Accumulation of tau is observed in dementia, with human tau displaying 6 isoforms grouped by whether they display either 3 or 4 C-terminal repeat domains (3R or 4R) and exhibit no (0N), one (1N) or ...two (2N) N terminal repeats. Overexpression of 4R0N-tau in rat hippocampal slices enhanced the L-type calcium (Ca
) current-dependent components of the medium and slow afterhyperpolarizations (AHPs). Overexpression of both 4R0N-tau and 4R2N-tau augmented Ca
1.2-mediated L-type currents when expressed in tsA-201 cells, an effect not observed with the third 4R isoform, 4R1N-tau. Current enhancement was only observed when the pore-forming subunit was co-expressed with Ca
β3 and not Ca
β2a subunits. Non-stationary noise analysis indicated that enhanced Ca
channel current arose from a larger number of functional channels. 4R0N-tau and Ca
β3 were found to be physically associated by co-immunoprecipitation. In contrast, the 4R1N-tau isoform that did not augment expressed macroscopic L-type Ca
current exhibited greatly reduced binding to Ca
β3. These data suggest that physical association between tau and the Ca
β3 subunit stabilises functional L-type channels in the membrane, increasing channel number and Ca
influx. Enhancing the Ca
-dependent component of AHPs would produce cognitive impairment that underlie those seen in the early phases of tauopathies.
Antibodies play major roles in immunity to malaria; however, a limited understanding of mechanisms mediating protection is a major barrier to vaccine development. We have demonstrated that acquired ...human anti-malarial antibodies promote complement deposition on the merozoite to mediate inhibition of erythrocyte invasion through C1q fixation and activation of the classical complement pathway. Antibody-mediated complement-dependent (Ab-C′) inhibition was the predominant invasion-inhibitory activity of human antibodies; most antibodies were non-inhibitory without complement. Inhibitory activity was mediated predominately via C1q fixation, and merozoite surface proteins 1 and 2 were identified as major targets. Complement fixation by antibodies was very strongly associated with protection from both clinical malaria and high-density parasitemia in a prospective longitudinal study of children. Ab-C′ inhibitory activity could be induced by human immunization with a candidate merozoite surface-protein vaccine. Our findings demonstrate that human anti-malarial antibodies have evolved to function by fixing complement for potent invasion-inhibitory activity and protective immunity.
Display omitted
•Antibodies function with complement to inhibit P. falciparum replication•Antibodies fix C1q to block invasion and lyse merozoites•Complement-fixing antibodies are strongly associated with immunity in children•Antibody-complement inhibition can be induced by human vaccination
Antibodies are important in immunity to malaria, but their protective function has been unclear. Boyle and colleagues report that acquired and vaccine-induced human antibodies recruit complement to block infection of erythrocytes and blood-stage replication of Plasmodium falciparum.
Controversy exists regarding the best option for revision surgery in refractory cubital tunnel syndrome (CuTS). The purpose of this systematic review was to evaluate the effectiveness of revision ...surgery and determine the optimal surgical approach for patients requiring revision surgery for CuTS.
A literature search was conducted. Characteristics of the included studies were summarized descriptively. The risk ratio between patient-reported preoperative and postoperative outcomes relating to pain, motor, and sensory deficits was calculated. A meta-regression analysis was performed to evaluate the postoperative symptom improvements based on the type of secondary surgery. Random-effects meta-analysis and descriptive statistics were used when appropriate.
A total of 471 patients were evaluated in 20 studies. In total, 254 (53.9%) male and 217 (46.1%) female patients, with an average age of 49.2 ± 14.1 years, were included in this study. Pain was the most common symptom (n = 346, 81.6%), followed by sensory and motor dysfunction in 342 (80.6%) and 223 (52.6%) patients, respectively. Meta-analysis comparing preoperative and postoperative symptoms between patients who had submuscular transposition (SMT), subcutaneous transposition (SCT), and neurolysis showed that a significant subgroup difference exists between the types of revision surgery in sensory and motor improvements. Meta-regression showed that SMT was associated with better outcomes compared with SCT in motor and sensory improvements.
Revision surgery for CuTS can be useful for addressing recurrent and persistent symptoms. Compared with neurolysis and SCT, SMT seems to be the superior option for revision surgery, demonstrating substantial improvement in all symptom domains.
Therapeutic IV.
The heterogeneous composition of solid tumors is known to impact disease progression and response to therapy. Malignant cells coexist in different regulatory states that can be accessed ...transcriptomically by single-cell RNA sequencing, but these methods have many caveats related to sensitivity, noise, and sample handling. We revised a statistical fluctuation analysis called stochastic profiling to combine with 10-cell RNA sequencing, which was designed for laser-capture microdissection (LCM) and extended here for immuno-LCM. When applied to a cohort of late-onset, early-stage luminal breast cancers, the integrated approach identified thousands of candidate regulatory heterogeneities. Intersecting the candidates from different tumors yielded a relatively stable set of 710 recurrent heterogeneously expressed genes (RHEG), which were significantly variable in >50% of patients. RHEGs were not strongly confounded by dissociation artifacts, cell-cycle oscillations, or driving mutations for breast cancer. Rather, RHEGs were enriched for epithelial-to-mesenchymal transition genes and, unexpectedly, the latest pan-cancer assembly of driver genes across cancer types other than breast. These findings indicate that heterogeneous transcriptional regulation conceivably provides a faster, reversible mechanism for malignant cells to evaluate the effects of potential oncogenes or tumor suppressors on cancer hallmarks. SIGNIFICANCE: Profiling intratumor heterogeneity of luminal breast carcinoma cells identifies a recurrent set of genes, suggesting sporadic activation of pathways known to drive other types of cancer.
.
Abstract
The expansion of salmonid aquaculture has resulted in environmental challenges, including salmon lice that may infest both farmed and wild fish. For wild Atlantic salmon post-smolts that ...migrate from their rivers to the ocean, the first phase of their journey in the coastal zone, where aquaculture occurs, is critical when considering lice exposure. To evaluate the lice influence during the post-smot migration we have developed a migration model. An archive with spatiotemporal concentrations of lice larvae in Norwegian coastal waters has been established using a combination of state-of-the-art hydrodynamic and lice biology models. To estimate lice-induced mortality of wild salmon from Norwegian rivers, the infestation level on the virtual post-smolts was calibrated to match that observed on wild post-smolts genetically assigned their rivers of origin. The lice infestation pressure was modelled on post-smolts from 401 rivers covering all of Norway. Based on this, aquaculture-produced salmon lice-induced mortality of wild salmon post-smolts was estimated as <10% for 179 rivers, 10–30% for 140 rivers, and >30% for 82 rivers in 2019. Estimated mortalities were used together with other data sets to evaluate aquaculture sustainability in Norway. The aquaculture regulatory system represents a globally leading example of science-based management that considers the environmental impact.
In silico toxicology (IST) approaches to rapidly assess chemical hazard, and usage of such methods is increasing in all applications but especially for regulatory submissions, such as for assessing ...chemicals under REACH as well as the ICH M7 guideline for drug impurities. There are a number of obstacles to performing an IST assessment, including uncertainty in how such an assessment and associated expert review should be performed or what is fit for purpose, as well as a lack of confidence that the results will be accepted by colleagues, collaborators and regulatory authorities. To address this, a project to develop a series of IST protocols for different hazard endpoints has been initiated and this paper describes the genetic toxicity in silico (GIST) protocol. The protocol outlines a hazard assessment framework including key effects/mechanisms and their relationships to endpoints such as gene mutation and clastogenicity. IST models and data are reviewed that support the assessment of these effects/mechanisms along with defined approaches for combining the information and evaluating the confidence in the assessment. This protocol has been developed through a consortium of toxicologists, computational scientists, and regulatory scientists across several industries to support the implementation and acceptance of in silico approaches.
The ICH M7 guideline describes a consistent approach to identify, categorize, and control DNA reactive, mutagenic, impurities in pharmaceutical products to limit the potential carcinogenic risk ...related to such impurities. This paper outlines a series of principles and procedures to consider when generating (Q)SAR assessments aligned with the ICH M7 guideline to be included in a regulatory submission. In the absence of adequate experimental data, the results from two complementary (Q)SAR methodologies may be combined to support an initial hazard classification. This may be followed by an assessment of additional information that serves as the basis for an expert review to support or refute the predictions. This paper elucidates scenarios where additional expert knowledge may be beneficial, what such an expert review may contain, and how the results and accompanying considerations may be documented. Furthermore, the use of these principles and procedures to yield a consistent and robust (Q)SAR-based argument to support impurity qualification for regulatory purposes is described in this manuscript.
•Summary of sources of existing bacterial mutagenicity and carcinogenicity data.•Description of how to combine (Q)SAR results.•Discussion of when an expert review might be useful.•Outline of expert review considerations.•Discussion of the scope and format for the (Q)SAR documentation.
Anadromous salmon and sea trout smolts face challenging migrations from freshwater to the marine environment characterised by high mortality. Therefore, the timing of smolt migration is likely to be ...critical for survival. Time-series comparing migration of Atlantic salmon and sea trout smolts in the same river, and their response to the same environmental cues, are scarce. Here, we analysed migration timing of ~41 000 Atlantic salmon and sea trout smolts over a 19-year period from the river Guddalselva, western Norway. Trout displayed a longer migration window in earlier years, which decreased over time to become more similar to the salmon migration window. On average, salmon migrated out of the river earlier than trout. Migration of both species was significantly influenced by river water temperature and water discharge, but their relative influence varied across the years. On average, body-length of smolts of both species overlapped, however, size differences were observed within the migration period and among the years. We conclude that salmon and trout smolts in this river are highly synchronised and migrate in response to the same range of linked environmental cues.
Thoracic outlet syndrome: a review Panther, Eric J.; Reintgen, Christian D.; Cueto, Robert J. ...
Journal of shoulder and elbow surgery,
November 2022, 2022-11-00, 20221101, Letnik:
31, Številka:
11
Journal Article
Recenzirano
Thoracic outlet syndrome (TOS) is a rare condition (1-3 per 100,000) caused by neurovascular compression at the thoracic outlet and presents with arm pain and swelling, arm fatigue, paresthesias, ...weakness, and discoloration of the hand. TOS can be classified as neurogenic, arterial, or venous based on the compressed structure(s). Patients develop TOS secondary to congenital abnormalities such as cervical ribs or fibrous bands originating from a cervical rib leading to an objectively verifiable form of TOS. However, the diagnosis of TOS is often made in the presence of symptoms with physical examination findings (disputed TOS). TOS is not a diagnosis of exclusion, and there should be evidence for a physical anomaly that can be corrected. In patients with an identifiable narrowing of the thoracic outlet and/or symptoms with a high probability of thoracic outlet neurovascular compression, diagnosis of TOS can be established through history, a physical examination maneuvers, and imaging. Neck trauma or repeated work stress can cause scalene muscle scaring or dislodging of a congenital cervical rib that can compress the brachial plexus. Nonsurgical treatment includes anti-inflammatory medication, weight loss, physical therapy/strengthening exercises, and botulinum toxin injections. The most common surgical treatments include brachial plexus decompression, neurolysis, and scalenotomy with or without first rib resection. Patients undergoing surgical treatment for TOS should be seen postoperatively to begin passive/assisted mobilization of the shoulder. By 8 weeks postoperatively, patients can begin resistance strength training. Surgical treatment complications include injury to the subclavian vessels potentially leading to exsanguination and death, brachial plexus injury, hemothorax, and pneumothorax. In this review, we outline the diagnostic tests and treatment options for TOS to better guide clinicians in recognizing and treating vascular TOS and objectively verifiable forms of neurogenic TOS.
Breast cancer is a collection of diseases in which molecular phenotypes can act as both indicators and mediators of therapeutic strategy. Therefore, candidate therapeutics must be assessed in the ...context of multiple cell lines with known molecular phenotypes. Docosahexaenoic acid (DHA) and curcumin (CCM) are dietary compounds known to antagonize breast cancer cell proliferation. We report that these compounds in combination exert a variable antiproliferative effect across multiple breast cell lines, which is synergistic in SK-BR-3 cells and triggers cell signaling events not predicted by the activity of either compound alone.
Dose response curves for CCM and DHA were generated for five breast cell lines. Effects of the DHA+ CCM combination on cell proliferation were evaluated using varying concentrations, at a fixed ratio, of CCM and DHA based on their individual ED₅₀. Detection of synergy was performed using nonlinear regression of a sigmoid dose response model and Combination Index approaches. Cell molecular network responses were investigated through whole genome microarray analysis of transcript level changes. Gene expression results were validated by RT-PCR, and western blot analysis was performed for potential signaling mediators. Cellular curcumin uptake, with and without DHA, was analyzed via flow cytometry and HPLC.
CCM+DHA had an antiproliferative effect in SK-BR-3, MDA-MB-231, MDA-MB-361, MCF7 and MCF10AT cells. The effect was synergistic for SK-BR-3 (ER⁻ PR⁻ Her2⁺) relative to the two compounds individually. A whole genome microarray approach was used to investigate changes in gene expression for the synergistic effects of CCM+DHA in SK-BR-3 cells lines. CCM+DHA triggered transcript-level responses, in disease-relevant functional categories, that were largely non-overlapping with changes caused by CCM or DHA individually. Genes involved in cell cycle arrest, apoptosis, inhibition of metastasis, and cell adhesion were upregulated, whereas genes involved in cancer development and progression, metastasis, and cell cycle progression were downregulated. Cellular pools of PPARγ and phospho-p53 were increased by CCM+DHA relative to either compound alone. DHA enhanced cellular uptake of CCM in SK-BR-3 cells without significantly enhancing CCM uptake in other cell lines.
The combination of DHA and CCM is potentially a dietary supplemental treatment for some breast cancers, likely dependent upon molecular phenotype. DHA enhancement of cellular curcumin uptake is one potential mechanism for observed synergy in SK-BR-3 cells; however, transcriptomic data show that the antiproliferation synergy accompanies many signaling events unique to the combined presence of the two compounds.
PDF
