Structural insights into respiratory complex I deficiency and assembly from the mitochondrial disease-related ndufs4-/- mouse.

Respiratory complex I (NADH:ubiquinone oxidoreductase) is essential for cellular energy production and NAD+ homeostasis. Complex I mutations cause neuromuscular, mitochondrial diseases, such as Leigh Syndrome, but their molecular-level consequences remain poorly understood. Here, we use a popular complex I-linked mitochondrial disease model, the ndufs4-/- mouse, to define the structural, biochemical, and functional consequences of the absence of subunit NDUFS4. Cryo-EM analyses of the complex I from ndufs4-/- mouse hearts revealed a loose association of the NADH-dehydrogenase module, and discrete classes containing either assembly factor NDUFAF2 or subunit NDUFS6. Subunit NDUFA12, which replaces its paralogue NDUFAF2 in mature complex I, is absent from all classes, compounding the deletion of NDUFS4 and preventing maturation of an NDUFS4-free enzyme. We propose that NDUFAF2 recruits the NADH-dehydrogenase module during assembly of the complex. Taken together, the findings provide new molecular-level understanding of the ndufs4-/- mouse model and complex I-linked mitochondrial disease.

Attosecond angular streaking and tunnelling time in atomic hydrogen.

The tunnelling of a particle through a potential barrier is a key feature of quantum mechanics that goes to the core of wave-particle duality. The phenomenon has no counterpart in classical physics, and there are no well constructed dynamical observables that could be used to determine 'tunnelling times'. The resulting debate1-5 about whether a tunnelling quantum particle spends a finite and measurable time under a potential barrier was reignited in recent years by the advent of ultrafast lasers and attosecond metrology6. Particularly important is the attosecond angular streaking ('attoclock') technique7, which can time the release of electrons in strong-field ionization with a precision of a few attoseconds. Initial measurements7-10 confirmed the prevailing view that tunnelling is instantaneous, but later studies11,12 involving multi-electron atoms-which cannot be accurately modelled, complicating interpretation of the ionization dynamics-claimed evidence for finite tunnelling times. By contrast, the simplicity of the hydrogen atom enables precise experimental measurements and calculations13-15 and makes it a convenient benchmark. Here we report attoclock and momentum-space imaging16 experiments on atomic hydrogen and compare these results with accurate simulations based on the three-dimensional time-dependent Schrödinger equation and our experimental laser pulse parameters. We find excellent agreement between measured and simulated data, confirming the conclusions of an earlier theoretical study17 of the attoclock technique in atomic hydrogen that presented a compelling argument for instantaneous tunnelling. In addition, we identify the Coulomb potential as the sole cause of the measured angle between the directions of electron emission and peak electric field: this angle had been attributed11,12 to finite tunnelling times. We put an upper limit of 1.8 attoseconds on any tunnelling delay, in agreement with recent theoretical findings18 and ruling out the interpretation of all commonly used 'tunnelling times'19 as 'time spent by an electron under the potential barrier'20.

Author Correction: Attosecond angular streaking and tunnelling time in atomic hydrogen.

In this Letter, the statement 'I.I. and A.B. performed computations at the NCI Australia' was missing from the Acknowledgements section. This has been corrected online.

Septins mediate a microtubule-actin crosstalk that enables actin growth on microtubules.

Cellular morphogenesis and processes such as cell division and migration require the coordination of the microtubule and actin cytoskeletons. Microtubule-actin crosstalk is poorly understood and largely regarded as the capture and regulation of microtubules by actin. Septins are filamentous guanosine-5'-triphosphate (GTP) binding proteins, which comprise the fourth component of the cytoskeleton along microtubules, actin, and intermediate filaments. Here, we report that septins mediate microtubule-actin crosstalk by coupling actin polymerization to microtubule lattices. Superresolution and platinum replica electron microscopy (PREM) show that septins localize to overlapping microtubules and actin filaments in the growth cones of neurons and non-neuronal cells. We demonstrate that recombinant septin complexes directly crosslink microtubules and actin filaments into hybrid bundles. In vitro reconstitution assays reveal that microtubule-bound septins capture and align stable actin filaments with microtubules. Strikingly, septins enable the capture and polymerization of growing actin filaments on microtubule lattices. In neuronal growth cones, septins are required for the maintenance of the peripheral actin network that fans out from microtubules. These findings show that septins directly mediate microtubule interactions with actin filaments, and reveal a mechanism of microtubule-templated actin growth with broader significance for the self-organization of the cytoskeleton and cellular morphogenesis.

Microtubule-associated septin complexes modulate kinesin and dynein motility with differential specificities.

Long-range membrane traffic is guided by microtubule-associated proteins and posttranslational modifications, which collectively comprise a traffic code. The regulatory principles of this code and how it orchestrates the motility of kinesin and dynein motors are largely unknown. Septins are a large family of GTP-binding proteins, which assemble into complexes that associate with microtubules. Using single-molecule in vitro motility assays, we tested how the microtubule-associated SEPT2/6/7, SEPT2/6/7/9, and SEPT5/7/11 complexes affect the motilities of the constitutively active kinesins KIF5C and KIF1A and the dynein-dynactin-bicaudal D (DDB) motor complex. We found that microtubule-associated SEPT2/6/7 is a potent inhibitor of DDB and KIF5C, preventing mainly their association with microtubules. SEPT2/6/7 also inhibits KIF1A by obstructing stepping along microtubules. On SEPT2/6/7/9-coated microtubules, KIF1A inhibition is dampened by SEPT9, which alone enhances KIF1A, showing that individual septin subunits determine the regulatory properties of septin complexes. Strikingly, SEPT5/7/11 differs from SEPT2/6/7, in permitting the motility of KIF1A and immobilizing DDB to the microtubule lattice. In hippocampal neurons, filamentous SEPT5 colocalizes with somatodendritic microtubules that underlie Golgi membranes and lack SEPT6. Depletion of SEPT5 disrupts Golgi morphology and polarization of Golgi ribbons into the shaft of somato-proximal dendrites, which is consistent with the tethering of DDB to microtubules by SEPT5/7/11. Collectively, these results suggest that microtubule-associated complexes have differential specificities in the regulation of the motility and positioning of microtubule motors. We posit that septins are an integral part of the microtubule-based code that spatially controls membrane traffic.

Anticoagulation Versus Antiplatelets in Spontaneous Cervical Artery Dissection: A Systematic Review and Meta-Analysis.

BACKGROUND: It is uncertain whether antiplatelets or anticoagulants are more effective in preventing early recurrent stroke in patients with cervical artery dissection. Following the publication of the observational Antithrombotic for STOP-CAD (Stroke Prevention in Cervical Artery Dissection) study, which has more than doubled available data, we performed an updated systematic review and meta-analysis comparing antiplatelets versus anticoagulation in cervical artery dissection. METHODS: The systematic review was registered in PROSPERO (CRD42023468063). We searched 5 databases using a combination of keywords that encompass different antiplatelets and anticoagulants, as well as cervical artery dissection. We included relevant randomized trials and included observational studies of dissection unrelated to major trauma. Where studies were sufficiently similar, we performed meta-analyses for efficacy (ischemic stroke) and safety (major hemorrhage, symptomatic intracranial hemorrhage, and death) outcomes using relative risks. RESULTS: We identified 11 studies (2 randomized trials and 9 observational studies) that met the inclusion criteria. These included 5039 patients (30% [1512] treated with anticoagulation and 70% [3527]) treated with antiplatelets]. In meta-analysis, anticoagulation was associated with a lower ischemic stroke risk (relative risk, 0.63 [95% CI, 0.43 to 0.94]; P=0.02; I2=0%) but higher major bleeding risk (relative risk, 2.25 [95% CI, 1.07 to 4.72]; P=0.03, I2=0%). The risks of death and symptomatic intracranial hemorrhage were similar between the 2 treatments. Effect sizes were larger in randomized trials. There are insufficient data on the efficacy and safety of dual antiplatelet therapy or direct oral anticoagulants. CONCLUSIONS: In this study of patients with cervical artery dissection, anticoagulation was superior to antiplatelet therapy in reducing ischemic stroke but carried a higher major bleeding risk. This argues for an individualized therapeutic approach incorporating the net clinical benefit of ischemic stroke reduction and bleeding risks. Large randomized clinical trials are required to clarify optimal antithrombotic strategies for management of cervical artery dissection.

Impact of genetic counseling strategy on diagnostic yield and workload for genome-sequencing-based tumor diagnostics.

PURPOSE: Genome sequencing (GS) enables comprehensive molecular analysis of tumors and identification of hereditary cancer predisposition. According to guidelines, directly determining pathogenic germline variants (PGVs) requires pretest genetic counseling, which is cost-ineffective. Referral for genetic counseling based on tumor variants alone could miss relevant PGVs and/or result in unnecessary referrals. METHODS: We validated GS for detection of germline variants and simulated 3 strategies using paired tumor-normal GS data of 937 metastatic patients. In strategy-1, genetic counseling before tumor testing allowed direct PGV analysis. In strategy-2 and -3, germline testing and referral for post-test genetic counseling is based on tumor variants using Dutch (strategy-2) or Europen Society for Medical Oncology (ESMO) Precision Medicine Working Group (strategy-3) guidelines. RESULTS: In strategy-1, PGVs would be detected in 50 patients (number-needed-to counsel; NTC = 18.7). In strategy-2, 86 patients would have been referred for genetic counseling and 43 would have PGVs (NTC = 2). In strategy-3, 94 patients would have been referred for genetic counseling and 32 would have PGVs (NTC = 2.9). Hence, 43 and 62 patients, respectively, were unnecessarily referred based on a somatic variant. CONCLUSION: Both post-tumor test counseling strategies (2 and 3) had significantly lower NTC, and strategy-2 had the highest PGV yield. Combining pre-tumor test mainstreaming and post-tumor test counseling may maximize the clinically relevant PGV yield and minimize unnecessary referrals.

Long-term effectiveness of transforaminal anterolateral approach CT-guided cervical epidural steroid injections for cervical radiculopathy treatment.

AIM: To evaluate the long-term clinical effectiveness of computed tomography (CT)-guided transforaminal cervical epidural steroid injection using an anterolateral approach for the treatment of cervical radiculopathy (CR) using well-established robust clinical scoring systems for neck pain and neck disability. Despite its widespread use, evidence to support the long-term benefit of routine cervical epidural steroid injection is currently very limited. MATERIALS AND METHODS: This study included 113 patients with magnetic resonance imaging (MRI)-confirmed CR who underwent a steroid injection at a single cervical level via a unilateral transforaminal anterolateral approach. Pain was assessed quantitatively at pre-injection, 15 minutes post-injection, 1 month, 3 months, and at 1 year. Neck disability was assessed using the Oswestry Neck Disability Index (NDI) at pre-injection, 1 month, 3 months, and 1 year time points. RESULTS: Eighty patients completed the study. Sixty per cent reported reduced neck pain (mean pain reduction, 55%), which was clinically significant in 45% cases. Furthermore, 66% reported an improvement in neck disability (mean improvement, 51%), which was clinically significant for 56% patients. Clinically significant good outcomes in both neck pain and neck disability were evident from as early as 1-month, and importantly, were independent both of pre-treatment CR characteristics (including severity of pre-injection neck pain or disability) and of findings on pre-injection MRI imaging. CONCLUSION: Transforaminal anterolateral approach CT-guided epidural steroid injection resulted in a clinically significant long-term improvement in both neck pain and disability for half of the present cohort of patients with unilateral single-level CR. This improvement was independent of the severity of the initial symptoms and pre-injection MRI findings.

Disabled-2: a protein up-regulated by high molecular weight hyaluronan has both tumor promoting and tumor suppressor roles in ovarian cancer.

Although the pro-tumorigenic functions of hyaluronan (HA) are well documented there is limited information on the effects and targets of different molecular weight HA. Here, we investigated the effects of 27 kDa, 183 kDa and 1000 kDa HA on ES-2 ovarian cancer cells overexpressing the stem cell associated protein, Notch3. 1000 kDA HA promoted spheroid formation in ES-2 cells mixed with ES-2 overexpressing Notch3 (1:3). We report disabled-2 (DAB2) as a novel protein regulated by 1000 kDa HA and further investigated its role in ovarian cancer. DAB2 was downregulated in ovarian cancer compared to normal tissues but increased in metastatic ovarian tumors compared to primary tumors. High DAB2 expression was associated with poor patient outcome and positively correlated with HA synthesis enzyme HAS2, HA receptor CD44 and EMT and macrophage markers. Stromal DAB2 immunostaining was significantly increased in matched ovarian cancer tissues at relapse compared to diagnosis and associated with reduced survival. The proportion of DAB2 positive macrophages was significantly increased in metastatic ovarian cancer tissues compared to primary cancers. However, DAB2 overexpression significantly reduced invasion by both A2780 and OVCAR3 cells in vivo. Our research identifies a novel relationship between HA signalling, Notch3 and DAB2. We highlight a complex relationship of both pro-tumorigenic and tumor suppressive functions of DAB2 in ovarian cancer. Our findings highlight that DAB2 has a direct tumor suppressive role on ovarian cancer cells. The pro-tumorigenic role of DAB2 may be mediated by tumour associated macrophages and requires further investigation.

National Football League Game Officials Self-Rating of Knowledge in Neuro-Ophthalmic Principles and Practice: A Pilot Program to Improve Precision and Accuracy of Game Official Calls.

BACKGROUND: To determine whether a neuro-ophthalmic curriculum would improve National Football League (NFL) game officials' self-rated knowledge and interest in neuro-ophthalmic principles to improve precision and accuracy of NFL play-calling. METHODS: The formalized and structured neuro-ophthalmic principles (NOP) curriculum was introduced to 121 NFL game officials, 17 replay officials, and 4 officiating staff who attended the NFL Official Training Camp in Irving, Texas, on September 8 and 9, 2023. Before and after the lecture and videos were introduced, participants completed an optional hard-copy feedback form pertaining to self-reported NOP knowledge, likelihood of using said terms, and interest in future content of NOP applicable NFL officiating. Paired 2-tailed t tests were used for statistical analysis to directly compare the self-reported knowledge before and after the neuro-ophthalmic curriculum introduction. RESULTS: One hundred forty-two participants completed the prelecture and postlecture feedback forms self-reported knowledge after the NOP curriculum was given to the NFL officiating staff. All (142/142) participants completed a survey. There was a statistically significant improvement in the mean ratings of the prelecture vs. postlecture understanding of the specific neuro-ophthalmic terms pertinent to NFL game officials (2.6 [95% CI, 2.3-3.0] vs. 7.9 [95% CI, 7.6-8.2], P < 0.001) and 2.7 [95% CI, 2.3-3.0] vs. 7.7 [95% CI, 7.4-8.0]), respectively. There was a statistically significant greater likelihood of using said terms prelecture vs. postlecture (2.9 [95% CI, 2.4-3.4] vs. 7.5 [95% CI, 7.2-7.9], P < 0.001). CONCLUSIONS: This study found a statistically significant improvement in neuro-ophthalmic knowledge and a greater likelihood of using NOP terms following the NOP curriculum. NFL game officials, replay officials, and staff are interested in expanding their knowledge in the vision science of neuro-ophthalmic concepts and applications involved in play-calling. We hope that our pilot data will lead to a model of education that will improve the precision and accuracy of NFL play-calls by officials on game days.

Cryo-electron microscopy reveals how acetogenins inhibit mitochondrial respiratory complex I.

Mitochondrial complex I (NADH:ubiquinone oxidoreductase), a crucial enzyme in energy metabolism, captures the redox potential energy from NADH oxidation/ubiquinone reduction to create the proton motive force used to drive ATP synthesis in oxidative phosphorylation. High-resolution single-particle electron cryo-EM analyses have provided detailed structural knowledge of the catalytic machinery of complex I, but not of the molecular principles of its energy transduction mechanism. Although ubiquinone is considered to bind in a long channel at the interface of the membrane-embedded and hydrophilic domains, with channel residues likely involved in coupling substrate reduction to proton translocation, no structures with the channel fully occupied have yet been described. Here, we report the structure (determined by cryo-EM) of mouse complex I with a tight-binding natural product acetogenin inhibitor, which resembles the native substrate, bound along the full length of the expected ubiquinone-binding channel. Our structure reveals the mode of acetogenin binding and the molecular basis for structure-activity relationships within the acetogenin family. It also shows that acetogenins are such potent inhibitors because they are highly hydrophobic molecules that contain two specific hydrophilic moieties spaced to lock into two hydrophilic regions of the otherwise hydrophobic channel. The central hydrophilic section of the channel does not favor binding of the isoprenoid chain when the native substrate is fully bound but stabilizes the ubiquinone/ubiquinol headgroup as it transits to/from the active site. Therefore, the amphipathic nature of the channel supports both tight binding of the amphipathic inhibitor and rapid exchange of the ubiquinone/ubiquinol substrate and product.

Neuro-ophthalmic manifestations of Ehlers-Danlos syndrome.

PURPOSE OF REVIEW: To review the neuro-ophthalmic manifestations of Ehlers-Danlos syndrome (EDS). RECENT FINDINGS: Ehlers-Danlos syndrome (EDS) is a rare genetic disorder with an estimated prevalence of 1 in 5000 individuals, but its true prevalence may be underestimated because of variable clinical presentations and limited awareness among healthcare professionals. The neuro-ophthalmic features of EDS may be difficult to recognize in context but new molecular genetic testing is now available for identification of specific subtypes of EDS. SUMMARY: Ophthalmic manifestations of EDS include loss of vision and double vision (strabismus), high myopia, retinal detachment, and blue sclera. The vascular subtype of EDS can present as a carotid-cavernous fistula, intracranial aneurysm, or arterial dissection.

Mechanisms of cell death induced by hexabromocyclododecane (HBCD) involves apoptosis, autophagy, and ER stress.

Hexabromocyclododecane (HBCD), was a widely utilized brominated flame retardant, commonly found in a wide range of household products. The pervasiveness of HBCD has identified the presence of this chemical in foods and in human tissues. Therefore, HBCD has been identified as a chemical of concern. The aim was to investigate the degree of cytotoxicity of HBCD in a range of cell lines derived from different tissues, (including hematopoietic, nerve, liver, and kidney-derived cells) with a view of determining any differential cell type effects. In addition, this study also investigated the mechanism(s) by which HBCD could cause cell death. The results showed that HCBD was considerably more toxic to leukocyte-derived (RBL2H3) and neuronal-derived (SHSY-5Y) cells with LC50 values of 1.5 and 6.1 µM, respectively, compared to cells derived from liver (HepG2) and kidney (Cos-7), which had LC50 values of 28.5 and 17.5 µM, respectively. A detailed investigation of the mechanism(s) of cell death showed that HBCD caused, at least in part, Ca2+ -dependent cell death, caspase-activated apoptosis, and autophagy, but there was little evidence for either necrosis or necroptosis occurring. Furthermore, it was shown that HBCD can also induce the ER stress response which is a known trigger of both apoptosis and autophagy and therefore this could be one of the crucial events by which cell death is initiated. As each of these cell death mechanisms was investigated in at least two different cell lines and no differences were identified, it is likely that the mode of action is not cell-type specific.

Assessment of practices and awareness regarding the disposal of unwanted pharmaceutical products among community pharmacies: a cross-sectional study in Palestine.

BACKGROUND: The improper disposal of pharmaceutical preparations substantially threatens human health and environmental safety. Pharmacists are responsible for properly disposing of unwanted medications and educating patients about how to do so themselves. This study aimed to assess community pharmacists' knowledge, determine their views on how to dispose of unwanted pharmaceuticals, and assess the extent to which they realize that it is their responsibility to guide patients toward the safe disposal of expired medications. METHODS: A descriptive cross-sectional study was conducted between December 2021 and April 2022 among 400 practicing pharmacists who were chosen to participate by random cluster sampling. Community pharmacists' practices, awareness, and beliefs about disposing of unused drugs were evaluated. The Statistical Package for Social Sciences (IBM-SPSS) version 21 was used for data entry and analysis. RESULTS: Of 400 pharmacists, 348 stated that they did not participate in courses on the safe disposal of unwanted medications. Disposal of drugs in the garbage, an unsafe method, was very frequently recommended by pharmacists to patients, especially regarding inhalers, antibiotics, hormonal drugs, and solid and semisolid drugs. However, many pharmacists advised patients to return their hormonal, category B, and category C drugs to the pharmacy. A total of 61.3% of pharmacists agreed and 26% strongly agreed that unsafe disposal of drugs negatively affects the environment. A total of 54.3% of the participants agreed that improper disposal of antibiotics might be a reason for increased antimicrobial resistance, and 54.5% of them agreed that improper disposal of hormonal drugs might contribute to the development of certain cancers. A total of 80.3% of the participants perceived that most unwanted drugs in pharmacies were those returned from patients. A total of 97.3% of the participants supported establishing a drug disposal system, with 77.5% choosing to have the district health board responsible for funding this system. A total of 48.5% of the participants indicated that a lack of education and awareness on the issue of getting rid of unused drugs constitutes a challenge to the safe disposal of medicines, and 66% of them said that a lack of law enforcement constitutes another challenge. A total of 95.5% of the participants agreed or strongly agreed that good training for health sector workers and organizing workshops to develop knowledge on this subject would improve practices. A total of 93.3% supported distributing educational brochures, and 92.8% supported placing special containers in every pharmacy to collect unwanted drugs. CONCLUSIONS: Most pharmacists in our study returned drugs to manufacturing companies and stores, and few followed the correct methods of incineration and return of drugs to the Ministry of Health. Current data emphasize the issue of improper disposal of medicine in Palestine and the need for improved education among healthcare workers.

Does a proactive procedure lead to a higher uptake of predictive testing in families with a pathogenic BRCA1/BRCA2 variant? A family cancer clinic evaluation.

The uptake of genetic counseling and predictive genetic testing by family members at risk for hereditary tumor syndromes is generally below 50%. To address this issue, a new guideline was introduced in the Netherlands in 2019 that aims to improve the sharing of information within families. In addition to cascade screening supported by follow-up telephone calls with the proband, municipal records were accessed to allow the geneticist to contact at-risk family members directly. We evaluated this procedure in 32 families with a (likely) pathogenic germline BRCA1/BRCA2 variant diagnosed at our hospital between May 1, 2020, and July 31, 2021, comparing current uptake with outcomes achieved for 33 families diagnosed in 2014. Fifteen months after diagnostic testing of the proband, the uptake was 43% (120/277), comparable to the 44% (87/200) registered previously. Among a subgroup of women at 50% risk aged 25-75 years, 71% (47/66) were tested, comparable to an earlier uptake of 69% (59/86). Of the 34 at-risk relatives we contacted directly, 17 (50%) underwent predictive testing. In conclusion, we found no evidence that the new procedure leads to a substantially increased uptake. Future research should be primarily aimed at understanding intrafamilial communication barriers.

Effect of chronic antiplatelet therapy on clinical outcomes of endovascular thrombectomy for treatment of acute ischemic stroke.

OBJECTIVE: The objective of this study was to investigate the prognostic significance of chronic antiplatelet therapy (APT) usage in acute ischemic stroke (AIS) treated with endovascular thrombectomy (EVT). Long-term APT may enhance recanalization but may also predispose patients to an increased risk of hemorrhagic transformation. METHODS: Weighted hospitalizations for anterior-circulation AIS treated with EVT were identified in a large United States claims-based registry. Baseline clinical characteristics and outcomes were compared between patients with and without chronic APT usage prior to admission. Multivariable logistic regression analysis was performed to assess adjusted associations between APT and study endpoints. RESULTS: This analysis identified 36,560 patients, of whom 8170 (22.3%) were on a chronic APT regimen prior to admission. These patients were older and demonstrated a higher burden of comorbid disease, but had similar stroke severity on presentation in comparison with those not on APT. On unadjusted analysis, patients with prior APT demonstrated higher rates of favorable outcomes (24.3% vs 21.5%, p < 0.001), lower rates of mortality (7.0% vs 10.1%, p < 0.001), and lower rates of any intracranial hemorrhage (ICH; 20.3% vs 24.2%, p < 0.001), but no difference in rates of symptomatic ICH (sICH). Following multivariable adjustment for baseline clinical characteristics including age, acute stroke severity, and comorbidity burden, prior APT was associated with favorable outcome (adjusted odds ratio [aOR] 1.21, 95% CI 1.17-1.24, p < 0.001) and a lower likelihood of mortality (aOR 0.73, 95% CI 0.70-0.77, p < 0.001), without an increased likelihood of ICH (any ICH aOR 0.84, 95% CI 0.81-0.87, p < 0.001; sICH aOR 0.92, 95% CI 0.82-1.03, p = 0.131). CONCLUSIONS: Retrospective evaluation of patients with AIS treated with EVT using registry-based data demonstrated an association of prior APT usage with favorable outcomes, without an increased risk of hemorrhagic transformation.

Failure Severity Prediction for Protective-Coating Disbondment via the Classification of Acoustic Emission Signals.

Structural health monitoring is a popular inspection method that utilizes acoustic emission (AE) signals for fault detection in engineering infrastructures. Diagnosis based on the propagation of AE signals along any surface material offers an attractive solution for fault identification. However, the classification of AE signals originating from failure events, especially coating failure (coating disbondment), is a challenging task given the AE signature of each material. Thus, different experimental settings and analyses of AE signals are required to classify the various types of coating failures, and they are time-consuming and expensive. Hence, to address these issues, we utilized machine learning (ML) classification models in this work to evaluate epoxy-based-protective-coating disbondment based on the AE principle. A coating disbondment experiment consisting of coated carbon steel test panels for the collection of AE signals was implemented. The obtained AE signals were then processed to construct the final dataset to train various state-of-the-art ML classification models to divide the failure severity of coating disbondment into three classes. Consequently, methods for the extraction of useful features, the handling of data imbalance, and a reduction in the bias of ML models were also effectively utilized in this study. Evaluations of state-of-the-art ML classification models on the AE signal dataset in terms of standard metrics revealed that the decision forest classification model outperformed the other state-of-the-art models, with accuracy, precision, recall, and F1 score values of 99.48%, 98.76%, 97.58%, and 98.17%, respectively. These results demonstrate the effectiveness of utilizing ML classification models for the failure severity prediction of protective-coating defects via AE signals.

Silicon-Vacancy Nanodiamonds as High Performance Near-Infrared Emitters for Live-Cell Dual-Color Imaging and Thermometry.

Nanodiamonds (NDs) with color centers are excellent emitters for various bioimaging and quantum biosensing applications. In our work, we explore new applications of NDs with silicon-vacancy centers (SiV) obtained by high-pressure high-temperature (HPHT) synthesis based on metal-catalyst-free growth. They are coated with a polypeptide biopolymer, which is essential for efficient cellular uptake. The unique optical properties of NDs with SiV are their high photostability and narrow emission in the near-infrared region. Our results demonstrate for the first time that NDs with SiV allow live-cell dual-color imaging and intracellular tracking. Also, intracellular thermometry and challenges associated with SiV atomic defects in NDs are investigated and discussed for the first time. NDs with SiV nanoemitters provide new avenues for live-cell bioimaging, diagnostic (SiV as a nanosized thermometer), and theranostic (nanodiamonds as drug carrier) applications.

Quantum Tunneling Effect in CsPbBr3 Multiple Quantum Wells.

Two-dimensional (2D) lead halide perovskites (LHPs) have garnered incredible attention thanks to their exciting optoelectronic properties and intrinsic strong quantum confinement effect. Herein, we carefully investigate and decipher the charge carrier dynamics at the interface between CsPbBr3 multiple quantum wells (MQWs) as the photoactive layer and TiO2 and Spiro-OMeTAD as electron and hole transporting materials, respectively. The fabricated MQWs comprise three monolayers of CsPbBr3 separated by 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline (BCP) as barriers. By varying the BCP thickness, we show that charge carrier extraction from MQWs to the corresponding extracting layer occurs through a quantum tunneling effect, as elaborated by steady-state and time-resolved photoluminescence measurements and further verified by femtosecond transient absorption experiments. Ultimately, we have investigated the impact of the barrier-thickness-dependent quantum tunneling effect on the photoelectric behavior of the synthesized QW photodetector devices. Our findings shed light on one of the most promising approaches for efficient carrier extraction in quantum-confined systems.

The role of adenosine receptor ligands on inflammatory pain: possible modulation of TRPV1 receptor function.

Chronic pain has a debilitating consequences on health and lifestyle. The currently available analgesics are often ineffective and accompanied by undesirable adverse effects. Although adenosine receptors (AR) activation can affect nociceptive, inflammatory, and neuropathic pain states, the specific regulatory functions of its subtypes (A1, A2A, A2B and A3 ARs) are not fully understood. The aim of this study was to investigate the role of different AR ligands on inflammatory pain. The von Frey filament test was used to assess the anti-nociceptive effects of adenosine ligands on Complete Freund's Adjuvant (CFA)-induced mechanical allodynia in (180-220 g) adult male Sprague Dawley rats (expressed as paw withdrawal threshold, PWT). Neither the A2AAR selective agonist CGS 21680 hydrochloride (0.1, 0.32 and 1 mg/kg) nor the A2BAR selective agonist BAY 60-6583 (0.1, 0.32 and 1 mg/kg) produced any significant reversal of the PWT. However, the A1AR selective agonist ( ±)-5'-Chloro-5'-deoxy-ENBA, the A3AR selective agonist 2-Cl-IB-MECA, the A2AAR selective antagonist ZM 241385 and the A2BAR selective antagonist PSB 603 produced a significant reversal of the PWT at the highest dose of 1 mg/kg. Co-administration of the selective antagonists of A1AR and A3AR PSB36 (1 mg/ml) and MRS-3777 (1 mg/ml); respectively, significantly reversed the anti-nociceptive effects of their corresponding agonists. Furthermore, calcium imaging studies reveled that the effective AR ligands in the behavioral assay also significantly inhibit capsaicin-evoked calcium responses in cultured rat dorsal root ganglia (DRG) neurons. In conclusion, modulating the activity of the transient receptor potential vanilloid 1 (TRPV1) receptor by ARs ligands could explain their anti-nociceptive effects observed in vivo. Therefore, the cross talk between ARs and TRPV1 receptor may represent a promising targets for the treatment of inflammatory pain conditions.