Iridium(III) carbene complexes as potent girdin inhibitors against metastatic cancers.

Many cancer-driving protein targets remain undruggable due to a lack of binding molecular scaffolds. In this regard, octahedral metal complexes with unique and versatile three-dimensional structures have rarely been explored as inhibitors of undruggable protein targets. Here, we describe antitumor iridium(III) pyridinium-N-heterocyclic carbene complex 1a, which profoundly reduces the viability of lung and breast cancer cells as well as cancer patient-derived organoids at low micromolar concentrations. Compound 1a effectively inhibits the growth of non-small-cell lung cancer and triple-negative breast cancer xenograft tumors, impedes the metastatic spread of breast cancer cells, and can be modified into an antibody-drug conjugate payload to achieve precise tumor delivery in mice. Identified by thermal proteome profiling, an important molecular target of 1a in cellulo is Girdin, a multifunctional adaptor protein that is overexpressed in cancer cells and unequivocally serves as a signaling hub for multiple pivotal oncogenic pathways. However, specific small-molecule inhibitors of Girdin have not yet been developed. Notably, 1a exhibits high binding affinity to Girdin with a Kd of 1.3 µM and targets the Girdin-linked EGFR/AKT/mTOR/STAT3 cancer-driving pathway, inhibiting cancer cell proliferation and metastatic activity. Our study reveals a potent Girdin-targeting anticancer compound and demonstrates that octahedral metal complexes constitute an untapped library of small-molecule inhibitors that can fit into the ligand-binding pockets of key oncoproteins.

LipidA-IDER to Explore the Global Lipid A Repertoire of Drug-Resistant Gram-Negative Bacteria.

With the global emergence of drug-resistant bacteria causing difficult-to-treat infections, there is an urgent need for a tool to facilitate studies on key virulence and antimicrobial resistant factors. Mass spectrometry (MS) has contributed substantially to the elucidation of the structure-function relationships of lipid A, the endotoxic component of lipopolysaccharide which also serves as an important protective barrier against antimicrobials. Here, we present LipidA-IDER, an automated structure annotation tool for system-level scale identification of lipid A from high-resolution tandem mass spectrometry (MS2) data. LipidA-IDER was validated against previously reported structures of lipid A in the reference bacteria, Escherichia coli and Pseudomonas aeruginosa. Using MS2 data of variable quality, we demonstrated LipidA-IDER annotated lipid A with a performance of 71.2% specificity and 70.9% sensitivity, offering greater accuracy than existing lipidomics software. The organism-independent workflow was further applied to a panel of six bacterial species: E. coli and Gram-negative members of ESKAPE pathogens. A comprehensive atlas comprising 188 distinct lipid A species, including remodeling intermediates, was generated and can be integrated with software including MS-DIAL and Metabokit for identification and semiquantitation. Systematic comparison of a pair of polymyxin-sensitive and polymyxin-resistant Acinetobacter baumannii isolated from a human patient unraveled multiple key lipid A structural features of polymyxin resistance within a single analysis. Probing the lipid A landscape of bacteria using LipidA-IDER thus holds immense potential for advancing our understanding of the vast diversity and structural complexity of a key lipid virulence and antimicrobial-resistant factor. LipidA-IDER is freely available at https://github.com/Systems-Biology-Of-Lipid-Metabolism-Lab/LipidA-IDER.

Mind your language: the importance of english language skills in an International Medical Programme (IMP).

BACKGROUND: Language proficiency is crucial for doctors as they communicate with patients, peers and other healthcare professionals. Although proficiency in English is part of admission requirements, there is a gap in the knowledge of medical students' perception of factors enhancing English language (EL) skills during training in international medical programmes (IMPs). The gap prevents educators and policy makers from helping students who struggle with communication skills during medical training. This study therefore explores the importance of English language skills from medical students' perspectives. METHODS: Six focus group interviews with 24 medical students were conducted in an IMP. Data were analysed using Braun and Clarke's framework of thematic analysis. RESULTS: Results established three themes that constitute the importance of EL skills, namely the use of EL in medical training and practice, influence of university culture in EL mastery and individual EL proficiency as perceived by medical students. CONCLUSIONS: Findings of this study demonstrate how students perceived the importance of EL skills as a professional and social requirement during medical training and for future practice. It also informs that setting English language admission pre requisites needs to be complemented with opportunities to practice context specific communication skills. Thus, international medical programmes should embed diverse and inclusive strategies to support and develop medical students' English language skills.

Characterization of Fowlpox virus in chickens and bird-biting mosquitoes: a molecular approach to investigating Avipoxvirus transmission.

Avian pox is a highly contagious avian disease, yet relatively little is known about the epidemiology and transmission of Avipoxviruses. Using a molecular approach, we report evidence for a potential link between birds and field-caught mosquitoes in the transmission of Fowlpox virus (FWPV) in Singapore. Comparison of fpv167 (P4b), fpv126 (VLTF-1), fpv175-176 (A11R-A12L) and fpv140 (H3L) gene sequences revealed close relatedness between FWPV strains obtained from cutaneous lesions of a chicken and four pools of Culex pseudovishnui, Culex spp. (vishnui group) and Coquellitidea crassipes caught in the vicinity of the study site. Chicken-derived viruses characterized during two separate infections two years later were also identical to those detected in the first event, suggesting repeated transmission of closely related FWPV strains in the locality. Since the study location is home to resident and migratory birds, we postulated that wild birds could be the source of FWPV and that bird-biting mosquitoes could act as bridging mechanical vectors. Therefore, we determined whether the FWPV-positive mosquito pools (n=4) were positive for avian DNA using a polymerase chain reaction-sequencing assay. Our findings confirmed the presence of avian host DNA in all mosquito pools, suggesting a role for Cx. pseudovishnui, Culex spp. (vishnui group) and Cq. crassipes mosquitoes in FWPV transmission. Our study exemplifies the utilization of molecular tools to understand transmission networks of pathogens affecting avian populations, which has important implications for the design of effective control measures to minimize disease burden and economic loss.

Detection and characterization of a novel bat-borne coronavirus in Singapore using multiple molecular approaches.

Bats are important reservoirs and vectors in the transmission of emerging infectious diseases. Many highly pathogenic viruses such as SARS-CoV and rabies-related lyssaviruses have crossed species barriers to infect humans and other animals. In this study we monitored the major roost sites of bats in Singapore, and performed surveillance for zoonotic pathogens in these bats. Screening of guano samples collected during the survey uncovered a bat coronavirus (Betacoronavirus) in Cynopterus brachyotis, commonly known as the lesser dog-faced fruit bat. Using a capture-enrichment sequencing platform, the full-length genome of the bat CoV was sequenced and found to be closely related to the bat coronavirus HKU9 species found in Leschenault's rousette discovered in the Guangdong and Yunnan provinces.

Toddlers' understanding and use of verbal negation in inferential reasoning search tasks.

Past research has demonstrated that young children and nonhuman animals are able to reason by elimination ("If not A, then B") by relying on visual cues such as seeing that one container is empty. Other research has shown that young children can solve similar, simple inferential reasoning tasks where "emptiness" is conveyed verbally through negation (e.g., "The toy is not in the box"). However, it is unclear whether these tasks involved reasoning through the disjunctive syllogism, which requires the representation of logical negation (NOT A) and disjunction (A OR B) or simpler, nondeductive strategies. In Study 1, we extended this work by investigating whether 2-year-olds can infer the location of a toy in typical two-location elimination trials, when given both affirmative and negative sentences, and more complex three-location trials, when information about emptiness was conveyed verbally and visually. Younger 2-year-olds performed significantly better on the search task when hearing affirmative than negative sentences, whereas older 2-year-olds were equally successful with both types of sentences. Study 2 examined children's ability to use verbal negation to solve a more complex deductive task involving disjunctive syllogism. Results showed that, in this linguistic version of the disjunctive reasoning task, both 2.5- and 3-year-olds made accurate inferences about the location of a reward, unlike prior (nonlinguistic) evidence that demonstrated this ability in 3-year-olds but not in younger children. We conclude that by the end of their second year of life, children have a robust understanding of negation which they can apply in abstract reasoning.

Luminescent Iridium(III) Pyridinium-Derived N-Heterocyclic Carbene Complexes as Versatile Photoredox Catalysts.

The development of novel luminescent iridium(III) complexes with highly tunable emission energy and versatile applications is of particular importance. In this Communication, a series of luminescent iridium(III) complexes supported by chromophoric pyridinium-derived N-heterocyclic carbene (NHC) ligands that display tunable emission from 516 to 682 nm were prepared. These complexes can be used as photocatalysts in photooxidation and photoreduction reactions and could have potential applications in pH sensing.

Early Rehabilitation for Patients with Hip Fractures: Spreading Change Across the System.

Evidence suggests that patients with hip fractures should begin rehabilitation no later than six days following surgery. The reality is often far different. In an initiative led by the Greater Toronto Area (GTA) Rehab Network, acute care and rehab/complex continuing care hospitals across the GTA have implemented a new early referral process to aid transition of patients from acute care to inpatient rehabilitation as early as possible to improve their outcomes. Two of the participating acute care hospitals have now surpassed the six-day target and two others are within range. The initiative also provides useful learnings to guide other cross-sector change and spread initiatives.

Physical measurements of Chinese children in Hong Kong-A pilot study in preschools and kindergartens.

Normal growth is essential to a developing child. Most syndromes with dysmorphic features demonstrate recognizable patterns of disproportionate growth, thus physical measurements are an important aspect of patient evaluation. Delineating the abnormal growth pattern depends greatly on the accuracy of the normal range. However, the currently available reference data are restricted in terms of ethnicity and geographical location, hence may not be applicable to all children worldwide. In Hong Kong, reference data are limited only to the neonatal period. The aim of our pilot study is to obtain a set of region-specific physical measurement data for Chinese children in Hong Kong. Two to six year olds were recruited from preschools and kindergartens in different regions of Hong Kong. Twenty-six parameters found in previous publications were measured with minor modifications. Three medical personnel trained by a clinical geneticist obtained these parameters. Satisfactory inter-rater reliability was achieved in a training cohort prior to the study. Raw measurement data collected were normalized and fitted into growth curves modeled by LMS method. We recruited 448 children (55.6% male) between 2 and 6 years old from five preschools and kindergartens. Growth curves with essential percentile lines were drawn. Significant differences were identified in 11 parameters when compared with Caucasian children, including canthal distances and facial width/height. Our current pilot study presents the first local- and ethnicity-specific data on physical measurements of 2-6 year olds. Our findings highlighted the substantial ethnic variability in physical measurements and the need for an ethnic-specific reference for Chinese children. © 2016 Wiley Periodicals, Inc.

Discovery of deoxyvasicinone derivatives as inhibitors of NEDD8-activating enzyme.

NEDD8-activating enzyme (NAE) controls the specific degradation of proteins regulated by cullin-RING ubiquitin E3 ligases, and has been considered as an attractive molecular target for the development of drugs against cancer. A pharmacophore model constructed from a training set of deoxyvasicinone derivatives was used to screen 376 compounds from an analogue database. From the initial screening, the valine-linked deoxyvasicinone derivative 9 and the N-isopropyl-linked deoxyvasicinone derivative 10 emerged as the top scoring candidates. Compounds 9 and 10 showed micromolar potencies in both cell-free and cell-based systems, with selectivity for NAE over the related enzymes SAE and UAE. Molecular modelling analysis suggested that 9 and 10 may inhibit NAE by blocking the ATP-binding domain. Thus, these deoxyvasicinone derivatives could be considered as promising lead molecules for the development of more potent inhibitors of NAE.

Deletion of Abca7 increases cerebral amyloid-ß accumulation in the J20 mouse model of Alzheimer's disease.

ATP-binding cassette transporter A7 (ABCA7) is expressed in the brain and has been detected in macrophages, microglia, and neurons. ABCA7 promotes efflux of lipids from cells to apolipoproteins and can also regulate phagocytosis and modulate processing of amyloid precursor protein (APP) to generate the Alzheimer's disease (AD) amyloid-ß (Aß) peptide. Genome-wide association studies have indicated that ABCA7 single nucleotide polymorphisms confer increased risk for late-onset AD; however, the role that ABCA7 plays in the brain in the AD context is unknown. In the present study, we crossed ABCA7-deficient (A7(-/-)) mice with J20 amyloidogenic mice to address this issue. We show that ABCA7 loss doubled insoluble Aß levels and thioflavine-S-positive plaques in the brain. This was not related to changes in APP processing (assessed by analysis of full-length APP and the APP ß C-terminal fragment). Apolipoprotein E regulates cerebral Aß homeostasis and plaque load; however, the apolipoprotein E concentration was not altered by ABCA7 loss. Spatial reference memory was significantly impaired in both J20 and J20/A7(-/-) mice compared with wild-type mice; however, there were no cognitive differences between J20 and J20/A7(-/-) mice. There were also no major differences detected in hippocampal or plaque-associated microglial/macrophage markers between J20 and J20/A7(-/-) mice, whereas the capacity for bone marrow-derived macrophages derived from A7(-/-) mice to take up oligomeric Aß was reduced by 51% compared with wild-type mice. Our results suggest that ABCA7 plays a role in the regulation of Aß homeostasis in the brain and that this may be related to altered phagocyte function.

Ytterbium(III) porpholactones: ß-lactonization of porphyrin ligands enhances sensitization efficiency of lanthanide near-infrared luminescence.

The near-infrared (NIR) luminescence efficiency of lanthanide complexes is largely dependent on the electronic and photophysical properties of antenna ligands. Although porphyrin ligands are efficient sensitizers of lanthanide NIR luminescence, non-pyrrolic porphyrin analogues, which have unusual symmetry and electronic states, have been much less studied. In this work, we used porpholactones, a class of ß-pyrrolic-modified porphyrins, as ligands and investigated the photophysical properties of lanthanide porpholactones Yb-1 a-5 a. Compared with Yb porphyrin complexes, the porpholactone complexes displayed remarkable enhancement of NIR emission (50-120 %). Estimating the triplet-state levels of porphyrin and porpholactone in Gd complexes revealed that ß-lactonization of porphyrinic ligands lowers the ligand T1 state and results in a narrow energy gap between this state and the lowest excited state of Yb(3+) . Transient absorption spectra showed that Yb(III) porpholactone has a longer transient decay lifetime at the Soret band than the porphyrin analogue (30.8 versus 17.0 µs). Thus, the narrower energy gap and longer lifetime arising from ß-lactonization are assumed to enhance NIR emission of Yb porpholactones. To demonstrate the potential applications of Yb porpholactone, a water-soluble Yb bioprobe was constructed by conjugating glucose to Yb-1 a. Interestingly, the NIR emission of this Yb porpholactone could be specifically switched on in the presence of glucose oxidase and then switched off by addition of glucose. This is the first demonstration that non-pyrrolic porphyrin ligands enhance the sensitization efficiency of lanthanide luminescence and also display switchable NIR emission in the region of biological analytes (800-1400 nm).

Ruthenium porphyrins with axial π-conjugated arylamide and arylimide ligands.

A series of ruthenium porphyrins [Ru(IV)(por)(NHY)2] and [Ru(VI)(por)(NY)2] bearing axially coordinated π-conjugated arylamide and arylimide ligands, respectively, have been synthesized. The crystal structures of [Ru(IV)(tmp)(NHY)2] (tmp = 5,10,15,20-tetramesitylporphyrinato(2-)) with Y = 4'-methoxy-biphenyl-4-yl (Ar-Ar-p-OMe), 4'-chloro-biphenyl-4-yl (Ar-Ar-p-Cl), and 9,9-dibutyl-fluoren-2-yl (Ar^Ar) show axial Ru-N(arylamide) distances of 1.978(4), 1.971(6), and 1.985(13) Å, respectively. [Ru(IV)(tmp)(NH{Ar^Ar})2] is an example of metalloporphyrins that bind an arylamide ligand featuring a co-planar biphenyl unit. The [Ru(IV)(por)(NHY)2] complexes show a quasi-reversible reduction couple or irreversible reduction wave attributed to Ru(IV)→Ru(III) with Epc from -1.06 to -1.40 V versus Cp2Fe(+/0) and an irreversible oxidation wave with Epa from -0.04 to 0.19 V versus Cp2Fe(+/0). Reaction of the [Ru(IV)(por)(NHY)2] with bromine afforded [Ru(IV)(por)(NHY)Br]. PhI(OAc)2 oxidation of the [Ru(IV)(por)(NHY)2] gave [Ru(VI)(por)(NY)2]; the latter can be prepared from reaction of [Ru(II)(por)(CO)] with aryl azides N3Y. The crystal structure of [Ru(VI)(tmp)(N{Ar-Ar-p-OMe})2] features Ru-N(arylimide) distances of 1.824(5) and 1.829(5) Å. Alkene aziridination and C-H amination catalyzed by "[Ru(II)(tmp)(CO)]+π-conjugated aryl azides", or mediated by [Ru(VI)(por)(NY)2] with Y = biphenyl-4-yl (Ar-Ar) and Ar-Ar-p-Cl, gave aziridines and amines in moderate yields. The electronic structure of [Ru(VI)(por)(NY)2] was examined by DFT calculations.

Factors associated with self-reported arthritis 7 to 24 years after a traumatic brain injury.

The purpose of this study was to profile characteristics of people with traumatic brain injury (TBI) who self-reported arthritis 7 to 24 yr. post-injury. Pre- and post-injury socio-demographic factors, injury-related factors, and postinjury standardized assessments measuring health, activity, and participation outcomes were assessed in a retrospective cohort study of 274 participants. The group self-reporting arthritis had significantly more sleep disturbances, poorer overall health, lower mental health and physical function, and decreased productivity. Also, they were older and reported a shorter length of loss of consciousness from TBI. These resulted suggest that musculoskeletal complaints from long-term survivors of TBI sholud be addressed in post-acute care and could guide future research on arthritis in the TBI population.

Return to work, work productivity loss and activity impairment in Chinese breast cancer survivors 12-month post-surgery: a longitudinal study.

Introduction: Existing evidence of returning-to-work (RTW) after cancer comes predominately from Western settings, with none prospectively examined since the initial diagnostic phase. This study prospectively documents RTW-rate, time-to-RTW, work productivity loss, and activity impairment, within the first-year post-surgery among Chinese women with breast cancer (BCW) and identify potential causal co-variants. Methods: This observational longitudinal study followed 371 Chinese BCW who were employed/self-employed at the time of diagnosis at 4-week post-surgery (baseline). RTW-status and time-to-RTW were assessed at baseline (T1), 4-month (T2), 6-month (T3), and 12-month (T4) post-baseline. WPAI work productivity loss and activity impairment were assessed at T4. Baseline covariates included demographics, medical-related factors, work satisfaction, perceived work demand, work condition, RTW self-efficacy, B-IPQ illness perception, COST financial well-being, EORTC QLQ-C30 and QLQ-BR23 physical and psychosocial functioning, and HADS psychological distress. Results: A 68.2% RTW-rate (at 12-month post-surgery), prolonged delay in RTW (median = 183 days), and significant proportions of T4 work productivity loss (20%), and activity impairment (26%), were seen. BCW who were blue-collar workers with lower household income, poorer financial well-being, lower RTW self-efficacy, poorer job satisfaction, poorer illness perception, greater physical symptom distress, impaired physical functioning, and unfavorable work conditions were more likely to experience undesired work-related outcomes. Discussion: Using a multifactorial approach, effective RTW interventions should focus on not only symptom management, but also to address psychosocial and work-environmental concerns. An organizational or policy level intervention involving a multidisciplinary team comprising nurses, psychologists, occupational health professionals, and relevant stakeholders in the workplace might be helpful in developing a tailored organizational policy promoting work-related outcomes in BCW.

A Comprehensive Review with Future Insights on the Processing and Safety of Fermented Fish and the Associated Changes.

As an easily spoiled source of valuable proteins and lipids, fish is preserved by fermentation in many cultures. Over time, diverse types of products have been produced from fish fermentation aside from whole fish, such as fermented fish paste and sauces. The consumption of fermented fish products has been shown to improve both physical and mental health due to the composition of the products. Fermented fish products can be dried prior to the fermentation process and include various additives to enhance the flavours and aid in fermentation. At the same time, the fermentation process and its conditions play a major role in determining the quality and safety of the product as the compositions change biochemically throughout fermentation. Additionally, the necessity of certain microorganisms and challenges in avoiding harmful microbes are reviewed to further optimise fermentation conditions in the future. Although several advanced technologies have emerged to produce better quality products and easier processes, the diversity of processes, ingredients, and products of fermented fish warrants further study, especially for the sake of the consumers' health and safety. In this review, the nutritional, microbial, and sensory characteristics of fermented fish are explored to better understand the health benefits along with the safety challenges introduced by fermented fish products. An exploratory approach of the published literature was conducted to achieve the purpose of this review using numerous books and online databases, including Google Scholar, Web of Science, Scopus, ScienceDirect, and PubMed Central, with the goal of obtaining, compiling, and reconstructing information on a variety of fundamental aspects of fish fermentation. This review explores significant information from all available library databases from 1950 to 2022. This review can assist food industries involved in fermented fish commercialization to efficiently ferment and produce better quality products by easing the fermentation process without risking the health and safety of consumers.

Pazopanib elicits remarkable response in metastatic porocarcinoma: a functional precision medicine approach.

Metastatic porocarcinomas (PCs) are vanishingly rare, highly aggressive skin adnexal tumors with mortality rates exceeding 70%. Their rarity has precluded the understanding of their disease pathogenesis, let alone the conduct of clinical trials to evaluate treatment strategies. There are no effective agents for unresectable PCs. Here, we successfully demonstrate how functional precision medicine was implemented in the clinic for a metastatic PC with no known systemic treatment options. Comprehensive genomic profiling of the tumor specimen did not yield any actionable genomic aberrations. However, ex vivo drug testing predicted pazopanib efficacy, and indeed, administration of pazopanib elicited remarkable clinicoradiological response. Pazopanib and its class of drugs should be evaluated for efficacy in other cases of PC, and the rationale for efficacy should be determined when PC tumor models become available. A functional precision medicine approach could be useful to derive effective treatment options for rare cancers.

KIR genotypic diversity can track ancestries in heterogeneous populations: a potential confounder for disease association studies.

Killer cell immunoglobulin-like receptors (KIR) are encoded by highly polymorphic genes that regulate the activation of natural killer (NK) cells and other lymphocyte subsets and likely play key roles in innate and adaptive immunity. Association studies increasingly implicate KIR in disease predisposition and outcome but could be confounded by unknown KIR genetic structure in heterogeneous populations. To examine this, we characterized the diversity of 16 KIR genes in 712 Northern Californians (NC) stratified by self-assigned ethnicities and compared the profiles of KIR polymorphism with other US and global populations using a reference database. Sixty-eight distinct KIR genotypes were characterized: 58 in 457 Caucasians (NCC), 17 in 47 African Americans (NCAA), 21 in 80 Asians (NCA), 20 in 74 Hispanics (NCH), and 18 in 54 "other" ethnicities (NCO). KIR genotype patterns and frequencies in the 4 defined ethnicities were compared with each other and with 34 global populations by phylogenetic analysis. Although there were no population-specific genotypes, the KIR genotype frequency patterns faithfully traced the ancestry of NCC, NCAA, and NCA but not of NCH whose ancestries are known to be more heterogeneous. KIR genotype frequencies can therefore track ethnic ancestries in modern urban populations. Our data emphasize the importance of selecting ethnically matched controls in KIR-based studies to avert spurious associations.

Supramolecular self-assembly of 1D and 3D heterometallic coordination polymers with triruthenium building blocks.

Ru(3)(TSA)(6) (1; H(2)TSA=2-thiosalicylic acid), which bears six peripheral carboxylate groups and was isolated in the form [NEt(4)](1.5)[Ru(3)(HTSA)(2)(TSA)(4)](OAc)(0.5)·3.5H(2)O, serves as a building block for assembly of heterometallic coordination polymers. Treatment of 1 with [Fe(acac)(3)] (acac=acetylacetonate) in EG/H(2)O (EG=ethylene glycol) afforded 1D Ru(3)-Fe coordination polymer 2 by means of the connection of the building block 1 through iron centers. Treatment of 1 with MnCl(2) in EG resulted in the formation of 1D Ru(3)-Mn(3) coordination polymer 3, which features self-assembled polynuclear linking units Mn(3)(OCH(2)CH(2)O)(3), each of which contains a planar Mn(3)O(3) ring. By treating 1 with Gd(NO(3))(3) and NaHCO(3) in EG, a 3D Ru(3)-Gd(6) coordination polymer 4 was obtained; this 3D coordination polymer features unprecedented Gd(6)(µ(3)-CO(3))(4) units. The magnetic properties of 1-4, along with DFT calculations on the electronic structure of 1, are also described.