Lawesson's Reagent: Providing a New Approach to the Forgotten 6-Thioverdazyl Radical.

A new method for the preparation of the underrepresented 1,5-dimethyl-6-thioverdazyl radicals has been developed employing Lawesson's reagent (LR). The synthetic route involves the direct thionation of the carbonyl group of the corresponding dialkylbishydrazone followed by cyclization to give the tetrazinanthione verdazyl precursor on a gram scale. Subsequent oxidation yields the 6-thioverdazyl radical. It was determined that thionation of substrates containing electron-withdrawing groups in the ortho- or para-positions was high yielding. In contrast, for the parent phenyl group or substrates bearing weakly electron-donating substituents, thionation efficiency was significantly reduced. This could be overcome by utilizing partial in situ cyclization, which occurs during work up, to generate the tetrazinanthione directly via a one-pot synthesis. Density functional theory suggests that the LR fragment interacts with the carbonyl prior to cycloaddition and subsequent to cycloreversion, leading to the thiocarbonyl. The electronic nature of the radical is characterized with electron paramagnetic resonance as well as the first report of 6-thioverdazyl redox properties.

The Fight Tumour Blindness Registry: Efficient capture of high-quality real-world data in uveal melanoma.

OBJECTIVE: To describe the development of a web-based data collection tool to track the management and outcomes of uveal melanoma patients. DESIGN: Description of a clinical registry. PARTICIPANTS: Patients with uveal melanoma. METHODS: A panel of expert ocular oncologists, with input from other relevant specialties and individuals with expertise in registry development, collaborated to formulate a minimum data set to be collected to track patient centred, real-world outcomes in uveal melanoma. This data set was used to create the Fight Tumour Blindness! (FTB!) registry within Save Sight Registries. RESULTS: The data set to be collected includes patient demographics and medical history, baseline visit, follow-up visit including tumour treatment, metastatic staging and surveillance, pathology, and patient-reported questionnaires. The inbuilt mechanisms to ensure efficient and complete data collection are described. CONCLUSIONS: The FTB! registry can be used to monitor outcomes for patients with uveal melanoma. It allows benchmarking of outcomes and comparisons between different clinics and countries.

Difference in association of carbohydrate intake with all-cause mortality between middle-aged and older Korean adults with and without diabetes mellitus: A prospective study.

BACKGROUND & AIMS: The relationship between diet and health, particularly the role of carbohydrates, has been extensively studied. However, carbohydrate intake based on individual health conditions remains unclear. Here, we aimed to investigate whether the association between carbohydrate intake and all-cause mortality varied between individuals with and without diabetes mellitus (DM). METHODS: This prospective cohort study used data from the Korean Genome and Epidemiology Study (KoGES). Overall, 143,050 participants were included, with 10.1% having DM. Dietary intake was assessed using a semiquantitative food frequency questionnaire. Cox proportional hazards regression models were used to assess the association between carbohydrate intake and mortality after adjusting for confounders. RESULTS: The study showed that 5436 deaths occurred during the median follow-up period of 10.1 years. A significant interaction between carbohydrate intake and DM was observed in the study population (interaction p = 0.061). Higher carbohydrate intake proportion was associated with an increased risk of all-cause mortality among individuals with DM (adjusted hazard ratio [HR], p-value = 1.10 [1.01-1.20], p = 0.032). Conversely, no association was observed between the proportion of carbohydrate intake and all-cause mortality in participants without DM. Additionally, both total sugar and added sugar intakes were associated with an increased risk of all-cause mortality in participants with DM (adjusted HR, p-value = 1.02 [1.01-1.04], p < 0.001 and 1.18 [1.13-1.24], p < 0.001). CONCLUSIONS: High carbohydrate (%) and added sugar intake were associated with an increased mortality risk in individuals with DM. Reducing carbohydrate intake and opting for healthy carbohydrates to mitigate mortality risk may be beneficial for individuals with DM, particularly when compared with the general population.

Normal postvoid residual urine in healthy adults.

OBJECTIVE: To establish a normal reference value of postvoid residual (PVR) urine volume in "healthy" adults. METHODS: Adults were recruited to undergo uroflowmetry and PVR. Those with neurological disorders, malignancy, diabetes, known lower urinary tract dysfunction, and urinary tract infection within the previous 3 months, were excluded from the study. Constipation was defined as Rome IV ≥ 2. RESULTS: Of the 883 adults enrolled in this study, 194 (22.3%) did not complete the questionnaires or perform the uroflowmetry, 103 (11.7%) met ≥1 exclusion criteria and thus were excluded. In addition, 30 and 38 uroflowmetry were excluded due to artifacts and low bladder volume (BV) (<100 mL), respectively. Finally, 515 uroflowmetry and PVR data from adults aged 36-89 (mean: 59.0 ± 9.5) were examined. There was a significant nonlinear relationship between BV and PVR (p < 0.05), with PVR significantly increased when BV was around 528 mL. Women had lower PVR than men (p < 0.05). PVR also increased as the International Prostatic Symptom Score (IPSS) increased. PVR was unaffected by age and functional constipation. A multivariate analysis revealed that BV (p < 0.05) and IPSS (p < 0.05) had significant influence on PVR, but age, gender, and Rome IV score did not. The 90th and 95th percentiles of PVR for men were 73.2 mL (25% of BV) and 102.6 mL (30% of BV), respectively, while for women they were 60.5 mL (21% of BV) and 93.8 mL (27% of BV), respectively. CONCLUSION: Women had lower PVR than men. The 90th percentile or 95th percentile of normal adults' PVR may serve as the upper limit of normal PVR, and readings above this level may necessitate additional evaluation and treatment. Further studies are required to substantiate these recommendations.

Stabilization and One Electron Reduction of a Silicon Analogue of a Carboxylic Acid Anhydride.

Reaction of the 1,2-disilylenes {(DipAr Am)Si}2 (DipAr Am=[(NDip)2 CAr]- , Dip=2,6-diisopropylphenyl, Ar=4-C6 H4 But (Ar') 1 a or Ph 1 b) and two abnormal N-heterocyclic silylenes, (DipAr Am)SiOCSi{(NDip)2 CAr} (Ar=Ar' 3 a or Ph 3 b) with N2 O led to formation of unprecedented examples of uncoordinated silicon analogues of carboxylic acid anhydrides, (DipAr Am)(O=)SiOSi(=O)(DipAr Am) (Ar=Ar' 2 a or Ph 2 b). Both compounds have been fully characterized, and the mechanism of formation of one explored using DFT calculations. Reduction of sila-acid anhydride 2 a with a dimagnesium(I) compound, [{(Mes Nacnac)Mg}2 ] (Mes Nacnac=[(MesNCMe)2 CH]- , Mes=mesityl), led to the one-electron reduction of the anhydride and formation of a magnesium complex of a sila-acid anhydride radical anion [(Mes Nacnac)Mg{(OSi(DipAr' Am)}2 O] 5. A combination of EPR spectroscopic studies and DFT calculations reveal the unpaired electron to largely reside on one of the amidinate ligands of the complex.

A one-pot reduction route to bimetallic manganese 1,8-naphthyridine complexes.

Reaction of the dinucleating ligand 2,7-bis(6-methyl-2-pyridyl)-1,8-naphthyridine (MeL) with the MnI and MnII precursors MnBr(CO)5 and MnCl2 resulted in the formation of the monometallic complexes [MnBr(CO)3(MeL)] (1) and [MnCl2(MeL)] (3). In both cases, formation of bimetallic manganese complexes could be achieved by reduction with KC8, yielding the carbonyl-bridged complex [Mn2(CO)6(MeL)] (2) and the helicate complex [Mn2(MeL)2] (4), respectively. EPR results demonstrate that 4 represents a novel, weakly antiferromagnetically coupled homovalent dimer (J = -0.85 cm-1). The two formally Mn0 ions are both high spin (S = 3/2) and exhibit a zero-field splitting of ≈1 cm-1, suggesting reduction of the complex is substantially ligand centered, and may be better described as a MnII complex coupled to two open shell singlet ligands [MnII2(MeL2-)2]. X-ray crystallography, UV-Vis spectroscopy and DFT analysis support this finding.

Evaluation of deep learning for detecting intraosseous jaw lesions in cone beam computed tomography volumes.

OBJECTIVE: The study aim was to develop and assess the performance of a deep learning (DL) algorithm in the detection of radiolucent intraosseous jaw lesions in cone beam computed tomography (CBCT) volumes. STUDY DESIGN: A total of 290 CBCT volumes from more than 12 different scanners were acquired. Fields of view ranged from 6 × 6 × 6 cm to 18 × 18 × 16 cm. CBCT volumes contained either zero or at least one biopsy-confirmed intraosseous lesion. 80 volumes with no intraosseous lesions were included as controls and were not annotated. 210 volumes with intraosseous lesions were manually annotated using ITK-Snap 3.8.0. 150 volumes (10 control, 140 positive) were presented to the DL software for training. Validation was performed using 60 volumes (30 control, 30 positive). Testing was performed using the remaining 80 volumes (40 control, 40 positive). RESULTS: The DL algorithm obtained an adjusted sensitivity by case, specificity by case, positive predictive value by case, and negative predictive value by case of 0.975, 0.825, 0.848, and 0.971, respectively. CONCLUSIONS: A DL algorithm showed moderate success at lesion detection in their correct locations, as well as recognition of lesion shape and extent. This study demonstrated the potential of DL methods for intraosseous lesion detection in CBCT volumes.

Pediatric ocular melanoma: a collaborative multicenter study and meta-analysis.

PURPOSE: To investigate clinical manifestations and prognoses in pediatric patients (≤12 years old) with ocular melanoma. METHODS: This was a retrospective, multicenter cohort study with individual participant data (IPD) meta-analysis pooling available published cases, and unpublished cases from an international collaboration of seven ocular oncology centers. RESULTS: There were 133 eyes of 133 pediatric patients with choroidal or ciliary body (n = 66 [50%]), iris (n = 33 [25%]), conjunctival (n = 26 [19%]), and eyelid (n = 8 [6%]) melanoma. Overall, the mean patient age at presentation was 7 years (median, 8; range, 1-12 years), with 63 males (49%). The mean age by tumor site was 6.50 ± 3.90, 7.44 ± 3.57, 9.12 ± 2.61, and 5.63 ± 2.38 years, for choroid/ciliary body, iris, conjunctiva, and eyelid melanoma, respectively (P = 0.001). Association with ocular melanocytosis was seen in 15%, 11%, 4%, and 0%, respectively (P = 0.01). Frequency of ocular melanoma family history did not vary by tumor site (7%, 17%, 9% and 12%, resp. [P = 0.26]). After mean follow-up of 74, 85, 50, and 105 months (P = 0.65), metastasis was seen in 12%, 9%, 19%, and 13% of choroid/ciliary body, iris, conjunctiva, and eyelid melanoma, respectively. Death was reported in 5%, 3%, 8%, and 0%, respectively, with survival analysis indicating higher mortality in choroidal/ciliary body and conjunctival melanoma patients. CONCLUSIONS: Ocular melanoma in the pediatric population is rare, with unique clinical features and outcomes. Iris melanoma accounts for about one-third of pediatric uveal melanoma cases.

Lapatinib dysregulates HER2 signaling and impairs the viability of human uveal melanoma cells.

Uveal melanoma (UM) is the principal type of intraocular malignancy in adults. Up to 50% of UM patients develop metastatic disease with very poor survival. There are few drugs available to treat the primary or metastatic UM. This study was undertaken to evaluate the anti-cancer effect of lapatinib and corroborate the potential of HER2 inhibition in the treatment of UM. The anti-UM activity of lapatinib was assessed using cell viability, cell death and cell cycle analysis, and its anti-metastatic actions were evaluated using would healing, invasion and colony formation assays. Immunoblotting was used to substantiate the actions of lapatinib on apoptotic and HER2 signaling. The anti-UM activity of lapatinib was further evaluated in a UM xenograft mouse model. Lapatinib decreased the viability of four UM cell lines (IC50: 3.67-6.53 µM). The antiproliferative activity of lapatinib was corroborated in three primary cell lines isolated from UM patient tumors. In UM cell lines, lapatinib promoted apoptosis and cell cycle arrest, and strongly inhibited cell migration, invasion and reproductive cell growth. Lapatinib dysregulated HER2-AKT/ERK/PI3K signalling leading to the altered expression of apoptotic factors and cell cycle mediators in UM cell lines. Importantly, lapatinib suppressed tumourigenesis in mice carrying UM cell xenografts. Together the present findings are consistent with the assertion that HER2 is a viable therapeutic target in UM. Lapatinib is active in primary and metastatic UM as a clinically approved HER2 inhibitor. The activity of lapatinib in UM patients could be evaluated in future clinical trials.

Correction: Chua et al. Cost-Effectiveness Analysis of HPV Extended versus Partial Genotyping for Cervical Cancer Screening in Singapore. Cancers 2023, 15, 1812.

The authors wish to revise two words in Table 1 row 3, and the first paragraph of Section 2 [...].

LQR approach to robust stabilization of state space systems with matched uncertainties.

This note shows an elegant relationship between the quadratic optimal control and robust stabilization for linear time-invariant (LTI) systems, where the former control can robustly stabilize the latter system, provided that the matched uncertainty is bounded. Through reviewing the relevant literature, some common mistakes in regard to this relationship are found. The correct results are obtained and proved in both frequency and time domains. The results are applicable to both single- and multi-input cases. They are significant as the simple LQR design for the nominal system can be utilized to directly solve-with no further effort-the complex robust stabilization problem for a class of linear uncertain systems.

Serosurveillance of SARS-CoV-2 in companion animals in Sarawak, Malaysia.

SARS-CoV-2 is a zoonotic betacoronavirus that was first reported at the dawn of 2019 in Wuhan, China and has since spread globally, causing an ongoing pandemic. Anthroponotic transmission was reported early, with confirmed infections reported in 26 species to date, including dogs and cats. However, there is a paucity of reports on the transmission of SARS-CoV-2 to companion animals, and thus, we aimed to estimate the seroprevalence of SARS-CoV-2 in dogs and cats in Sarawak, Malaysia. From August 2022 to 2023, we screened plasma samples of 172 companion animals in Sarawak, Malaysia, using a species-independent surrogate virus neutralization test. Our findings revealed the presence of neutralizing antibodies of SARS-CoV-2 in 24.5% (27/110) of dogs and 24.2% (15/62) of cats. To the best of our knowledge, this is the first report of the seroprevalence of SARS-CoV-2 in companion animals in Malaysia. Our findings emphasize the need for pet owners to distance themselves from their pets when unwell, and a strategy must be in place to monitor SARS-CoV-2 in companion animals to assess the potential impact of the virus on companion animals.

One- and two-electron reductions of a bulky BODIPY compound.

The redox reaction between a bulky BODIPY and a magnesium(I) reducing agent leads to the formal one-electron reduction of the BODIPY, initially generating a dipyrromethene-centred radical compound that dimerises via C-C bond formation. In contrast, reduction with magnesium anthracene leads to the formal two-electron reduction of the BODIPY, resulting in the formation of the corresponding anion.

Methyl Palmitate Modulated NMDA-Induced Cerebral Hyperemia in Hypertensive Rats.

N-methyl-D-aspartate (NMDA) receptors were found to be dysfunctional in hypertensive rats. Methyl palmitate (MP) has been shown to diminish the nicotine-induced increase in blood flow in the brainstem. The aim of this study was to determine how MP modulated NMDA-induced increased regional cerebral blood flow (rCBF) in normotensive (WKY), spontaneously hypertensive (SHR), and renovascular hypertensive (RHR) rats. The increase in rCBF after the topical application of experimental drugs was measured using laser Doppler flowmetry. Topical NMDA application induced an MK-801-sensitive increase in rCBF in anesthetized WKY rats, which was inhibited by MP pretreatments. This inhibition was prevented by pretreatment with chelerythrine (a PKC inhibitor). The NMDA-induced increase in rCBF was also inhibited by the PKC activator in a concentration-dependent manner. Neither MP nor MK-801 affected the increase in rCBF induced by the topical application of acetylcholine or sodium nitroprusside. Topical application of MP to the parietal cortex of SHRs, on the other hand, increased basal rCBF slightly but significantly. MP enhanced the NMDA-induced increase in rCBF in SHRs and RHRs. These results suggested that MP had a dual effect on the modulation of rCBF. MP appears to play a significant physiological role in CBF regulation.

Age- and gender-specific normal post void residual urine volume in healthy adolescents.

INTRODUCTION: Elevated post void residual (PVR) is a significant risk factor for urinary tract infections (UTI). It is also a significant predictor of treatment outcomes in cases of vesicoureteral reflux, pediatric enuresis, and non-neurogenic LUT dysfunction. However, the absence of age-specific nomograms for adolescents may limit PVR's use in clinical practice. OBJECTIVE: To establish age- and gender-specific normal PVR urine volume in adolescents. MATERIAL AND METHODS: Healthy adolescents aged 12-18 years were recruited to undergo two uroflowmetry and PVR studies whenever they felt the urge to urinate. Adolescents with neurological disorders, known LUT dysfunction or UTI were excluded. RESULTS: A total of 1050 adolescents were invited, but only 651 consented. Fourteen participants were excluded due to low bladder volume (BV < 100 ml) in both assessments (n = 12), BV < 100 ml in one assessment (n = 1), or failure to provide relevant history (n = 1). From the 1084 uroflowmetry and PVR obtained from 637 adolescents, 190 results were further excluded due to artefacts (n = 152), BV < 100 ml (n = 27), PVR >100 ml (n = 5) and missing information (n = 6). Ultimately, 894 uroflowmetry and PVR from 605 adolescents (mean age 14.6 ± 1.5 years) were analyzed. PVRs were higher in adolescents aged 15-18 years than in those aged 12-14 years (P < 0.001). Moreover, they were higher in females than in males (P < 0.001). Multivariate analysis revealed that PVR was positively influenced by age (P = 0.001) and BV (P < 0.001). The age- and gender-specific percentiles of PVR in ml and percentage of BV were calculated. We recommend a repeat PVR and close monitoring if PVR is above the 90th percentile, i.e., PVR >20 ml (7% BV) for males of both the age groups, and PVR >25 ml (9% BV) and PVR >35 ml (>10% BV) for females aged 12-14 and 15-18 years, respectively. Further investigation may be warranted if the repeat PVR is above the 95th percentile, i.e., PVR >30 ml (8% BV) and >30 ml (11% BV) for males aged 12-14 and 15-18 years, respectively, and PVR >35 ml (11% BV) and >45 ml (13% BV) for females aged 12-14 and 15-18 years, respectively. CONCLUSION: PVR increases with age and varies by gender; thus, age-and gender-specific reference values should be used. Further data from other countries is required to determine whether the study's recommendations can be applied globally.

Incidental findings involving the temporomandibular joint on computed tomography and magnetic resonance imaging.

The temporomandibular joint (TMJ) is frequently imaged in head and neck computed tomography (CT) and magnetic resonance imaging (MRI) studies. Depending on the indication for the study, an abnormality of the TMJ may be an incidental finding. These findings encompass both intra- and extra-articular disorders. They may also be related to local, regional or systemic conditions. Familiarity with these findings along with pertinent clinical information helps narrow the list of differential diagnoses. While definitive diagnosis may not be immediately apparent, a systematic approach contributes to improved discussions between clinicians and radiologists and better patient management.

A computational model of prefrontal and striatal interactions in perceptual category learning.

Work on multiple-system theories of cognition mostly focused on the systems themselves, while limited work has been devoted to understanding the interactions between systems. Generally, multiple-system theories include a model-based decision system supported by the prefrontal cortex and a model-free decision system supported by the striatum. Here we propose a neurobiological model to describe the interactions between model-based and model-free decision systems in category learning. The proposed model used spiking neurons to simulate activity of the hyperdirect pathway of the basal ganglia. The hyperdirect pathway acts as a gate for the response signal from the model-free system located in the striatum. We propose that the model-free system's response is inhibited when the model-based system is in control of the response. The new model was used to simulate published data from young adults, people with Parkinson's disease, and aged-matched older adults. The simulation results further suggest that system-switching ability may be related to individual differences in executive function. A new behavioral experiment tested this model prediction. The results show that an updating score predicts the ability to switch system in a categorization task. The article concludes with new model predictions and implications of the results for research on system interactions.

Increasing lysergic acid levels for ergot alkaloid biosynthesis: Directing catalysis via the F-G loop of Clavine oxidases.

Most ergot alkaloid drugs are semi-synthetically derived from the natural product lysergic acid, a valuable precursor for the development of novel ergot alkaloid drugs. Clavine oxidase (CloA) is a putative cytochrome P450, identified in the ergot alkaloid biosynthesis pathway, and a key enzyme that catalyzes the formation of lysergic acid from the precursor alkaloid agroclavine in a two-step oxidation reaction. We demonstrated in this study that Saccharomyces cerevisiae can be used as a viable host for the functional expression of CloA from Claviceps purpurea and its orthologs. We also showed that CloA orthologs differ in their ability to oxidize the substrate agroclavine, with some orthologs only able to perform the first oxidation reaction to produce elymoclavine. Of particular note, we identified a region between the F-G helices of the enzyme that may be involved in directing oxidation of agroclavine by substrate recognition and uptake. Using this knowledge, engineered CloAs were shown to produce lysergic acid at levels exceeding that of wildtype CloA orthologs; a CloA variant, chimeric AT5 9Hypo CloA, increased production levels of lysergic acid to 15 times higher as compared to the wildtype enzyme, demonstrating future utility for the industrial production of ergot alkaloids using biosynthetic routes.

Non-Toxic CuInS2 /ZnS Colloidal Quantum Dots for Near-Infrared Light-Emitting Diodes.

Ternary CuInS2 quantum dots (QDs) with photoluminescence that is tunable from the visible to the near-infrared (NIR) region are promising light-emitters for consumer electronics due to the absence of toxic elements such as Pb, Cd, or As. Despite the compelling performance of visible-light-emitting CuInS2 QDs, reports on NIR emission remain limited, with modest efficiencies at wavelengths beyond 900 nm. In this work, the facile synthesis of NIR-emitting CuInS2 /ZnS QDs is reported. A combination of two sulfur precursors w as used in the synthesis, comprising 1-dodecanethiol (DDT) and hexamethyldisilathiane (HMDS). The reactive HMDS facilitates faster nucleation and leads to a higher density of emissive Cu-deficiency sites. The resulting QDs exhibit high photoluminescence quantum efficiency (PLQE) of 65% at a long emission wavelength of 920 nm. Using these QDs, NIR light-emitting diodes (LED) are fabricated, which attain an external quantum efficiency (EQE) of 8.2%. This efficiency is comparable to the best reported PbS and InAs QD LEDs, and the emission wavelength exceeds that of lead iodide perovskites. This work thus marks one of the first reports of efficient NIR LEDs based on environmentally benign CuInS2 QDs and may open up promising new applications in consumer electronic products.

The Acute Effects and Mechanism of Ketamine on Nicotine-Induced Neurogenic Relaxation of the Corpus Cavernosum in Mice.

The present study aimed to investigate the acute effects and the mechanism of ketamine on nicotine-induced relaxation of the corpus cavernosum (CC) in mice. This study measured the intra-cavernosal pressure (ICP) of male C57BL/6 mice and the CC muscle activities using an organ bath wire myograph. Various drugs were used to investigate the mechanism of ketamine on nicotine-induced relaxation. Direct ketamine injection into the major pelvic ganglion (MPG) inhibited MPG-induced increases in ICP. D-serine/L-glutamate-induced relaxation of the CC was inhibited by MK-801 (N-methyl-D-aspartate (NMDA) receptor inhibitor), and nicotine-induced relaxation was enhanced by D-serine/L-glutamate. NMDA had no effect on CC relaxation. Nicotine-induced relaxation of the CC was suppressed by mecamylamine (a non-selective nicotinic acetylcholine receptor antagonist), lidocaine, guanethidine (an adrenergic neuronal blocker), Nw-nitro-L-arginine (a non-selective nitric oxide synthase inhibitor), MK-801, and ketamine. This relaxation was almost completely inhibited in CC strips pretreated with 6-hydroxydopamine (a neurotoxic synthetic organic compound). Ketamine inhibited cavernosal nerve neurotransmission via direct action on the ganglion and impaired nicotine-induced CC relaxation. The relaxation of the CC was dependent on the interaction of the sympathetic and parasympathetic nerves, which may be mediated by the NMDA receptor.