Major source categories of PM2.5 oxidative potential in wintertime Beijing and surroundings based on online dithiothreitol-based field measurements.

Fine particulate matter (PM2.5) causes millions of premature deaths each year worldwide. Oxidative potential (OP) has been proposed as a better metric for aerosol health effects than PM2.5 mass concentration alone. In this study, we report for the first time online measurements of PM2.5 OP in wintertime Beijing and surroundings based on a dithiothreitol (DTT) assay. These measurements were combined with co-located PM chemical composition measurements to identify the main source categories of aerosol OP. In addition, we highlight the influence of two distinct pollution events on aerosol OP (spring festival celebrations including fireworks and a severe regional dust storm). Source apportionment coupled with multilinear regression revealed that primary PM and oxygenated organic aerosol (OOA) were both important sources of OP, accounting for 41 ± 12 % and 39 ± 10 % of the OPvDTT (OP normalized by the sampled air volume), respectively. The small remainder was attributed to fireworks and dust, mainly resulting from the two distinct pollution events. During the 3.5-day spring festival period, OPvDTT spiked to 4.9 nmol min-1 m-3 with slightly more contribution from OOA (42 ± 11 %) and less from primary PM (31 ± 15 %). During the dust storm, hourly-averaged PM2.5 peaked at a very high value of 548 µg m-3 due to the dominant presence of dust-laden particles (88 % of total PM2.5). In contrast, only mildly elevated OPvDTT values (up to 1.5 nmol min-1 m-3) were observed during this dust event. This observation indicates that variations in OPvDTT cannot be fully explained using PM2.5 alone; one must also consider the chemical composition of PM2.5 when studying aerosol health effects. Our study highlights the need for continued pollution control strategies to reduce primary PM emissions, and more in-depth investigations into the source origins of OOA, to minimize the health risks associated with PM exposure in Beijing.

Spatial analysis of dengue transmission in an endemic city in Brazil reveals high spatial structuring on local dengue transmission dynamics.

In the last decades, dengue has become one of the most widespread mosquito-borne arboviruses in the world, with an increasing incidence in tropical and temperate regions. The mosquito Aedes aegypti is the dengue primary vector and is more abundant in highly urbanized areas. Traditional vector control methods have showing limited efficacy in sustaining mosquito population at low levels to prevent dengue virus outbreaks. Considering disease transmission is not evenly distributed in the territory, one perspective to enhance vector control efficacy relies on identifying the areas that concentrate arbovirus transmission within an endemic city, i.e., the hotspots. Herein, we used a 13-month timescale during the SARS-Cov-2 pandemic and its forced reduction in human mobility and social isolation to investigate the spatiotemporal association between dengue transmission in children and entomological indexes based on adult Ae. aegypti trapping. Dengue cases and the indexes Trap Positive Index (TPI) and Adult Density Index (ADI) varied seasonally, as expected: more than 51% of cases were notified on the first 2 months of the study, and higher infestation was observed in warmer months. The Moran's Eigenvector Maps (MEM) and Generalized Linear Models (GLM) revealed a strong large-scale spatial structuring in the positive dengue cases, with an unexpected negative correlation between dengue transmission and ADI. Overall, the global model and the purely spatial model presented a better fit to data. Our results show high spatial structure and low correlation between entomological and epidemiological data in Foz do Iguaçu dengue transmission dynamics, suggesting the role of human mobility might be overestimated and that other factors not evaluated herein could be playing a significant role in governing dengue transmission.

Source attribution of carbonaceous fraction of particulate matter in the urban atmosphere based on chemical and carbon isotope composition.

Air quality is of large concern in the city of Krakow, southern Poland. A comprehensive study was launched by us in which two PM fractions (PM1 and PM10) were sampled during 1-year campaign, lasting from April 21, 2018 to March 19, 2019. A suite of modern analytical methods was used to characterize the chemical composition of the collected samples. The contents of 14 sugars, sugar alcohols and anhydrosugars, 16 polycyclic aromatic hydrocarbons, selected metals and non-metals and ions were analyzed, in addition to organic and elemental carbon content. The carbon isotope composition in both analysed PM fractions, combined with an isotope-mass balance method, allowed to distinguish three main components of carbonaceous emissions in the city: (1) emissions related to combustion of hard coal, (2) emissions related to road transport, and (3) biogenic emissions. The heating season emissions from coal combustion had the biggest contribution to the reservoir of carbonaceous aerosols in the PM10 fraction (44%) and, together with the biogenic emission, they were the biggest contributors to the PM1 fraction (41% and 44%, respectively). In the non-heating season, the dominant source of carbon in PM10 and PM1 fraction were the biogenic emissions (48 and 54%, respectively).

Cannabidiol modulates hippocampal genes involved in mitochondrial function, ribosome biogenesis, synapse organization, and chromatin modifications.

BACKGROUND: Cannabidiol (CBD) is one of the main cannabinoids present in Cannabis sativa female flowers. Previous investigation has already provided insights into the CBD molecular mechanism; however, there is no transcriptome data for CBD effects on hippocampal subfields. Here, we investigate transcriptomic changes in dorsal and ventral CA1 of adult mice hippocampus after 100 mg/kg of CBD administration (i.p.) for one or seven consecutive days. METHODS: C57BL/6JUnib mice were treated with either vehicle or CBD for 1 or 7 days. The collected brains were sectioned, and the hippocampal sub-regions were laser microdissected for RNA-Seq analysis. RESULTS: The transcriptome analysis following 7 days of CBD administration indicates the differential expression of 1559 genes in dCA1 and 2924 genes in vCA1. Furthermore, GO/KEGG analysis identified 88 significantly enriched biological process and 26 significantly enriched pathways for dCBD7, whereas vCBD7 revealed 128 enriched BPs and 24 pathways. CONCLUSION: This dataset indicates a widespread decrease of electron transport chain and ribosome biogenesis transcripts in CA1, while chromatin modifications and synapse organization transcripts were increased following CBD administration for 7 days.

Scheimpflug-Based Corneal Biomechanical Analysis As A Predictor of Glaucoma in Eyes With High Myopia.

Purpose: To address if corneal biomechanical behavior has a predictive value for the presence of glaucomatous optical neuropathy in eyes with high myopia. Patients and Methods: This observational cross-sectional study included 209 eyes from 108 consecutive patients, divided into four groups: high myopia and primary open-angle glaucoma (POAG) - HMG, n = 53; high myopia without POAG - HMNG, n = 53; non-myopic with POAG - POAG, n = 50; non-myopic and non-POAG- NMNG, n = 53. Biomechanical assessment was made through a Scheimpflug-camera-based technology. Receiver operating characteristic curves were made for the discrimination between groups. Multivariable logistic regression models were performed to address the predictive value of corneal biomechanics for the presence of glaucoma. Results: Areas Under the Receiver Operating Characteristic (AUROCs) above 0.6 were found in 6 parameters applied to discriminate between HMG and HMNG and six parameters to discriminate between POAG and NMNG. The biomechanical models with the highest power of prediction for the presence of glaucoma included 5 parameters with an AUROC of 0.947 for eyes with high myopia and 6 parameters with an AUROC of 0.857 for non-myopic eyes. In the final model, including all eyes, and adjusted for the presence of high myopia, the highest power of prediction for the presence of glaucoma was achieved including eight biomechanical parameters, with an AUROC of 0.917. Conclusion: Corneal biomechanics demonstrated differences in eyes with glaucoma and mainly in myopic eyes. A biomechanical model based on multivariable logistic regression analysis and adjusted for high myopia was built, with an overall probability of 91.7% for the correct prediction of glaucomatous damage.

In vitro neuronal and glial response to magnetically stimulated piezoelectric poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV)/cobalt ferrite (CFO) microspheres.

Polymer biomaterials are being considered for tissue regeneration due to the possibility of resembling different extracellular matrix characteristics. However, most current scaffolds cannot respond to physical-chemical modifications of the cell microenvironment. Stimuli-responsive materials, such as electroactive smart polymers, are increasingly gaining attention once they can produce electrical potentials without external power supplies. The presence of piezoelectricity in human tissues like cartilage and bone highlights the importance of electrical stimulation in physiological conditions. Although poly(vinylidene fluoride) (PVDF) is one of the piezoelectric polymers with the highest piezoelectric response, it is not biodegradable. Poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) is a promising copolymer of poly(hydroxybutyrate) (PHB) for tissue engineering and regeneration applications. It offers biodegradability, piezoelectric properties, biocompatibility, and bioactivity, making it a superior option to PVDF for biomedical purposes requiring biodegradability. Magnetoelectric polymer composites can be made by combining magnetostrictive particles and piezoelectric polymers to further tune their properties for tissue regeneration. These composites convert magnetic stimuli into electrical stimuli, generating local electrical potentials for various applications. Cobalt ferrites (CFO) and piezoelectric polymers have been combined and processed into different morphologies, maintaining biocompatibility for tissue engineering. The present work studied how PHBV/CFO microspheres affected neural and glial response in spinal cord cultures. It is expected that the electrical signals generated by these microspheres due to their magnetoelectric nature could aid in tissue regeneration and repair. PHBV/CFO microspheres were not cytotoxic and were able to impact neurite outgrowth and promote neuronal differentiation. Furthermore, PHBV/CFO microspheres led to microglia activation and induced the release of several bioactive molecules. Importantly, magnetically stimulated microspheres ameliorated cell viability after an in vitro ROS-induced lesion of spinal cord cultures, which suggests a beneficial effect on tissue regeneration and repair.

Strength training improves heart function, collagen and strength in rats with heart failure.

BACKGROUND/OBJECTIVES: Myocardial infarction (MI) frequently leads to cardiac remodeling and failure with impaired life quality, playing an important role in cardiovascular deaths. Although physical exercise is a well-recognized effective non-pharmacological therapy for cardiovascular diseases, the effects of strength training (ST) on the structural and functional aspects of cardiac remodeling need to be further documented. In this study, we aimed to investigate the role of a linear block ST protocol in the rat model of MI. METHODS AND RESULTS: After 6 weeks of MI induction or sham surgery, male adult rats performed ST for the following 12 weeks. The ladder-based ST program was organized in three mesocycles of 4 weeks, with one load increment for each block according to the maximal carrying load test. After 12 weeks, the infarcted-trained rats exhibited an increase in performance, associated with reduced cardiac hypertrophy and pulmonary congestion compared with the untrained group. Despite not changing MI size, the ST program partially prevented cardiac dilatation and ventricular dysfunction assessed by echocardiography and hemodynamics, and interstitial fibrosis evaluated by histology. In addition, isolated cardiac muscles from infarcted-trained rats had improved contractility parameters in a steady state, and in response to calcium or stimuli pauses. CONCLUSIONS: The ST in infarcted rats increased the capacity to carry mass, associated with attenuation of cardiac remodeling and pulmonary congestion with improving cardiac function that could be attributed, at least in part, to the improvement of myocardial contractility.

Refractive outcomes of immediately sequential bilateral cataract surgery in eyes with long and short axial lengths.

PURPOSE: To report the refractive outcomes of long (≥25.00 mm) and short (≤22.00 mm) axial length (AL) eyes undergoing immediately sequential bilateral cataract surgery (ISBCS). METHODS: In this retrospective cohort study, patients who underwent ISBCS were identified and eyes of patients with bilateral long and short ALs were included. Pre- and postoperative biometry, autorefraction, and ocular comorbidities or complications were recorded. The primary outcome was the mean refractive prediction error. RESULTS: Thirty-seven patients (74 eyes) with long ALs and 18 patients (36 eyes) with short ALs were included. The means ± standard deviations of the ALs were 26.40 ± 1.38 mm and 21.44 ± 0.46 mm in the long and short AL groups, respectively. In long AL eyes, the mean absolute error from the biometry-predicted refraction was - 0.16 ± 0.46 D, corresponding to 74% of eyes achieving a refraction within ±0.50 D of the predicted value. In short AL eyes, the mean absolute error was - 0.63 ± 0.73 D, corresponding to 44% of eyes achieving a refraction within ±0.50 D of the predicted value. Eight (44.4%) patients with short AL eyes had a myopic deviation greater than ±0.50 D from the predicted result in both eyes. CONCLUSIONS: Compared to patients with long AL eyes, ISBCS in patients with short ALs had a wider variance in refractive outcome and a lower rate of achieving a postoperative refraction within ±0.50 D of the predicted target.

Uncovering the dominant contribution of intermediate volatility compounds in secondary organic aerosol formation from biomass-burning emissions.

Organic vapors from biomass burning are a major source of secondary organic aerosols (SOAs). Previous smog chamber studies found that the SOA contributors in biomass-burning emissions are mainly volatile organic compounds (VOCs). While intermediate volatility organic compounds (IVOCs) are efficient SOA precursors and contribute a considerable fraction of biomass-burning emissions, their contribution to SOA formation has not been directly observed. Here, by deploying a newly-developed oxidation flow reactor to study SOA formation from wood burning, we find that IVOCs can contribute ∼70% of the formed SOA, i.e. >2 times more than VOCs. This previously missing SOA fraction is interpreted to be due to the high wall losses of semi-volatile oxidation products of IVOCs in smog chambers. The finding in this study reveals that SOA production from biomass burning is much higher than previously thought, and highlights the urgent need for more research on the IVOCs from biomass burning and potentially other emission sources.

Covered versus bare-metal stenting of the mesenteric arteries in patients with chronic mesenteric ischaemia (CoBaGI): a multicentre, patient-blinded and investigator-blinded, randomised controlled trial.

BACKGROUND: Mesenteric artery stenting with a bare-metal stent is the current treatment for atherosclerotic chronic mesenteric ischaemia. Long-term patency of bare-metal stents is unsatisfactory due to in-stent intimal hyperplasia. Use of covered stents might improve long-term patency. We aimed to compare the patency of covered stents and bare-metal stents in patients with chronic mesenteric ischaemia. METHODS: We conducted a multicentre, patient-blinded and investigator-blinded, randomised controlled trial including patients with chronic mesenteric ischaemia undergoing mesenteric artery stenting. Six centres in the Netherlands participated in this study, including two national chronic mesenteric ischaemia expert centres. Patients aged 18 years or older were eligible for inclusion when an endovascular mesenteric artery revascularisation was scheduled and a consensus diagnosis of chronic mesenteric ischaemia was made by a multidisciplinary team of gastroenterologists, interventional radiologists, and vascular surgeons. Exclusion criteria were stenosis length of 25 mm or greater, stenosis caused by median arcuate ligament syndrome or vasculitis, contraindication for CT angiography, or previous target vessel revascularisation. Digital 1:1 block randomisation with block sizes of four or six and stratification by inclusion centre was used to allocate patients to undergo stenting with bare-metal stents or covered stents at the start of the procedure. Patients, physicians performing follow-up, investigators, and radiologists were masked to treatment allocation. Interventionalists performing the procedure were not masked. The primary study outcome was the primary patency of covered stents and bare-metal stents at 24 months of follow-up, evaluated in the modified intention-to-treat population, in which stents with missing data for the outcome were excluded. Loss of primary patency was defined as the performance of a re-intervention to preserve patency, or 75% or greater luminal surface area reduction of the target vessel. CT angiography was performed at 6 months, 12 months, and 24 months post intervention to assess patency. The study is registered with ClinicalTrials.gov (NCT02428582) and is complete. FINDINGS: Between April 6, 2015, and March 11, 2019, 158 eligible patients underwent mesenteric artery stenting procedures, of whom 94 patients (with 128 stents) provided consent and were included in the study. 47 patients (62 stents) were assigned to the covered stents group (median age 69·0 years [IQR 63·0-76·5], 28 [60%] female) and 47 patients (66 stents) were assigned to the bare-metal stents group (median age 70·0 years [63·5-76·5], 33 [70%] female). At 24 months, the primary patency of covered stents (42 [81%] of 52 stents) was superior to that of bare-metal stents (26 [49%] of 53; odds ratio [OR] 4·4 [95% CI 1·8-10·5]; p<0·0001). A procedure-related adverse event occurred in 17 (36%) of 47 patients in the covered stents group versus nine (19%) of 47 in the bare-metal stent group (OR 2·4 [95% CI 0·9-6·3]; p=0·065). Most adverse events were related to the access site, including haematoma (five [11%] in the covered stents group vs six [13%] in the bare-metal stents group), pseudoaneurysm (five [11%] vs two [4%]), radial artery thrombosis (one [2%] vs none), and intravascular closure device (none vs one [2%]). Six (13%) patients in the covered stent group versus one (2%) in the bare-metal stent group had procedure-related adverse events not related to the access site, including stent luxation (three [6%] vs none), major bleeding (two (4%) vs none), mesenteric artery perforation (one [2%] vs one [2%]), mesenteric artery dissection (one [2%] vs one [2%]), and death (one [2%] vs none). INTERPRETATION: The findings of this trial support the use of covered stents for mesenteric artery stenting in patients with chronic mesenteric ischaemia. FUNDING: Atrium Maquet Getinge Group.

Draft genome assemblies for two species of Escallonia (Escalloniales).

OBJECTIVES: Escallonia (Escalloniaceae) belongs to the Escalloniales, a diverse clade of flowering plants with unclear placement in the tree of life. Escallonia species show impressive morphological and ecological diversity and are widely distributed across three hotspots of biodiversity in the Neotropics. To shed light on the genomic substrate of this radiation and the phylogenetic placement of Escalloniales as well as to generate useful data for comparative evolutionary genomics across flowering plants, we produced and annotated draft genomes for two species of Escallonia. DATA DESCRIPTION: Genomic DNA from E. rubra and E. herrerae was sequenced with Oxford Nanopore sequencing chemistry, generating 3.4 and 12 million sequence reads with an average read length of 9.4 and 9.1 Kb (approximately 31 and 111 Gb of sequence data), respectively. In addition, we generated Illumina 100-bp paired-end short read data for E. rubra (approximately 75 Gb of sequence data). The Escallonia rubra genome was 566 Mb, with 3,233 contigs and an N50 of 285 Kb. The assembled genome for E. herrerae was 994 Mp, with 5,760 contigs and an N50 of 317 Kb. The genome sequences were annotated with 31,038 (E. rubra) and 47,905 (E. herrerea) protein-coding gene models supported by transcriptome/protein evidence and/or Pfam domain content. BUSCO assessments indicated completeness levels of approximately 98% for the genome assemblies and 88% for the genome annotations.

Multimorbidity measured with Charlson Comorbidity Index is not associated with clinically relevant risk of revision after primary total hip arthroplasty: a population-based cohort study on 98,647 patients from the Danish Hip Arthroplasty Register.

BACKGROUND AND PURPOSE: Evidence for guiding healthcare professionals on the risks of total hip arthroplasty (THA) in multimorbid patients is sparse. We aimed to examine the association between multimorbidity and the risk of revision due to any cause and specific causes after primary THA due to osteoarthritis. PATIENTS AND METHODS: We identified 98,647 THA patients and subsequent revisions in the Danish Hip Arthroplasty Register from 1995 to 2018. Multimorbidity was measured with the Charlson Comorbidity Index (CCI). Using the CCI (low, medium, high), we calculated the cumulative incidence function (CIF) of first revision up to 10 years after THA. Adjusted cause-specific hazard ratios (aHRs) were estimated using Cox regressions. All estimates are presented with 95% confidence intervals (CI). RESULTS: Overall, the prevalence of patients with low, medium, and high CCI was 70%, 24%, and 6%. The CIF of any revision within 10 years was 6.5% (CI 6.2-6.7) in low and 6.5% (CI 5.8-7.3) in high CCI, with an aHR of 1.4 (CI 1.2-1.6) for patients with high compared with low CCI. The corresponding aHRs for cause-specific revision were 1.3 (CI 1.0-1.6) for aseptic loosening within 10 years, 1.2 (CI 0.9-1.6) for infection, and 1.7 (CI 1.3-2.2) for dislocation, both within 2 years. CONCLUSION: Multimorbidity is associated with a minor but not clinically relevant increased risk of revision up to 10 years after primary THA.

Neonatal treatment with para-chlorophenylalanine (pCPA) induces adolescent hyperactivity associated with changes in the paraventricular nucleus Crh and Trh expressions.

Disruption of the brain serotoninergic (5-HT) system during development induces long-lasting changes in molecular profile, cytoarchitecture, and function of neurons, impacting behavioral regulation throughout life. In male and female rats, we investigate the effect of neonatal tryptophan hydroxylase (TPH) inhibition by using para-chlorophenylalanine (pCPA) on the expression of 5-HTergic system components and neuropeptides related to adolescent social play behavior regulation. We observed sex-dependent 5-HT levels decrease after pCPA-treatment in the dorsal raphe nucleus (DRN) at 17 and 35 days. Neonatal pCPA-treatment increased playing, social and locomotory behaviors assessed in adolescent rats of both sexes. The pCPA-treated rats demonstrated decreased Crh (17 days) and increased Trh (35 days) expression in the hypothalamic paraventricular nucleus (PVN). There was sex dimorphism in Htr2c (17 days) and VGF (35 days) in the prefrontal cortex, with the females expressing higher levels of it than males. Our results indicate that neonatal pCPA-treatment results in a long-lasting and sex-dependent DRN 5-HT synthesis changes, decreased Crh, and increased Trh expression in the PVN, resulting in a hyperactivity-like phenotype during adolescence. The present work demonstrates that the impairment of TPH function leads to neurobehavioral disorders related to hyperactivity and impulsivity, such as attention deficit hyperactivity disorder (ADHD).

Contribution of fossil and biomass-derived secondary organic carbon to winter water-soluble organic aerosols in Delhi, India.

Delhi, among the world's most polluted megacities, is a hotspot of particulate matter emissions, with high contribution from organic aerosol (OA), affecting health and climate in the entire northern India. While the primary organic aerosol (POA) sources can be effectively identified, an incomplete source apportionment of secondary organic aerosol (SOA) causes significant ambiguity in the management of air quality and the assessment of climate change. Present study uses positive matrix factorization analysis on the water-soluble organic aerosol (WSOA) data from the offline-aerosol mass spectrometry (AMS). It revealed POA as the dominant source of WSOA, with biomass-burning OA (31-34 %) and solid fuel combustion OA (∼21 %) being two major contributors. Here we use water-solubility fingerprints to track the SOA precursors, such as oxalates or organic nitrates, instead of identifying them based on their O:C ratio. Non-fossil precursors dominate in more oxidized oxygenated organic carbon (MO-OOC) (∼90 %), a proxy for aged secondary organic carbon (SOC), by coupling offline-AMS with 14C measurements. On the contrary, the oxidation of fossil fuel emissions produces a large quantity of fresh fossil SOC, which accounts for ∼75 % of less oxidized oxygenated organic carbon (LO-OOC). Our study reveals that apart from major POA contributions, large fractions of fossil (10-14 %) and biomass-derived SOA (23-30 %) contribute significantly to the total WSOA load, having impact on climate and air quality of the Delhi megacity. Our study reveals that large-scale unregulated biomass burning was not only found to dominate in POA but was also observed to be a significant contributor to SOA with implications on human health, highlighting the need for effective control strategies.

Association Between Indication for Descemet Stripping Automated Endothelial Keratoplasty and Rural Residency.

PURPOSE: Residing in rural locations can be a barrier to health care access. This study investigated the impact of residing in rural and small town (RST) areas on Descemet stripping automated endothelial keratoplasty (DSAEK) indications and outcomes in Atlantic Canada. METHODS: A retrospective cohort analysis examined consecutive DSAEKs performed in Nova Scotia between 2017 and 2020. Patient rurality was determined by the Statistical Area Classification system developed by Statistics Canada. Univariate and multivariate logistic regression models were used to assess for factors associated with DSAEK indication, including repeat keratoplasty, RST residence status, and travel time. RESULTS: Of 271 DSAEKs during the study period, 87 (32.1%) were performed on the eyes of RST residents. The median postoperative follow-up time was 1.6 years. Undergoing DSAEK for a previous failed keratoplasty was not associated with a higher odds of RST residency (odds ratio [OR], 0.50; 95% confidence interval [CI], 0.19-1.16; P = 0.13) but was associated with travel time (OR, 0.78 for each increasing hour of travel; 95% CI, 0.61-0.99; P = 0.044). RST residency was not associated with the occurrence of graft failure (OR, 0.48; 95% CI, 0.17-1.17; P = 0.13). CONCLUSIONS: Residing in a rural area in Atlantic Canada was not associated with DSAEK graft failure. Repeat endothelial keratoplasty was associated with shorter travel time for corneal surgery but not rural residency status. Further research in this field could inform regional health strategies aimed at improving equity and accessibility to ophthalmology subspecialist care.

Bachmann-Bupp syndrome and treatment.

Bachmann-Bupp syndrome (BABS) is a neurodevelopmental disorder characterized by developmental delay, hypotonia, and varying forms of non-congenital alopecia. The condition is caused by 3'-end mutations of the ornithine decarboxylase 1 (ODC1) gene, which produce carboxy (C)-terminally truncated variants of ODC, a pyridoxal 5'-phosphate-dependent enzyme. C-terminal truncation of ODC prevents its ubiquitin-independent proteasomal degradation and leads to cellular accumulation of ODC enzyme that remains catalytically active. ODC is the first rate-limiting enzyme that converts ornithine to putrescine in the polyamine pathway. Polyamines (putrescine, spermidine, spermine) are aliphatic molecules found in all forms of life and are important during embryogenesis, organogenesis, and tumorigenesis. BABS is an ultra-rare condition with few reported cases, but it serves as a convincing example for drug repurposing therapy. α-Difluoromethylornithine (DFMO, also known as eflornithine) is an ODC inhibitor with a strong safety profile in pediatric use for neuroblastoma and other cancers as well as West African sleeping sickness (trypanosomiasis). Patients with BABS have been treated with DFMO and have shown improvement in hair growth, muscle tone, and development.

Discovery of pyrazolo[3,4-d]pyrimidines as novel mitogen-activated protein kinase kinase 3 (MKK3) inhibitors.

The dual-specificity protein kinase MKK3 has been implicated in tumor cell proliferation and survival, yet its precise role in cancer remains inconclusive. A critical step in elucidating the kinase's involvement in disease biology is the identification of potent, cell-permeable kinase inhibitors. Presently, MKK3 lacks a dedicated tool compound for these purposes, along with validated methods for the facile screening, identification, and optimization of inhibitors. In this study, we have developed a TR-FRET-based enzymatic assay for the detection of MKK3 activity in vitro and a BRET-based assay to assess ligand binding to this enzyme within intact human cells. These assays were instrumental in identifying hit compounds against MKK3 that share a common chemical scaffold, sourced from a library of bioactive kinase inhibitors. Initial hits were subsequently expanded through the synthesis of novel analogs. The resulting structure-activity relationship (SAR) was rationalized using molecular dynamics simulations against a homology model of MKK3. We expect our findings to expedite the development of novel, potent, selective, and bioactive inhibitors, thus facilitating investigations into MKK3's role in various cancers.