Linkholmes2850

Spermiogenesis in nematodes is a process whereby round and quiescent spermatids differentiate into asymmetric and crawling spermatozoa. The molecular mechanism underlying this symmetry breaking remains uncharacterized. In this study, we revealed that sperm-specific Na+/K+-ATPase (NKA) is evenly distributed on the plasma membrane (PM) of Caenorhabditis elegans spermatids but is translocated to and subsequently enters the invaginated membrane of the spermatozoa cell body during sperm activation. The polarization of NKA depends on the transport of cholesterol from the PM to membranous organelles (MOs) via membrane contact sites (MCSs). The inositol 5-phosphatase CIL-1 and the MO-localized PI4P phosphatase SAC-1 may mediate PI4P metabolism to drive cholesterol countertransport via sterol/lipid transport proteins through MCSs. Furthermore, the NKA function is required for C. elegans sperm motility and reproductive success. Our data imply that the lipid dynamics mediated by MCSs might play crucial roles in the establishment of cell polarity. eGraphical abstract.

Intravenous benzylpenicillin is the gold-standard treatment for neurosyphilis, but it requires prolonged hospitalisation. Ceftriaxone is a possible alternative treatment, the effectiveness of which remains unclear. We aimed to assess the effectiveness of ceftriaxone compared with benzylpenicillin in the treatment of neurosyphilis.

We did a retrospective multicentre study including patients with neurosyphilis who were treated at one of eight tertiary care centres in France, from Jan 1, 1997, to Dec 31, 2017. We defined neurosyphilis as positive treponemal and non-treponemal tests and at least one of otic syphilis, ocular syphilis, either neurological symptom with a positive result on cerebrospinal fluid (CSF)-VDRL or CSF-PCR tests, or more than five leukocytes in a CSF cell count. Patients with neurosyphilis were identified from the medical information department database of each centre and assigned to one of two groups on the basis of the initial treatment received (ie, benzylpenicillin group or ceftriaxon group had a complete response (crude OR 2·26 [95% CI 1·12-4·41], p=0·031), with no significant difference after propensity score weighting (OR 1·08 [95% CI 0·94-1·24], p=0·269). Serological response at 6 months did not differ between the groups (21 [88%] of 24 in the ceftriaxone group vs 76 [82%] of 93 in the benzylpenicillin group; crude OR 1·56 [95% CI 0·42-5·86], p=0·50), whereas hospital stay was shorter for patients in the ceftriaxone group than for those in the benzylpenicillin group (mean 13·8 days [95% CI 12·8-14·8] vs 8·9 days [5·7-12·0], p<0·0001). this website No major adverse effects were reported in either group.

Our results suggest that ceftriaxone is similarly effective to benzylpenicillin for the treatment of neurosyphilis, potentially decreasing the length of hospital stay. Randomised, controlled trials should be done to confirm these results.

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None.Gene fragments derived from structural domains mediating physical interactions can modulate biological functions. Utilizing this, we developed lentiviral overexpression libraries of peptides comprehensively tiling high-confidence cancer driver genes. Toward inhibiting cancer growth, we assayed ~66,000 peptides, tiling 65 cancer drivers and 579 mutant alleles. Pooled fitness screens in two breast cancer cell lines revealed peptides, which selectively reduced cellular proliferation, implicating oncogenic protein domains important for cell fitness. Coupling of cell-penetrating motifs to these peptides enabled drug-like function, with peptides derived from EGFR and RAF1 inhibiting cell growth at IC50s of 27-63 μM. We anticipate that this peptide-tiling (PepTile) approach will enable rapid de novo mapping of bioactive protein domains and associated interfering peptides.Genetic diversity leads to protein robustness, adaptability, and failure. Some sequence variants are structurally robust but functionally disturbed because mutations bring the protein onto unfolding/refolding routes resulting in misfolding diseases (e.g., Parkinson). We assume dynamic perturbations introduced by mutations foster the alternative unfolding routes and test this possibility by comparing the unfolding dynamics of the heat-labile enterotoxin B pentamers and the cholera toxin B pentamers, two pentamers structurally and functionally related and robust to 17 sequence variations. The B-subunit thermal unfolding dynamics are monitored by broadband dielectric spectroscopy in nanoconfined and weakly hydrated conditions. Distinct dielectric signals reveal the different B-subunits unfolding dynamics. Combined with network analyses, the experiments pinpoint the role of three mutations A1T, E7D, and E102A, in diverting LTB5 to alternative unfolding routes that protect LTB5 from dissociation. Altogether, the methodology diagnoses dynamics faults that may underlie functional disorder, drug resistance, or higher virulence of sequence variants.Structural variations (SVs) and gene copy number variations (gCNVs) have contributed to crop evolution, domestication, and improvement. link2 Here, we assembled 31 high-quality genomes of genetically diverse rice accessions. Coupling with two existing assemblies, we developed pan-genome-scale genomic resources including a graph-based genome, providing access to rice genomic variations. Specifically, we discovered 171,072 SVs and 25,549 gCNVs and used an Oryza glaberrima assembly to infer the derived states of SVs in the Oryza sativa population. Our analyses of SV formation mechanisms, impacts on gene expression, and distributions among subpopulations illustrate the utility of these resources for understanding how SVs and gCNVs shaped rice environmental adaptation and domestication. Our graph-based genome enabled genome-wide association study (GWAS)-based identification of phenotype-associated genetic variations undetectable when using only SNPs and a single reference assembly. Our work provides rich population-scale resources paired with easy-to-access tools to facilitate rice breeding as well as plant functional genomics and evolutionary biology research.

To assess the feasibility of tongue conservation treatment with induction chemotherapy (ICT), tongue conservation surgery, and risk-adapted postoperative adjuvant therapy in oral tongue squamous cell carcinoma (OTSCC).

Patients with newly diagnosed OTSCC cT2-4N0-2 M0 were recruited. The ICT with a regimen of docetaxel, cisplatin, and oral tegafur/uracil (DCU) was administrated every 21 days. After the first cycle of ICT (DCU1), patients with a more than 30% decrease in the longest diameter of primary tumor underwent a second cycle of ICT (DCU2). Tongue conservation surgery was performed after ICT, and risk-adapted adjuvant therapy was organized based on pathological features.

From July 2011 to December 2015, a total of 23 patients were enrolled, 87% of whom were classified as stage III-IV. Clinical responders to DCU1 and DCU2 were determined in 90.5% (19/21) and 88.2% (15/17) of patients. Tongue conservation surgery was performed in 16 responders to ICT. Only one patient had a positive margin (6.3%), and a complete pathologic response was achieved in eight patients (50%). Only one patient developed local recurrence after a median follow-up of 58.6months (range, 7.9-105.2). The 5-year overall survival (0% vs. 87.5%, P=0.001) and disease-specific survival (0% vs. 93.3%, P=0.000) were significantly different between the DCU1 nonresponders and responders.

Tongue conservation treatment with ICT, followed by conservation surgery and risk-adapted adjuvant therapy, is feasible for patients with OTSCC who are good responders to ICT. However, the outcomes of nonresponders are dismal. Further study in a larger patient population is warranted.

Tongue conservation treatment with ICT, followed by conservation surgery and risk-adapted adjuvant therapy, is feasible for patients with OTSCC who are good responders to ICT. However, the outcomes of nonresponders are dismal. Further study in a larger patient population is warranted.

We sought to determine the safety and performance of intravascular lithotripsy in the treatment of severe calcified atherosclerotic lesions.

The modification of severe calcified atherosclerotic lesions with noncompliant or specialty balloons, as well as orbital or rotational atherectomy has limitations and may be ineffective, increasing the risk of periprocedural complications and worsening long-term results. Intravascular lithotripsy has recently been shown to be a safe and feasible alternative to the above methods.

All consecutive patients treated with Shockwave Medical Intravascular Lithotripsy (S-IVL) between May 2019 and June 2020 were included in current analysis. Device safety and efficacy were the critical endpoints of the study. The primary safety endpoint was 30-day major adverse cardiac events (MACE). In turn, device and clinical success were the primary performance endpoints.

In total, 46 patients undergoing percutaneous coronary intervention were treated with S-IVL before stent deployment (65% male; age, 71 ± 7 years). Device success was achieved in 45 (97.8%) patients with reduction of diameter stenosis from 80% to 5.2% with an acute gain of 2.5 mm. Clinical success was demonstrated in 95.6% of cases. link3 During the 30-day follow-up, one sudden death was recorded, regarded as probable subacute stent thrombosis. During 6-month follow up one target lesion and target vessel revascularizations occurred. The rate of MACE after 6month was 6.2%.

S-IVL appears to be a safe and effective treatment modality in coronary calcium modification to optimize stent expansion. In selected cases this device obviates the need for more complex lesion preparation strategies such as atherectomy.

S-IVL appears to be a safe and effective treatment modality in coronary calcium modification to optimize stent expansion. In selected cases this device obviates the need for more complex lesion preparation strategies such as atherectomy.

The French left atrial appendage (LAA) closure registry (FLAAC) aimed to assess the safety and efficacy of LAA closure in daily practice.

LAA closure has emerged as an alternative for preventing thromboembolic events (TE) in patients with non-valvular atrial fibrillation (NVAF). Clinical data in this field remains limited and few investigator-initiated, real-world registries have been reported.

This nationwide, prospective study was performed in 36 French centers. The primary endpoint was the TE rate after successful LAA closure.

The FLAAC registry included 816 patients with a mean age of 75.5 ± 0.3 years, mean follow-up of 16.0 ± 0.3months, high TE (CHA

DS

-VASc score 4.6 ± 0.1) and bleeding risks (HAS-BLED score 3.2 ± 0.05) and common contraindications to long-term anticoagulation (95.7%). Procedure or device-related serious adverse events occurred in 49 (6.0%) patients. The annual rate of ischemic stroke/systemic embolism was 3.3% (2.4-4.6). This suggests a relative 57% reduction compared to the risk of stroke in historical NVAF populations without antithrombotic therapy. By multivariate analysis, history of TE was the only factor associated with stroke/systemic embolism during follow-up (HR, 3.3 [1.58-6.89], p=0.001). The annual mortality rate was 10.2% (8.4-12.3). Most of the deaths were due to comorbidities or underlying cardiovascular diseases and unrelated to the device or to TE.

Our study suggests that LAA closure can be an option in patients with NVAF. Long-term follow-up mortality was high, mostly due to comorbidities and underlying cardiovascular diseases, highlighting the importance of multidisciplinary management after LAA closure.

NCT02252861.

NCT02252861.