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Study was conducted for six weeks on 240, day-old Cobb-430Y strain broiler chicks randomly assigned to four groups (60 chicks per group) containing three replicates. Group 'A' was Negative Control (NC) contained 3% low protein (LP) than Positive Control (PC) group 'B'. Group B contained normal protein (NP) [22.50, 21.00, and 19.50% CP for broiler pre-starter (BPS), starter (BS) and finisher (BF) phases, respectively] as per strain requirement. Group 'C' (NC+Gly1) was formed by adding 0.640, 0.810, and 0.630% L-Glycine in NC diet to arrive 2.30, 2.30, and 2.00% Digestible (Dig.) Gly + Ser levels, while group 'D' (NC+Gly2) was formed by adding 0.755, 0.985, and 0.740% L-Glycine in NC diet to arrive 2.40, 2.40, and 2.10% Dig. Gly + Ser levels in BPS, BS, and BF diets, respectively. Dig. Gly + Ser levels of NC group were 1.71, 1.56, and 1.43%; and of PC group were 2.02, 1.91, and 1.76%, respectively, for BPS, BS and BF diets. Ratio of Dig. Met, Thr, Trp, Arg, and Val. to Lys. were balanced (AA-balanced) in all diets. All diets were isocaloric (3010, 3100, and 3200 Kcal ME/kg feed for BPS, BS, and BF, respectively). Results showed that the L-Glycine supplementation in AA-balanced 3% LP diet significantly (p=0.05) improved overall BW, WG, and FCR in broilers. Dig. Gly + Ser levels of 2.30, 2.30, and 2.00% in AA-balanced 3% LP diets (0.640, 0.810, and 0.630% L-Glycine) in BPS, BS, and BF phases, respectively, were found to be cost-effective for improving BW, WG, and FCR with less feed intake. Study concludes that the L-Glycine is recommended to maintain Dig. Gly + Ser levels of 2.30, 2.30, and 2.00% in BPS, BS, and BF phases for cost-effective formulation with a reduction of 3% CP in a standard commercial broiler diet. [ABSTRACT FROM AUTHOR]

Prior studies show visual (Cherenkov light) and olfactory sensations can occur while radiation to head, neck, and brain is on. However, few studies examine a wider range of sensations and compare sensations experienced between photon and proton radiation. The present IRB-approved study evaluates the relationship between radiation site, radiation type, and sensation experienced. We hypothesized that the rates and qualities of sensations vary to treatment site and radiation modality. Subjects were consentable English-speaking patients ≥ 18 years old. During their radiation course, they completed a survey regarding the presence and quality of sensations. Type and anatomic site of radiation (proton or photon) was collected from medical records. Radiation site was categorized as head, neck, brain (HNB), other radiation site (ORS, which included thorax, breast, abdomen, pelvis and extremity), or total body (TBI). Sensation was categorized as visual, olfactory, skin, or other. Linear regressions were used to determine the respective relationships between radiation site and type with sensation. Chi squared analyses assessed differences in incidences of sensations between groups of patients. 201 subjects participated, including 96 proton patients, 84 non-TBI photon patients, and 21 TBI patients. 41% of subjects reported ≥ 1 sensation, including 62% of HNB, 26% of TBI, and 60% of TBI. The HNB and TBI patients differed in the rates of visual sensations (45% vs 14%, P = 0.012), and skin/other sensations (25% vs 48%, P = 0.046, but not in olfactory sensations (31% vs 14%, P = 0.18)). There was a significant relationship between radiation site and sensation (P < 0.001), with the odds of sensation during HNB and TBI radiation being 4.33 (95% CI = [2.27 to 8.29]), and 3.61 (95% CI = [1.39-9.41]), respectively, compared to ORS patients. There was also a significant relationship between type of radiation and sensation (P = 0.035), with there being 1.84 times higher odds of experiencing sensation during proton therapy than photon therapy (95% CI = [1.04-3.04]). Patients frequently experience sensations while external beam radiation is on, but the rates and types of sensations varied by site treated and modality of radiation. Radiation oncologists should counsel patients that they may experience these sensations. [ABSTRACT FROM AUTHOR]

To describe left anterior descending coronary artery (LAD) and heart dosimetry in patients with left-side breast cancer undergoing adjuvant hypo-fractionated whole breast irradiation with a concomitant boost with a dedicated prone position cardiac-sparing protocol. In a consecutive series of 524 women, LAD and heart doses were reviewed from their radiation treatment plans retrospectively. For all patients, the setup was in the prone position and the medial edge of the breast tangents was placed at least 2.5 mm from the contoured LAD. A descriptive variables statistical analysis was performed. The Spearman's coefficients and linear regression models were applied to explore correlations between LAD and heart doses with breast and boost volumes. For LAD dosimetry, the mean values for Dmean, Dmax, and D2% were 2.20 Gy, 4.44 Gy, 3.57 Gy, respectively. For heart dosimetry, the mean values for Dmean, Dmax and D2% were 0.69 Gy, 7.92 Gy, 2.35 Gy, respectively. The mean volumes for PTV-breast and PTV-boost were 699.6 cc and 110.8 cc, respectively. No correlations were found among the cardiac dosimetry indices and breast/boost volumes. A linear relationship was found between Heart D2% and LAD Dmean, LAD D2% and LAD Dmax. A constraint of maintaining the Heart D2% dose less than 3 Gy achieved a LAD Dmean, LAD D2% and LAD Dmax less than 2.77, 4.36 and 5.16 Gy, respectively. A dedicated prone position cardiac-sparing protocol for hypo-fractionated breast irradiation minimizes LAD and heart exposure, regardless of individual body conformation and treatment volumes. The approach results in dosimetry superior or equivalent to that of more complex and costly radiotherapy techniques. Keeping the medial edge of the breast tangents at least 2.5 mm from the contoured LAD while limiting Heart D2% dose to <3 Gy will best prevent long term radiation associated cardiotoxicity. [ABSTRACT FROM AUTHOR]

While reactive oxygen species (ROS) have long been known to drive aging and neurodegeneration, their persistent depletion below basal levels also disrupts organismal function. Cells counteract loss of basal ROS via the reductive stress response, but the identity and biochemical activity of ROS sensed by this pathway remain unknown. Here, we show that the central enzyme of the reductive stress response, the E3 ligase Cullin 2-FEM1 homolog B (CUL2 FEM1B ), specifically acts at mitochondrial TOM complexes, where it senses ROS produced by complex III of the electron transport chain (ETC). ROS depletion during times of low ETC activity triggers the localized degradation of CUL2 FEM1B substrates, which sustains mitochondrial import and ensures the biogenesis of the rate-limiting ETC complex IV. As complex III yields most ROS when the ETC outpaces metabolic demands or oxygen availability, basal ROS are sentinels of mitochondrial activity that help cells adjust their ETC to changing environments, as required for cell differentiation and survival., Competing Interests: Declaration of interests M.R. is a cofounder and SAB member of Nurix, Zenith, and Lyterian Therapeutics; SAB member for Vicinitas Therapeutics; and iPartner at The Column Group. J.K. is cofounder and SAB member of Nurix. L.P., C.R., and B.B. are employees of Genentech., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of interest: None.

In all biological systems, DNA is under high mechanical stress from bending and twisting. For example, DNA is tightly bent in nucleosome complexes, virus capsids, bacterial chromosomes, or complexes with transcription factors that regulate gene expression. A structurally and mechanically accurate model of DNA is therefore necessary to understand some of the most fundamental molecular mechanisms in biology including DNA packaging, replication, transcription and gene regulation. An iconic feature of DNA is its double helical nature with an average repeat h 0 of ~10.45 base pairs per turn, which is commonly believed to be independent of curvature. We developed a ligation assay on nicked DNA circles of variable curvature that reveals a strong unwinding of DNA to over 11 bp/turn for radii around 3-4 nm. Our work constitutes a major modification of the standard mechanical model of DNA and requires reassessing the molecular mechanisms and energetics of all processes involving tightly bent DNA., Competing Interests: Competing interests: Authors declare that they have no competing interests.

Macrocyclic natural products, particularly those with no functionalities except unsaturation, are recognized for their therapeutic potential but are notoriously challenging to synthesize. In this study, we report the first total synthesis of an unconventional 18-membered, C 25 macrocyclic terpenoid, which has demonstrated substantial immunosuppressive activity. This synthesis was achieved through strategic modifications and innovative reaction engineering, utilizing α-terpineol and geraniol as starting materials, highlighting a novel approach in macrocyclic terpenoid synthesis.

Biallelic variants in SUMF1 are associated with multiple sulfatase deficiency (MSD), a rare lysosomal storage disorder typically diagnosed in early infancy or childhood, marked by severe neurodegeneration and early mortality. We present clinical and molecular characterisation of three unrelated patients aged 13 to 58 years with milder clinical manifestations due to SUMF1 disease variants, including two adult patients presenting with apparent non-syndromic retinal dystrophy. Whole genome sequencing identified biallelic SUMF1 variants in all three patients; Patient 1 homozygous for a complex allele c.[290G>T;293T>A]; p.[(Gly97Val);(Val98Glu)], Patient 2 homozygous for c.866A>G; p.(Tyr289Cys), and Patient 3 compound heterozygous for c.726-1G>C and p.(Tyr289Cys). Electroretinography indicated a rod-cone dystrophy with additional possible inner retinal dysfunction in all three patients. Biochemical studies confirmed reduced, but not absent, sulfatase enzyme activity in the absence of extra-ocular disease (Patient 1) or only mild systemic disease (Patients 2, 3). These cases are suggestive that non-null SUMF1 genotypes can cause an attenuated clinical phenotype, including retinal dystrophy without systemic complications, in adulthood., (© 2024 The Author(s). Clinical Genetics published by John Wiley & Sons Ltd.)

Coronary artery anomalies encompass a spectrum of congenital abnormalities affecting the origin, course, or termination of the major epicardial coronary arteries. Despite their rarity, coronary artery anomalies represent a significant burden on cardiovascular health due to their potential to disrupt myocardial blood flow and precipitate adverse cardiac events. While historically diagnosed postmortem, the widespread availability of imaging modalities has led to an increased recognition of coronary artery anomalies, particularly in adults. This review synthesizes current knowledge on the classification, mechanisms, and clinical implications of coronary anomalies, focusing on prevalent variants with significant clinical impact. We discuss strategies for medical and surgical management, as well as contemporary screening recommendations, acknowledging the evolving understanding of these anomalies. Given the breadth of possible variants and the limited data on some presentations, this review provides a framework to aid clinicians in the recognition and management of coronary anomalies, with a particular emphasis on their stratification by anatomical location. By consolidating existing knowledge and highlighting areas of uncertainty, this review aims to enhance clinical decision-making and improve outcomes for individuals with coronary anomalies., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Biallelic variants in USH2A are associated with retinitis pigmentosa (RP) and Type 2 Usher Syndrome (USH2), leading to impaired vision and, additionally, hearing loss in the latter. Although the introduction of next-generation sequencing into clinical diagnostics has led to a significant uplift in molecular diagnostic rates, many patients remain molecularly unsolved. It is thought that non-coding variants or variants of uncertain significance contribute significantly to this diagnostic gap. This study aims to demonstrate the clinical utility of the reverse transcription-polymerase chain reaction (RT-PCR)-Oxford Nanopore Technology (ONT) sequencing of USH2A mRNA transcripts from nasal epithelial cells to determine the splice-altering effect of candidate variants. Five affected individuals with USH2 or non-syndromic RP who had undergone whole genome sequencing were recruited for further investigation. All individuals had uncertain genotypes in USH2A , including deep intronic rare variants, c.8682-654C>G, c.9055+389G>A, and c.9959-2971C>T; a synonymous variant of uncertain significance, c.2139C>T; p.(Gly713=); and a predicted loss of function duplication spanning an intron/exon boundary, c.3812-3&#95;3837dup p.(Met1280Ter). In silico assessment using SpliceAI provided splice-altering predictions for all candidate variants which were investigated using ONT sequencing. All predictions were found to be accurate; however, in the case of c.3812-3&#95;3837dup, the outcome was a complex cryptic splicing pattern with predominant in-frame exon 18 skipping and a low level of exon 18 inclusion leading to the predicted stop gain. This study detected and functionally characterised simple and complex mis-splicing patterns in USH2A arising from previously unknown deep intronic variants and previously reported variants of uncertain significance, confirming the pathogenicity of the variants.

Background: Coronary artery disease (CAD) is a highly prevalent condition which can lead to myocardial ischemia as well as acute coronary syndrome. Early diagnosis of CAD can improve patient outcomes through guiding risk factor modification and treatment modalities., Summary: Testing for CAD comes with increased cost and risk; therefore, physicians must determine which patients require testing, and what testing modality will offer the most useful data to diagnose patients with CAD. Patients should have an initial risk stratification for pretest probability of CAD based on symptoms and available clinical data. Patients with a pretest probability less than 5% should receive no further testing, while patients with a high pretest probability should be considered for direct invasive coronary angiography. In patients with a pretest probability between 5 and 15%, coronary artery calcium score and or exercise electrocardiogram can be obtained to further risk stratify patients to low-risk versus intermediate-high-risk. Intermediate-high-risk patients should be tested with coronary computed tomography angiography (preferred) versus positron emission tomography or single photon emission computed tomography based on their individual patient characteristics and institutional availability., Key Messages: This comprehensive review aimed to describe the available CAD testing modalities, detail their risks and benefits, and propose when each should be considered in the evaluation of a patient with suspected CAD., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

A practical and efficient synthesis of the C8-C23 fragment of antarlides A-H, incorporating six stereocenters and a conjugated diene, is reported. A strategic combination of synthetic methods, including CBS reduction, Evans' aldol reaction, Keck-Maruoka allylation, and enzymatic resolution, enabled the selective introduction of these stereocenters. Furthermore, the pivotal coupling of key fragments is successfully executed through a Julia-Kocienski olefination reaction, connecting the C8-C14 and C15-C23 subunits.

An aryne annulation strategy for the synthesis of fused carbazoles is developed using indolyl β-ketonitrile in a cascade manner. The reaction sequence involves aryne-mediated [2 + 2] cycloaddition cleavage and intramolecular Michael addition, followed by oxidation under transition-metal-free reaction conditions. Subsequently, conversion of benzo[ b ]carbazole-6-carbonitrile to carbazole quinone is observed upon prolongation of the reaction time. Furthermore, these materials exhibit high quantum efficiency, which promotes the light-emitting diode applications.

Rational design of unnatural amino acid building blocks capable of stabilizing predictable secondary structures similar to protein fragments is pivotal for foldamer chemistry/catalysis. Here, we introduce novel β-amino acid building blocks: [1S,2R,4R]exoCDA and [1S,2S,4R]endoCDA, derived from the abundantly available R(+)-camphor, which is traditionally known for its medicinal value. Further, we demonstrate that the homooligomers of exoCDA adopt 6-strand conformation, which switches to a robust 10/12-helix simply by inserting flexible β-hGly spacer at alternate positions (1 : 1 β-hGly/exoCDA heterooligomers), as evident by DFT-calculations, solution-state NMR spectroscopy and X-ray crystallography. To the best of our knowledge, this is the first example of crystalline-state structure of left-handed 10/12-mixed helix, that is free from the conventional approach of employing β-amino acids of either alternate chirality or alternate β 2 /β 3 substitutions, to access the 10/12-helix. The results also show that the homooligomers of heterochiral exoCDA don't adopt helical fold, instead exhibit banana-shaped strands, whereas the homodimers of the other diastereomer endoCDA, nucleate 8-membered turns. Furthermore, the homo-exoCDA and hetero-[β-hGly-exoCDA] oligomers are found to exhibit self-association properties with distinct morphological features. Overall, the results offer new possibilties of constructing discrete stable secondary and tertiary structures based on CDAs, which can accommodate flexible residues with desired side-chain substitutions., (© 2024 GDCh.)

Researchers over the past ∼200 years have accomplished the synthesis of simple to very complex molecules; however, the concept of ideal synthesis has still not reached maturity. Of late, the "Net Zero" concept has captured the imagination of many fields of technology, in tune with Ideal Synthesis. The current Viewpoint covers the principles of ideal synthesis being discussed in the literature and how one could take up the synthesis of organic molecules considering the Net Zero concept to make this central science well-accepted by critics of this important field., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

The number of applications of self-assembled deoxyribonucleic acid (DNA) origami nanoparticles (DNA NPs) has increased drastically, following the development of a variety of single-stranded template DNA (ssDNA) that can serve as the scaffold strand. In addition to viral genomes, such as M13 bacteriophage and lambda DNAs, enzymatically produced ssDNA from various template sources is rapidly gaining traction and being applied as the scaffold for DNA NP preparation. However, separating fully formed DNA NPs that have custom scaffolds from crude assembly mixes is often a multistep process of first separating the ssDNA scaffold from its enzymatic amplification process and then isolating the assembled DNA NPs from excess precursor strands. Only then is the DNA NP sample ready for downstream characterization and application. In this work, we highlight a single-step purification of custom sequence- or M13-derived scaffold-based DNA NPs using photocleavable biotin tethers. The process only requires an inexpensive ultraviolet (UV) lamp, and DNA NPs with up to 90% yield and high purity are obtained. We show the versatility of the process in separating two multihelix bundle structures and a wireframe polyhedral architecture.

A novel one-pot protocol that enables sequential execution of an aza-Piancatelli rearrangement and a Conia-ene type reaction has been developed under Lewis acid catalysis. Here, a combination of B(C 6 F 5 ) 3 and Cu(OTf) 2 , triethylamine, and triphenylphosphine yielded a wide range of cis -fused cyclopentenone-pyrrolidine scaffolds in one pot with good yields and diastereoselectivity.

An efficient functionalization of tyrosine residues in phenolic regions is achieved under metal-free conditions. The strategy involves the conversion of a tyrosine residue to 4-amino phenylalanine or 4-amino-3-methoxy phenylalanine in short peptides through a controlled oxidative dearomatization. This transformation is achieved in one pot with good yields and excellent regioselectivity. Consequently, the self-assembly of the peptide compounds has been studied at the nanoscopic level before and after functionalization. The results suggest that the peptide derivatives comprising amide groups promote intermolecular H-bonding interactions and the difference in -OH and -NH 2 functional groups is found to be responsible for the morphological changes. Morphological transitions from 1D nanowires to 2D nanosheets were observed during functional group modification.

Technological advancements in organic chemistry cannot be imagined without solvents, an essential evil due to well-recognized safety, health, and environmental risks and yet an integral part of the value chain for almost all industrially manufactured products intended for human use. A solvent serves as an essential liquid medium for different molecules to interact and react, generating products totally different from the original reactants. Reminiscences reveal water to be the first solvent used in the art of organic chemistry. This Viewpoint attempts to capture anecdotal theories and evidence on the use of this "magic liquid" and the progressive adoption of alternative liquid solvents, which have played a pivotal role in the evolution of synthetic organic chemistry. Synthetic organic chemistry, in turn, has sought to compete with nature in mimicking complex natural product syntheses in the laboratory on miniscule time scales compared with millions of years of evolutionary processes., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Functional coronary angiography (FCA) is a novel modality for assessing the physiology of coronary lesions, going beyond anatomical visualization by traditional coronary angiography. FCA incorporates indices like fractional flow reserve (FFR) and instantaneous wave-free ratio (IFR), which utilize pressure measurements across coronary stenoses to evaluate hemodynamic impacts and to guide revascularization strategies. In this review, we present traditional and evolving modalities and uses of FCA. We will also evaluate the existing evidence and discuss the applicability of FCA in various clinical scenarios. Finally, we provide insight into emerging evidence, current challenges, and future directions in FCA.

Background: Percutaneous Hepatic Perfusion (PHP) is a liver directed regional therapy recently FDA approved for metastatic uveal melanoma to the liver involving percutaneous isolation of liver, saturation of the entire liver with high-dose chemotherapy and filtration extracorporeally though in line filters and veno-venous bypass. The procedure is associated with hemodynamic shifts requiring hemodynamic support and blood product resuscitation due to coagulopathy., Objective: To assess the cardiac safety and subsequent clinically significant sequalae of this therapy., Methods: Consecutive PHP procedures done at our center between 2010-2022 were assessed retrospectively. Cardiac risk factors, post procedural cardiac enzymes, electrocardiograms, and transthoracic echocardiograms along with 90-day cardiac outcomes were reviewed. All data were reviewed by cardio-oncologists at our institution., Results: Of 37 patients reviewed, mean age was 63 years and 57% were women. 132 procedures were performed with an average of 3.57 procedures per patient. 68.6% of patients had elevated troponin during at least 1 procedure. No patients were found to have acute coronary syndrome, heart failure, unstable arrhythmias, or cardiac death. No patients had notable echocardiographic changes. 10.8% of patients with positive troponin had asymptomatic transient electrocardiographic changes not meeting criteria for myocardial infarction. One patient had non-sustained ventricular tachycardiac intra-operatively which did not recur subsequently. Three patients died from non-cardiac causes within 90-days. There was no oncology treatment interruption, even in those with troponin elevation. In multivariable analysis, a history of hyperlipidemia was a predictor of postoperative troponin elevation. ( P = .042)., Conclusion: Percutaneous Hepatic Perfusion is safe and associated with a transient, asymptomatic troponin elevation peri-operatively without major adverse cardiac events at 90 days. The observed troponin elevation is likely secondary to coronary demand-supply mismatch related to procedural hemodynamic shifts, hypotension, and anemia., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.