Impact of the Acetyl Group on Cysteine: A Study of N-Acetyl-Cysteine through Rotational Spectroscopy.

Herein, we report a spectroscopic study of N-acetyl-L-cysteine, an important antioxidant drug, using Fourier-transform microwave techniques and in isolated conditions. Two conformers are observed, where most stable structure adopts a cis disposition, and the second conformer has a lower abundance and adopts a trans disposition. The rotational constants and the barriers to methyl internal rotation are determined for each conformer, allowing a precise conformation identification. The results show that the cis form adopts an identical structure in the crystal, solution, and gas phases. Additionally, the structures are contrasted against those of cysteine.

Telomere and subtelomere high polymorphism might contribute to the specificity of homologous recognition and pairing during meiosis in barley in the context of breeding.

Barley (Hordeum vulgare) is one of the most popular cereal crops globally. Although it is a diploid species, (2n = 2x = 14) the study of its genome organization is necessary in the framework of plant breeding since barley is often used in crosses with other cereals like wheat to provide them with advantageous characters. We already have an extensive knowledge on different stages of the meiosis, the cell division to generate the gametes in species with sexual reproduction, such as the formation of the synaptonemal complex, recombination, and chromosome segregation. But meiosis really starts with the identification of homologous chromosomes and pairing initiation, and it is still unclear how chromosomes exactly choose a partner to appropriately pair for additional recombination and segregation. In this work we present an exhaustive molecular analysis of both telomeres and subtelomeres of barley chromosome arms 2H-L, 3H-L and 5H-L. As expected, the analysis of multiple features, including transposable elements, repeats, GC content, predicted CpG islands, recombination hotspots, G4 quadruplexes, genes and targeted sequence motifs for key DNA-binding proteins, revealed a high degree of variability both in telomeres and subtelomeres. The molecular basis for the specificity of homologous recognition and pairing occurring in the early chromosomal interactions at the start of meiosis in barley may be provided by these polymorphisms. A more relevant role of telomeres and most distal part of subtelomeres is suggested.

Prognostic Value of Cardiac MRI and FDG PET in Cardiac Sarcoidosis: A Systematic Review and Meta-Analysis.

Background There is no consensus regarding the relative prognostic value of cardiac MRI and fluorodeoxyglucose (FDG) PET in cardiac sarcoidosis. Purpose To perform a systematic review and meta-analysis of the prognostic value of cardiac MRI and FDG PET for major adverse cardiac events (MACE) in cardiac sarcoidosis. Materials and Methods In this systematic review, MEDLINE, Ovid Epub, CENTRAL, Embase, Emcare, and Scopus were searched from inception until January 2022. Studies that evaluated the prognostic value of cardiac MRI or FDG PET in adults with cardiac sarcoidosis were included. The primary outcome of MACE was assessed as a composite including death, ventricular arrhythmia, and heart failure hospitalization. Summary metrics were obtained using random-effects meta-analysis. Meta-regression was used to assess covariates. Risk of bias was assessed using the Quality in Prognostic Studies, or QUIPS, tool. Results Thirty-seven studies were included (3489 patients with mean follow-up of 3.1 years ± 1.5 [SD]); 29 studies evaluated MRI (2931 patients) and 17 evaluated FDG PET (1243 patients). Five studies directly compared MRI and PET in the same patients (276 patients). Left ventricular late gadolinium enhancement (LGE) at MRI and FDG uptake at PET were both predictive of MACE (odds ratio [OR], 8.0 [95% CI: 4.3, 15.0] [P < .001] and 2.1 [95% CI: 1.4, 3.2] [P < .001], respectively). At meta-regression, results varied by modality (P = .006). LGE (OR, 10.4 [95% CI: 3.5, 30.5]; P < .001) was also predictive of MACE when restricted to studies with direct comparison, whereas FDG uptake (OR, 1.9 [95% CI: 0.82, 4.4]; P = .13) was not. Right ventricular LGE and FDG uptake were also associated with MACE (OR, 13.1 [95% CI: 5.2, 33] [P < .001] and 4.1 [95% CI: 1.9, 8.9] [P < .001], respectively). Thirty-two studies were at risk for bias. Conclusion Left and right ventricular late gadolinium enhancement at cardiac MRI and fluorodeoxyglucose uptake at PET were predictive of major adverse cardiac events in cardiac sarcoidosis. Limitations include few studies with direct comparison and risk of bias. Systematic review registration no. CRD42021214776 (PROSPERO) © RSNA, 2023 Supplemental material is available for this article.

Bringing Machine-Learning Enhanced Quantum Chemistry and Microwave Spectroscopy to Conformational Landscape Exploration: the Paradigmatic Case of 4-Fluoro-Threonine.

A combined experimental and theoretical study has been carried out on 4-fluoro-threonine, the only naturally occurring fluorinated amino acid. Fluorination of the methyl group significantly increases the conformational complexity with respect to the parent amino acid threonine. The conformational landscape has been characterized in great detail, with special attention given to the inter-conversion pathways between different conformers. This led to the identification of 13 stable low-energy minima. The equilibrium population of so many conformers produces a very complicated and congested rotational spectrum that could be assigned through a strategy that combines several levels of quantum chemical calculations with the principles of machine learning. Twelve conformers out of 13 could be experimentally characterized. The results obtained from the analysis of the intra-molecular interactions can be exploited to accurately model fluorine-substitution effects in biomolecules.

The Use of Brexpiprazole Combined With a Stimulant in Adults With Treatment-Resistant Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: This is the first controlled pharmacologic study in either adults or children with uncomplicated, treatment-resistant attention-deficit/hyperactivity disorder (ADHD). This study augmented stimulant therapy with the atypical antipsychotic brexpiprazole. The Food and Drug Administration preapproved primary outcome measure (Conners' Adult ADHD Rating Scale [CAARS]) showed no drug-placebo differences. Often studies showing no efficacy on the prestudy, defined primary outcome variable go unpublished. While this is decried, publishing studies with equivocal results remains rare. This reanalysis highlights trends in secondary measures having implications for treatment and research regarding treatment resistant ADHD. METHODS: Initially, 559 stimulant-naive and 174 prior stimulant nonresponders received methylphenidate osmotic-release oral system, dexmethylphenidate hydrochloride, lisdexamfetamine, or mixed amphetamine salts. After 5 weeks, 168 stimulant-naive patients and 68 prior stimulant nonresponders who failed treatment were randomized to brexpiprazole or placebo in a 2:1 ratio while the remaining were on the stimulant. Outcome was measured with the CAARS, Montgomery-Asberg Depression Rating Scale, Beck Depression Inventory, Clinical Global Impression, and the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS). The WRAADDS contains 2 factors: attention and emotional dysregulation. RESULTS: Stimulant-naive patients showed no improvement with adjunctive brexpiprazole. Prior stimulant nonresponders displayed no brexpiprazole effect on the CAARS, Montgomery-Asberg Depression Rating Scale, or Beck Depression Inventory. In contrast, the WRAADDS detected a trend in treatment benefit, primarily through emotional dysregulation symptoms. Adverse effects on brexpiprazole and placebo were equivalent. CONCLUSIONS: Brexpiprazole might be effective in ADHD adults who are nonresponders to 2 or more stimulants. Future trials in treatment-resistant ADHD should use a 1:1 randomization and use a measure of ADHD symptoms that includes emotional dysregulation.

Understanding the abundance of the rare sugar ß-D-allose.

The conformational landscape of ß-D-allose, a rare sugar, was investigated using laser ablation in combination with high-resolution rotational spectroscopy. Altogether, three species are identified, exhibiting a counter-clockwise intramolecular hydrogen bond network. The effect of epimerization on the main aldohexose is also studied and, despite the main conformers being very similar, the position of the hydroxyl groups in allose allows the formation of considerably stronger intramolecular hydrogen bonds than in glucose, and this could explain the low abundance of ß-D-allose in Nature.

Unveiling the Shape of N-Acetylgalactosamine: A Cancer-Associated Sugar Derivative.

In the present work, we report the first rotational study of N-acetylgalactosamine, a cancer-associated sugar derivative, by means of high-resolution rotational spectroscopy. Two different conformers have been conclusively characterized using broadband Fourier transform microwave spectroscopy coupled with a laser ablation vaporization system. Additionally, we performed a comprehensive analysis of the intramolecular interactions that govern these structures, which allowed us to both characterize the existence of intramolecular hydrogen bond networks that drive the intrinsic conformation panorama of N-acetylgalactosamine and further rationalize the biological role of this aminosugar derivative as part of the Tn antigen.

Gas-Phase Conformational Map of the Amino Acid Isovaline.

Four conformers of the non-proteinogenic α-amino acid isovaline, vaporized by laser ablation, are characterized by Fourier-transform microwave techniques in a supersonic expansion. The comparison between the experimental rotational and 14 N nuclear quadrupole coupling constants and the ab initio calculated ones provides conclusive evidence for the identification of the conformers. The most stable species is stabilized by an N-H⋅⋅⋅O =C intramolecular hydrogen bond and a cis-COOH interaction, whereas the higher-energy conformers exhibit an N⋅⋅⋅H-O intramolecular hydrogen bond and trans-COOH, as in other aliphatic amino acids. The spectroscopic data herein reported can be used for the astrophysical purpose in a possible detection of isovaline in space.

Trial of restarting and tolerating metformin (TreatMet).

This randomized, double-blind, placebo-controlled, n-of-1 crossover study assessed whether metformin's side effects are reproducible in patients with a history of metformin intolerance. Participants completed up to four cycles of 2 weeks of metformin exposure and 2 weeks of placebo exposure. Participants completed surveys based on the Gastrointestinal Symptom Rating Scale and the Treatment Satisfaction Questionnaire for Medication. The primary hypotheses were that treatment satisfaction would be equal for placebo and metformin and that more than 30% of the study enrollees would be able to adhere to a higher dose of metformin 6 months after participation. Thirteen patients (all women, mean age 52.4 years) enrolled, three of whom were lost to follow-up or were non-adherent to study protocol. Metformin was associated with significantly lower global treatment satisfaction scores compared with placebo (39.58 vs. 53.75, P < .05 ) but participants could not distinguish metformin from placebo and did not report higher rates of gastrointestinal side effects on metformin. Two out of 10 participants adhered to a higher dose of metformin after trial completion. Metformin appears to have barriers to use beyond its classic gastrointestinal side effects.

A rotational study of the AlaAla dipeptide.

Herein, we present the first rotational study of the AlaAla dipeptide, brought into the gas phase by laser ablation. Two different structures have been unveiled in the isolated environment of a supersonic expansion by Fourier transform microwave spectroscopy. These structures have been identified through their rotational and 14N quadrupole coupling constants. The flexibility of the -NH2 and -COOH ends allows the formation of strong intramolecular interactions giving rise to five- and seven-membered ring configurations.

Renal function at admission as a prognostic marker for patients hospitalised for a first episode of heart failure. Results of the PREDICE study. / Función renal al ingreso como marcador pronóstico en pacientes hospitalizados por un primer episodio de insuficiencia cardíaca. Resultados del estudio PREDICE.

BACKGROUND AND OBJECTIVE: Heart failure (HF) is a frequent condition that deteriorates quality of life and results in high morbidity and mortality. A considerable number of studies have been implemented in recent years to determine the factors that affect the prognosis of HF; however, few studies have assessed the prognosis of patients hospitalised for their first episode of HF. The aim of our study was to analyse the prognostic impact of renal function on patients hospitalised for a first episode of HF. MATERIAL AND METHODS: We recruited 600 patients hospitalised for a first episode of HF in 3 tertiary Spanish hospitals. We analysed the mortality risk during the first year of follow-up according to renal function at the time of admission. RESULTS: The patients with the highest degree of kidney failure at admission were older (P<.001), were more often women (p=.01) and presented a higher degree of dependence (P<.05), as well as a higher prevalence of arterial hypertension (P<.001), chronic renal failure (P<.001) and anaemia (P<.001). In the multivariate analysis, the degree of kidney failure at admission remained an independent predictor of increased mortality risk during the first year of follow-up. CONCLUSIONS: The presence of kidney failure at admission was a marker of poor prognosis in our cohort of patients hospitalised for a first episode of HF.

6-Methoxyquinoline complexes as lung carcinoma agents: induction of oxidative damage on A549 monolayer and multicellular spheroid model.

The aim of this work was to study the antitumor effects and the mechanisms of toxic action of a series of 6-methoxyquinoline (6MQ) complexes in vitro. The Cu(II) and Zn(II) complexes (Cu6MQ and Zn6MQ) are formulated as M(6MQ)2Cl2; the Co(II) and Ag(I) compounds (Co6MQ and Ag6MQ) are ionic with formulae [Ag(6MQ)2]+NO3- and H(6MQ)+[Co(6MQ)Cl3]- (where H(6MQ)+ is the protonated ligand). We found that the copper complex, outperformed the Co(II), Zn(II) and Ag(I) complexes with a lower IC50 (57.9 µM) in A549 cells exposed for 24 h. Cu6MQ decreased cell proliferation and induced oxidative stress detected with H2DCFDA at 40 µM, which reduces GSH/GSSG ratio. This redox imbalance induced oxidative DNA damage revealed by the Micronucleus test and the Comet assay, which turned into a cell cycle arrest at G2/M phase and induced apoptosis. In multicellular spheroids, the IC50 values tripled the monolayer model (187.3 µM for 24 h). At this concentration, the proportion of live/dead cells diminished, and the spheroids could not proliferate or invade. Although Zn6MQ also decreased GSH/GSSG ratio from 200 µM and the cytotoxicity is related to oxidative stress, the induction of the hydrogen peroxide levels only doubled the control value. Zn6MQ induced S phase arrest, which relates with the increased micronucleus frequency and with the induction of necrosis. Finally, our results reveal a synergistic activity with a 1:1 ratio of both complexes in the monolayer and multicellular spheroids.

The impact of food order on postprandial glycaemic excursions in prediabetes.

Data suggest that nutrient order during a meal significantly impacts postprandial glucose and insulin excursions in type 2 diabetes, while its effects in prediabetes have not been reported. Fifteen participants with prediabetes consumed the same meal on 3 days in random order: carbohydrate first, followed 10 minutes later by protein and vegetables (CF); protein and vegetables first, followed 10 minutes later by carbohydrate (PVF); or vegetables first followed by protein and carbohydrate (VF). Blood was sampled for glucose and insulin measurements at 0, 30, 60, 90, 120, 150 and 180 minutes. Incremental glucose peaks were similarly attenuated by >40% in the PVF and VF meal conditions compared with CF. The incremental area under the curve for glucose was 38.8% lower following the PVF meal order, compared with CF, and postprandial insulin excursions were significantly lower in the VF meal condition compared with CF. The CF meal pattern showed marked glycaemic variability whereas glucose levels were stable in the PVF and VF meal conditions. Food order presents a novel, simple behavioural strategy to reduce glycaemic excursions in prediabetes.

Evaluation of the aggregation process in a mixture of propofol and benzocaine.

We report on a mass-resolved IR spectrosopic study on propofol-benzocaine aggregates. This is a complex system due to the several conformational isomers that both monomers may adopt and to the combination of functional groups they present, which allow the molecules to interact in many possible ways. However, our results demonstrate that a single conformation is favored for each stoichiometry. In the heterodimer, propofol acts as a proton donor to the ester group of benzocaine, while the whole cluster is stabilized by dispersive forces. These dispersive forces account for an important part of the system's stabilization energy as the calculations suggest. Propofol does not show any affinity for the amino group of benzocaine, even when a second molecule of propofol is introduced. These results demonstrate the difficulty in anticipating the aggregation preferences of even small organic molecules.

Elucidating the multiple structures of pipecolic acid by rotational spectroscopy.

The complex conformational space of the non-proteinogenic cyclic amino acid pipecolic acid has been explored in the gas phase for the first time. Solid pipecolic acid samples were vaporized by laser ablation and expanded in a supersonic jet where the rotational spectral signatures owing to nine different conformers were observed by Fourier transform microwave spectroscopy. All species were identified by comparison of the experimental rotational and nuclear quadrupole coupling constants with those predicted theoretically. Observation of type-III conformers, leading to a difference when compared against the conformational behavior of the analog amino acid proline, has been interpreted by an increment in steric hindrance when increasing the number of carbons present in the ring.

Alcoholic family marital heterogeneity aggregates different child behavior problems both pre- and postseparation.

Children of alcoholics (COAs) are at risk for elevated internalizing and externalizing symptoms. Yet, little is known about the familial and behavioral adjustments of COAs following parental separation. Using an ecological-transactional framework, we examined how multiple risk factors contributed to the formation of different alcoholic family structures and how living in heterogeneous family structures affected COAs' behavioral problems. The Michigan Longitudinal Study, a multiwave study on initially intact alcoholic and control families with preschool-age children (n = 503), was used to evaluate outcomes of offspring, when families either remained intact or were separated when the child was aged 12-14. Alcoholic families who later transitioned into stepfamilies were characterized with higher paternal antisociality, marital aggression, and serious family crises than alcoholic families that remained intact. COAs in stepfamilies (but not in single-parent families) exhibited higher levels of internalizing and externalizing symptoms in preadolescence compared with those in alcoholic intact families, in part because of elevated behavioral risk at age 3. Structural equation modeling indicated that the aggregated risk of stepfamily residence directly related to COAs' internalizing and indirectly related to COAs' externalizing problems, partially mediated by family stressors. Findings suggest targeting COAs in separated families for early intervention.

Practical Use of Pharmacotherapy for Obesity.

Obesity management requires a multidisciplinary approach, as there are many factors that contribute to the development of obesity, as well as the preservation of excess weight once it has been gained. Diet, exercise, and behavior modification are key components of treatment. In addition to lifestyle changes, weight gain secondary to medications is an important modifiable risk factor. Even after appropriate lifestyle modification, and medication adjustments (where possible) to avoid agents that can contribute to weight gain, many patients are still unable to achieve clinically meaningful weight loss. Pharmacotherapy for obesity management can fill an important role for these patients. This article will review medications that can lead to weight gain and potential alternatives, currently approved anti-obesity medications and best practices to individualize the selection process, and the use of testosterone in men with hypogonadism and obesity.

Serotype Diversity and Antimicrobial Resistance among Salmonella enterica Isolates from Patients at an Equine Referral Hospital.

Although Salmonella enterica can produce life-threatening colitis in horses, certain serotypes are more commonly associated with clinical disease. Our aim was to evaluate the proportional morbidity attributed to different serotypes, as well as the phenotypic and genotypic antimicrobial resistance (AMR) of Salmonella isolates from patients at an equine referral hospital in the southern United States. A total of 255 Salmonella isolates was obtained from clinical samples of patients admitted to the hospital between 2007 and 2015. Phenotypic resistance to 14 antibiotics surveilled by the U.S. National Antimicrobial Resistance Monitoring System was determined using a commercially available panel. Whole-genome sequencing was used to identify serotypes and genotypic AMR. The most common serotypes were Salmonella enterica serotype Newport (18%), Salmonella enterica serotype Anatum (15.2%), and Salmonella enterica serotype Braenderup (11.8%). Most (n = 219) of the isolates were pansusceptible, while 25 were multidrug resistant (≥3 antimicrobial classes). Genes encoding beta-lactam resistance, such as blaCMY-2, blaSHV-12, blaCTX-M-27, and blaTEM-1B, were detected. The qnrB2 and aac(6')-Ib-cr genes were present in isolates with reduced susceptibility to ciprofloxacin. Genes encoding resistance to gentamicin (aph(3')-Ia, aac(6')-IIc), streptomycin (strA and strB), sulfonamides (sul1), trimethoprim (dfrA), phenicols (catA), tetracyclines [tet(A) and tet(E)], and macrolides [ere(A)] were also identified. The main predicted incompatibility plasmid type was I1 (10%). Core genome-based analyses revealed phylogenetic associations between isolates of common serotypes. The presence of AMR Salmonella in equine patients increases the risk of unsuccessful treatment and causes concern for potential zoonotic transmission to attending veterinary personnel, animal caretakers, and horse owners. Understanding the epidemiology of Salmonella in horses admitted to referral hospitals is important for the prevention, control, and treatment of salmonellosis.IMPORTANCE In horses, salmonellosis is a leading cause of life-threatening colitis. At veterinary teaching hospitals, nosocomial outbreaks can increase the risk of zoonotic transmission, lead to restrictions on admissions, impact hospital reputation, and interrupt educational activities. The antimicrobials most often used in horses are included in the 5th revision of the World Health Organization's list of critically important antimicrobials for human medicine. Recent studies have demonstrated a trend of increasing bacterial resistance to drugs commonly used to treat Salmonella infections. In this study, we identify temporal trends in the distribution of Salmonella serotypes and their mechanisms of antimicrobial resistance; furthermore, we are able to determine the likely origin of several temporal clusters of infection by using whole-genome sequencing. These data can be used to focus strategies to better contain the dissemination and enhance the mitigation of Salmonella infections and to provide evidence-based policies and guidelines to steward antimicrobial use in veterinary medicine.

The last link of the x-aminobutyric acid series: the five conformers of ß-aminobutyric acid.

ß-Aminobutyric acid is a non-proteinogenic amino acid that is known to protect plants against various pathogens. Its structure is midway between α-aminobutyric acid and γ-aminobutyric acid. The structural differences in the position of the amino group in the conformational stabilization of ß-aminobutyric acid have been studied by laser ablation Fourier transform microwave spectroscopy. Five conformers have been detected, and their rotational and quadrupole coupling constants of the 14N nucleus determined. Three of the conformers, including the most stable structure, are stabilized by a non-bifurcated N-HO[double bond, length as m-dash]C intramolecular hydrogen bond. The other two conformers possess a NH-O intramolecular interaction. In this work we highlight that ß-aminobutyric acid shows the conformational peculiarities of α-aminobutyric acid and γ-aminobutyric acid completing the rotational spectroscopic study of the x-aminobutyric acid series.