ApoA-I and Diabetes.

ApoA-I-the main apolipoprotein constituent of the HDL (high-density lipoprotein) fraction of human plasma-is of therapeutic interest because it has several cardioprotective functions. Recent reports have established that apoA-I also has antidiabetic properties. In addition to improving glycemic control by increasing insulin sensitivity, apoA-I improves pancreatic ß-cell function by amplifying expression of transcription factors that are essential for ß-cell survival and increasing insulin production and secretion in response to a glucose challenge. These findings indicate that increasing circulating apoA-I levels may be of therapeutic value in patients with diabetes in whom management of glycemic control is suboptimal. This review summarizes current knowledge of the antidiabetic functions of apoA-I and the mechanistic basis of these effects. It also evaluates the therapeutic potential of small, clinically relevant peptides that mimic the antidiabetic functions of full-length apoA-I and describes potential strategies for development of these peptides into innovative options for treatment of diabetes.

Impact of Impaired Cholesterol Homeostasis on Neutrophils in Atherosclerosis.

Atherosclerosis is complex chronic disease characterized by intimal cholesterol accumulation and vascular inflammation. There is a well-established relationship of hypercholesterolemia and inflammation with atherosclerosis. However, the link between inflammation and cholesterol is not completely understood. Myeloid cells, in particular, monocytes, macrophages, and neutrophils play essential roles in the pathogenesis of atherosclerotic cardiovascular disease. It is well known that macrophages accumulate cholesterol, forming foam cells, which drive atherosclerosis-associated inflammation. However, the interaction between cholesterol and neutrophils remains poorly defined-an important gap in the literature given that neutrophils represent up to 70% of total circulating leukocytes in humans. Elevated levels of biomarkers of neutrophil activation (myeloperoxidase and neutrophil extracellular traps) and higher absolute neutrophil counts are both associated with increased rates of cardiovascular events. Neutrophils contain the necessary machinery to uptake, synthesize, efflux and esterify cholesterol; yet, the functional consequence of dysregulated cholesterol homeostasis on neutrophil activity remains poorly defined. Preclinical animal data suggest a direct link between cholesterol metabolism and hematopoiesis, although current evidence in humans has been unable to corroborate such findings. This review will explore the impact of impaired cholesterol homeostasis neutrophils and draw focus on the discordant data from animal models and atherosclerotic disease in humans.

Quantum Efficiency Measurement and Modeling of Silicon Sensors Optimized for Soft X-ray Detection.

Hybrid pixel detectors have become indispensable at synchrotron and X-ray free-electron laser facilities thanks to their large dynamic range, high frame rate, low noise, and large area. However, at energies below 3 keV, the detector performance is often limited because of the poor quantum efficiency of the sensor and the difficulty in achieving single-photon resolution due to the low signal-to-noise ratio. In this paper, we address the quantum efficiency of silicon sensors by refining the design of the entrance window, mainly by passivating the silicon surface and optimizing the dopant profile of the n+ region. We present the measurement of the quantum efficiency in the soft X-ray energy range for silicon sensors with several process variations in the fabrication of planar sensors with thin entrance windows. The quantum efficiency for 250 eV photons is increased from almost 0.5% for a standard sensor to up to 62% as a consequence of these developments, comparable to the quantum efficiency of backside-illuminated scientific CMOS sensors. Finally, we discuss the influence of the various process parameters on quantum efficiency and present a strategy for further improvement.

Synthesis of sp3-rich heterocyclic frameworks by a divergent synthesis strategy.

Fragment-based lead discovery (FBLD) often relies on flat, aromatic compounds which display undesirable physicochemical properties with limited exit vectors for fragment growth. Herein, we report concise synthetic strategies to sp3-rich heterocyclic fragments encompassing polar exit vectors poised for fragment-to-lead (F2L) development.

Neonatal cutaneous inflammatory syndrome associated with homozygous epidermal growth factor receptor mutation.

The epidermal growth factor receptor (EGFR) is a transmembrane protein with tyrosine kinase signaling activity regulating many essential cellular functions, and loss of function mutations in EGFR result in a life-threatening neonatal syndrome. We present the case of a preterm boy born with intrauterine growth restriction who developed multisystem disease due to a homozygous mutation in the EGFR gene. He experienced a tumultuous and complex clinical course with recurrent skin infections and sepsis, nephrocalcinosis, failure to thrive, severe electrolyte imbalances, rectal perforation, and thrombus formation, and died after 11 months due to renal failure. This case report builds on work recently published in 2020 describing a case series of 18 similar patients and adds to the growing literature describing the severe phenotype and multisystem disease associated with loss of EGFR mutation in the Roma population.

Screening Echocardiography in Adults with Down Syndrome.

Down syndrome is the most common chromosomal disorder in the United States, occurring in about 14.14/10,000 births. It is associated with multiple medical anomalies, including cardiac, gastrointestinal, musculoskeletal, and genitourinary abnormalities, which increases the burden of morbidity for this patient population. Management is typically directed toward optimizing health and function throughout childhood and into adulthood; however, consensus regarding their management in adulthood is controversial. The burden of congenital cardiac diseases in children with trisomy 21 is well established, seen in more than 40% of cases. Although screening echocardiography is performed routinely within 1 month of birth, current consensus advocates for diagnostic echocardiography only in symptomatic adults with Down syndrome. Here, we advocate that screening echocardiography should be performed routinely in this patient population at all ages, particularly in late adolescence and early adulthood, because of a high percentage of residual cardiac defects and an increased risk of developing valvular and structural cardiac disease.

A single-dose, comparative bioavailability study comparing amphetamine extended-release oral suspension with extended-release mixed amphetamine salts capsules.

BACKGROUND: To evaluate the relative bioavailability of a single dose of amphetamine extended-release oral suspension (AMPH EROS) compared with a single dose of extended-release mixed amphetamine salts (ER MAS) in healthy, fasted adult subjects. METHODS: The study population consisted of healthy adult volunteers. The study drug used in this study was 7.5 mL of 2.5 mg/mL AMPH EROS equivalent to 18.8 mg of amphetamine base administered after an overnight fast of at least 10 hours. AMPH EROS comprises a 3.2:1 enantiomeric ratio of d-amphetamine to l-amphetamine. The reference product was one 30 mg ER MAS capsule (equivalent to 18.8 mg of amphetamine base). Relative bioavailability between the products was determined by a statistical comparison of the area under the curve and maximum concentration (Cmax) for d-amphetamine and l-amphetamine. PK (PK) blood samples were collected prior to dosing (0-hour) and at 1, 2, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 12, 14, 16, 24, 36, 48, and 60 hours after drug administration, totaling 20 samples in each period. RESULTS: The mean subject age was 35.0 (standard deviation ±8) years, and the overall study population comprised 19 (63.3%) males and 11 (36.7%) females. The contrasts for geometric mean ratios for all assessed PK parameters (for both l- and d-amphetamine) between the test article AMPH EROS and reference product ER MAS fell within the prescribed 80% to 125% limits. CONCLUSIONS: The overall PK profile of single-dose AMPH EROS 7.5 mL was found to be comparable with a single dose of oral ER MAS 30 mg.

Finding the "Sweet Spot": Sharing the decision-making in ADHD treatment selection.

BACKGROUND: Stimulants are often prescribed as first-line therapy for attention-deficit/hyperactivity disorder. Currently, there are many therapeutic options available for clinicians and families to consider when making the decision to use a medication. In practice, selection of a stimulant medication for ADHD is highly personalized and can be narrowed down to two major factors: finding the optimal duration of the medication effect, and then estimating a starting dose and subsequently "fine-tuning" the medication to the optimal dosage of the medication. With the possibility of titrating to an optimal stimulant dosage within one prescription of a liquid stimulant, prescribers can recruit the parent/caregiver to actively participate in managing the transition to medication, allowing for greater ownership and a sense of shared control over the process. CASE PRESENTATION: The short case series offers a communication method by which clinicians can apply the principles of shared decision-making in helping the parent or caregiver of a newly diagnosed patient with ADHD make informed decisions about medication selection, and to obtain a greater sense of comfort with the new medication regimen. CONCLUSIONS: Much has been published on the importance of clinicians and their patients fostering an environment of clear and unrestricted information-sharing. This short case series illustrates the effectiveness of this approach. Once parents are comfortable with the decision to start drug treatment for ADHD, it is incumbent upon the healthcare provider to ensure that an open channel of communication is maintained, and that parent/caregivers are encouraged to raise concerns as soon as possible.

Photocatalytic methods for amino acid modification.

Amino acid modification plays an important role across several fields, including synthetic organic chemistry, materials science, targeted drug delivery and the probing of biological function. Although a myriad of methods now exist for the modification of peptides or proteins, many of these target a handful of the most reactive proteinogenic amino acids. Photocatalysis has recently emerged as a mild approach for amino acid modification, generating a sizable toolbox of reactions capable of modifying almost all of the canonical amino acids. These reactions are characterised by their mild, physiologically compatible conditions, greatly enhancing their usefulness for amino acid modification. This review aims to introduce the field of photocatalytic amino acid modification and discusses the most recent advances.

Biodegradation Potential of Bacillus sp. PAH-2 on PAHs for Oil-Contaminated Seawater.

Microbial degradation is a useful tool for inhibiting or preventing polycyclic aromatic hydrocarbons (PAHs) widely distributed in marine environment after oil spill accidents. This study aimed to evaluate the potential and diversity of bacteria Bacillus sp. PAH-2 on Benzo (a) anthracene (BaA), Pyrene (Pyr), and Benzo (a) pyrene (BaP), their composite system, aromatic components system, and crude oil. The seven-day degradation rates against BaA, Pyr, and BaP were 20.6%, 12.83%, and 17.49%, respectively. Further degradation study of aromatic components demonstrated PAH-2 had a high degradation rate of substances with poor stability of molecular structure. In addition, the degradation of PAHs in crude oil suggested PAH-2 not only made good use of PAHs in such a more complex structure of pollutants but the saturated hydrocarbons in the crude oil also showed a good application potential.

Outcomes in unilateral primary aldosteronism after surgical or medical therapy.

CONTEXT: Studies find surgery superior to medications in the treatment of primary aldosteronism (PA). It would be ideal to compare surgical and medical therapy in patients with unilateral PA only, who have the option between these treatment modalities. However, this is challenging as most patients with unilateral PA on adrenal vein sampling (AVS) undergo surgery. OBJECTIVE: To compare outcomes of surgery and medications in patients with confirmed or likely unilateral PA. DESIGN: Retrospective cohort study of 274 patients with PA managed at two referral centres from 2000 to 2019. PATIENTS: 154 patients identified with unilateral PA using AVS and a validated clinical prediction model were treated with surgical (n = 86) or medical (n = 68) therapy. MEASUREMENTS: Primary outcome was a composite incident cardiovascular event comprising acute myocardial infarction, coronary revascularization, stroke, atrial fibrillation or congestive cardiac failure. Secondary outcomes were clinical and biochemical control. RESULTS: Cardiovascular outcomes were comparable, with the surgery group having an adjusted hazard ratio of 0.93 (95% CI: 0.32-2.67), p = .89. Both treatments improved clinical and biochemical control, but surgery resulted in better systolic blood pressure, 133.0 ± 11.7 mmHg versus 137.9 ± 14.6 mmHg, p = .02, and lower defined daily dosages of antihypertensive medications, 1.0 (IQR 0.0-2.0) versus 2.6 (IQR 0.8-4.3), p < .001. In addition, 12 of 86 patients in the surgery group failed medical therapy before opting for surgery. CONCLUSION: In patients with unilateral PA who can tolerate medications, medical therapy improves clinical and biochemical control, and may offer similar cardiovascular protection. However, surgery reduces pill burden, may cure hypertension and is recommended for unilateral PA.

Strategies for the Diversity-Oriented Synthesis of Macrocycles.

Macrocycles have long been recognized as useful chemical entities for medicine, with naturally occurring and synthetic macrocycles clinically approved for use as prescription drugs. Despite this promise, the synthesis of collections of macrocycles has been historically challenging due to difficulties in the formation of large rings. Diversity-Oriented Synthesis (DOS) emerged in the early 2000s as a powerful strategic solution to the construction of diverse molecular libraries. This review details the various strategies developed within the field of DOS for the synthesis of macrocycle libraries, utilizing modern synthetic methodology to deliver structurally diverse collections of macrocyclic molecules, and the exploration of their therapeutic potential. Section 1 of this work details the use of algorithmic strategies and is divided into Build/Couple/Pair, Advanced Build/Couple/Pair, Initiate/Propagate/Terminate, Fragment-Based Domain Shuffling, Two-Directional Synthesis, and Successive Ring Expansion. Section 2 covers strategies based on ring distortion reactions, including Sequential Cycloaddition/Fragmentation, Ring Expansions, and Miscellaneous.

Soil lead (Pb) and urban grown lettuce: Sources, processes, and implications for gardener best management practices.

Urban community gardeners employ a range of best practices that limit crop contamination by toxicants like lead (Pb). While Pb root uptake is generally low, the relative significance of various Pb deposition processes and the effectiveness of best practices in reducing these processes have not been sufficiently characterized. This study compared leafy lettuce (Lactuca sativa) grown in high Pb (1150 mg/kg) and low Pb (90 mg/kg) soils, under three different soil cover conditions: 1) bare soil, 2) mulch cover to limit splash, and 3) mulch cover under hoophouses to limit splash and air deposition, in a New York City (NYC) community garden and a rural site in Ithaca, New York (NY). The lettuces were further compared to greenhouse (Ithaca) and supermarket (NYC) samples. Atmospheric deposition was monitored by passive trap collection through funnel samplers. Results show that in low Pb soils, splash and atmospheric deposition accounted for 84 and 78% of lettuce Pb in NYC and Ithaca, respectively. In high Pb soils, splash and atmospheric deposition accounted for 88 and 93% of Pb on lettuces, with splash being the dominant mechanism. Soil covers were shown to be effective at significantly (p < 0.05) reducing lettuce Pb contamination, and mulching is strongly recommended as a best practice.

Recurrent Losses and Rapid Evolution of the Condensin II Complex in Insects.

Condensins play a crucial role in the organization of genetic material by compacting and disentangling chromosomes. Based on studies in a few model organisms, the condensins I and II complexes are considered to have distinct functions, with the condensin II complex playing a role in meiosis and somatic pairing of homologous chromosomes in Drosophila. Intriguingly, the Cap-G2 subunit of condensin II is absent in Drosophila melanogaster, and this loss may be related to the high levels of chromosome pairing seen in flies. Here, we find that all three non-SMC subunits of condensin II (Cap-G2, Cap-D3, and Cap-H2) have been repeatedly and independently lost in taxa representing multiple insect orders, with some taxa lacking all three. We also find that all non-Dipteran insects display near-uniform low-pairing levels regardless of their condensin II complex composition, suggesting that some key aspects of genome organization are robust to condensin II subunit losses. Finally, we observe consistent signatures of positive selection in condensin subunits across flies and mammals. These findings suggest that these ancient complexes are far more evolutionarily labile than previously suspected, and are at the crossroads of several forms of genomic conflicts. Our results raise fundamental questions about the specific functions of the two condensin complexes in taxa that have experienced subunit losses, and open the door to further investigations to elucidate the diversity of molecular mechanisms that underlie genome organization across various life forms.

Single-dose pharmacokinetics of amphetamine extended-release tablets compared with amphetamine extended-release oral suspension.

OBJECTIVE: Evaluate the relative bioavailability of single-dose amphetamine extended-release tablet (AMPH ER TAB) 20 mg, swallowed whole or chewed, and amphetamine extended-release oral suspension (AMPH EROS) 2.5 mg/mL; evaluate food effect on AMPH ER TAB. METHODS: Healthy volunteers (18-55 years) were randomized to 1 dose of AMPH ER TAB 20 mg swallowed (fasted), chewed (fed/fasted), or 20 mg AMPH EROS (fasted). A crossover study design was used. Plasma samples were collected each period predose and at time points to 60 hours postdose. d- and l-amphetamine were measured and pharmacokinetic (PK) was calculated (90% confidence intervals of the ratios of the plasma levels) for AUC0-t, AUC0-∞, and Cmax. Comparative relative bioavailability between formulations was determined when ratios were within 80% and 125%. Safety was also assessed. RESULTS: Thirty-two subjects completed the study. AMPH ER TAB swallowed versus AMPH EROS (fasted): for d- and l-amphetamine, the total and peak exposure was similar: d: AUC0-t: 100.68% to 108.08%, AUC0-∞: 101.47% to 109.52%, Cmax: 98.10% to 103.17%; l: AUC0-t: 100.31% to 108.57%, AUC0-∞: 101.27% to 111.09%, Cmax: 98.2% to 103.37%. For d- and l-amphetamine when the tablet is swallowed whole, Tmax was 5.00 hours (with a range of 2.00-9.00 hours). AMPH ER TAB chewed versus AMPH EROS (fasted): for d- and l-amphetamine, the total and peak exposure was similar: d: AUC0-t: 99.23% to 106.62%, AUC0-∞: 99.58% to 107.59%, Cmax: 99.91% to 105.14%; l: AUC0-t: 98.16% to 106.35%, AUC0-∞: 98.44% to 108.11%, Cmax: 99.53% to 104.75%. For d- and l-amphetamine when the tablet has been chewed, Tmax was 5.00 hours (with a range of 3.00-7.00 hours). PK results were similar for patients in the fasted and fed groups, indicative of no presence of food effect. No serious adverse events (AEs) were reported, overall AE profiles between the tablet and oral suspension were comparable without any unanticipated safety concerns. CONCLUSIONS: Single doses of AMPH ER TAB for both d- and l-amphetamine demonstrated comparable bioavailability to a 20 mg dose of AMPH EROS, 2.5 mg/mL under fasted conditions when chewed and swallowed whole, and demonstrated equivalent peak and overall exposure without apparent food effect. AMPH ER TAB was well-tolerated and consistent with adverse events noted in other amphetamine formulations.

How to Design AI for Social Good: Seven Essential Factors.

The idea of artificial intelligence for social good (henceforth AI4SG) is gaining traction within information societies in general and the AI community in particular. It has the potential to tackle social problems through the development of AI-based solutions. Yet, to date, there is only limited understanding of what makes AI socially good in theory, what counts as AI4SG in practice, and how to reproduce its initial successes in terms of policies. This article addresses this gap by identifying seven ethical factors that are essential for future AI4SG initiatives. The analysis is supported by 27 case examples of AI4SG projects. Some of these factors are almost entirely novel to AI, while the significance of other factors is heightened by the use of AI. From each of these factors, corresponding best practices are formulated which, subject to context and balance, may serve as preliminary guidelines to ensure that well-designed AI is more likely to serve the social good.

Artificial Intelligence Crime: An Interdisciplinary Analysis of Foreseeable Threats and Solutions.

Artificial intelligence (AI) research and regulation seek to balance the benefits of innovation against any potential harms and disruption. However, one unintended consequence of the recent surge in AI research is the potential re-orientation of AI technologies to facilitate criminal acts, term in this article AI-Crime (AIC). AIC is theoretically feasible thanks to published experiments in automating fraud targeted at social media users, as well as demonstrations of AI-driven manipulation of simulated markets. However, because AIC is still a relatively young and inherently interdisciplinary area-spanning socio-legal studies to formal science-there is little certainty of what an AIC future might look like. This article offers the first systematic, interdisciplinary literature analysis of the foreseeable threats of AIC, providing ethicists, policy-makers, and law enforcement organisations with a synthesis of the current problems, and a possible solution space.

Metagenomic and metatranscriptomic responses of natural oil degrading bacteria in the presence of dispersants.

Oil biodegradation has been extensively studied in the wake of the deepwater horizon spill, but the application of dispersant to oil spills in marine environments remains controversial. Here, we report metagenomic (MG) and metatranscriptomic (MT) data mining from microcosm experiments investigating the oil degrading potential of Canadian west and east coasts to estimate the gene abundance and activity of oil degrading bacteria in the presence of dispersant. We found that the addition of dispersant to crude oil mainly favours the abundance of Thalassolituus in the summer and Oleispira in the winter, two key natural oil degrading bacteria. We found a high abundance of genes related not only to n-alkane and aromatics degradation but also associated with transporters, two-component systems, bacterial motility, secretion systems and bacterial chemotaxis.

Potential for Microbially Mediated Natural Attenuation of Diluted Bitumen on the Coast of British Columbia (Canada).

Western Canada produces large amounts of bitumen, a heavy, highly weathered crude oil. Douglas Channel and Hecate Strait on the coast of British Columbia are two water bodies that may be impacted by a proposed pipeline and marine shipping route for diluted bitumen (dilbit). This study investigated the potential of microbial communities from these waters to mitigate the impacts of a potential dilbit spill. Microcosm experiments were set up with water samples representing different seasons, years, sampling stations, and dilbit blends. While the alkane fraction of the tested dilbit blends was almost completely degraded after 28 days, the majority of the polycyclic aromatic hydrocarbons (PAHs) remained. The addition of the dispersant Corexit 9500A most often had either no effect or an enhancing effect on dilbit degradation. Dilbit-degrading microbial communities were highly variable between seasons, years, and stations, with dilbit type having little impact on community trajectories. Potential oil-degrading genera showed a clear succession pattern and were for the most part recruited from the "rare biosphere." At the community level, dispersant appeared to stimulate an accelerated enrichment of genera typically associated with hydrocarbon degradation, even in dilbit-free controls. This suggests that dispersant-induced growth of hydrocarbon degraders (and not only increased bioavailability of oil-associated hydrocarbons) contributes to the degradation-enhancing effect previously reported for Corexit 9500A.IMPORTANCE Western Canada hosts large petroleum deposits, which ultimately enter the market in the form of dilbit. Tanker-based shipping represents the primary means to transport dilbit to international markets. With anticipated increases in production to meet global energy needs, the risk of a dilbit spill is expected to increase. This study investigated the potential of microbial communities naturally present in the waters of a potential dilbit shipping lane to mitigate the effects of a spill. Here we show that microbial degradation of dilbit was mostly limited to n-alkanes, while the overall concentration of polycyclic aromatic hydrocarbons, which represent the most toxic fraction of dilbit, decreased only slightly within the time frame of our experiments. We further investigated the effect of the oil dispersant Corexit 9500A on microbial dilbit degradation. Our results highlight the fact that dispersant-associated growth stimulation, and not only increased bioavailability of hydrocarbons and inhibition of specific genera, contributes to the overall effect of dispersant addition.

Cycloaddition Strategies for the Synthesis of Diverse Heterocyclic Spirocycles for Fragment-Based Drug Discovery.

In recent years the pharmaceutical industry has benefited from the advances made in fragment-based drug discovery (FBDD) with more than 30 fragment-derived drugs currently marketed or progressing through clinical trials. The success of fragment-based drug discovery is entirely dependent upon the composition of the fragment screening libraries used. Heterocycles are prevalent within marketed drugs due to the role they play in providing binding interactions; consequently, heterocyclic fragments are important components of FBDD libraries. Current screening libraries are dominated by flat, sp2-rich compounds, primarily owing to their synthetic tractability, despite the superior physicochemical properties displayed by more three-dimensional scaffolds. Herein, we report step-efficient routes to a number of biologically relevant, fragment-like heterocyclic spirocycles. The use of both electron-deficient and electron-rich 2-atom donors was explored in complexity-generating [3+2]-cycloadditions to furnish products in 3 steps from commercially available starting materials. The resulting compounds were primed for further fragment elaboration through the inclusion of synthetic handles from the outset of the syntheses.