifically, when analog climates were considered on the background of each pairwise range comparison, accidentally-established Eastern North American populations showed a different climatic niche expansion than their deliberately introduced Australian or Western North American counterparts, in particular towards colder and more humid climates. We discuss our results in the context of the widely divergent introduction histories of
O. taurus
in Australia and North America, and highlight the possible roles of contrasting propagule sizes, disparate genetic profiles and variances, adaptive processes and invadable landscapes in shaping invasion outcomes in the different exotic ranges.
Cancer is the second most common cause of death in the USA. Among the known classes of anticancer agents, the microtubule-targeted antimitotic drugs are considered to be one of the most important. ...They are usually classified into microtubule-destabilizing (e.g., Vinca alkaloids) and microtubule-stabilizing (e.g., paclitaxel) agents. Combretastatin A4 (CA-4), which is a natural stilbene isolated from Combretum caffrum, is a microtubule-destabilizing agent that binds to the colchicine domain on β-tubulin and exhibits a lower toxicity profile than paclitaxel or the Vinca alkaloids. In this paper, we describe the docking study, synthesis, antiproliferative activity and selectivity index of the N-acylhydrazone derivatives (5a-r) designed as CA-4 analogues. The essential structural requirements for molecular recognition by the colchicine binding site of β-tubulin were recognized, and several compounds with moderate to high antiproliferative potency (IC50 values ≤18 µM and ≥4 nM) were identified. Among these active compounds, LASSBio-1586 (5b) emerged as a simple antitumor drug candidate, which is capable of inhibiting microtubule polymerization and possesses a broad in vitro and in vivo antiproliferative profile, as well as a better selectivity index than the prototype CA-4, indicating improved selective cytotoxicity toward cancer cells.
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