bluuebunny/crossref_metadata_2025 huggingface dataset:
The Use of a Seminal Vesicle Specific Protein (MHS‐5 Antigen) for Diagnosis of Agenesis of Vas Deferens and Seminal Vesicles in Azoospermic Men
Authors: BARAK MIRA , CALDERON ILAN , ABRAMOVICI HAIM , GRUENER NACHMAN , YAVEZ HAIM , PAZ GEDALIA , HOMONNAI ZVI T.
Published: October 2023

ABSTRACT: Azoospermia is the cause of infertility in 8% of infertile male patients. Ten percent of those patients suffer from agenesis of the seminal vesicle (SV) and vas deferens (VD) agenesis. Currently, the diagnosis of SV and VD agenesis is based on low semen volume, low pH, and low fructose content of the seminal fluid of azoospermic men who have normal serum gonadotropins. In this study, an SV‐specific sperm‐coating antigen, the MHS‐5 antigen, was used as a marker for the presence of SVs. The SV‐specific protein (SVSP), MHS‐5, was present in the control group but was not found in any of the seven samples from azoospermic men with proven agenesis of SV and VD. Another semen component, the prostate‐specific antigen (PSA), whose presence in the semen is not influenced by the SV and VD agenesis, was found in both the study and the control groups. Its presence ruled out the possibility of azoospermia due to ejaculatory duct obstruction. The absence of MHS‐5 antigen in seminal fluid can be used as a tool for a reliable diagnosis of agenesis of SV and VD in azoospermic men.
Dual DNA Staining Assessment of Bovine Sperm Viability Using SYBR‐14 and Propidium Iodide
Authors: GARNER D. L. , JOHNSON L. A. , YUE S. T. , ROTH B. L. , HAUGLAND R. P.
Published: October 2023

ABSTRACT: A new membrane‐permeant DNA stain, SYBR‐14, was used in combination with propidium iodide (PI) to estimate the proportion of living sperm in bovine semen. The SYBR‐14 stained living sperm while PI only stained degenerate cells that had lost their membrane integrity. Staining with SYBR‐14 resulted in the nuclei of living sperm fluorescing bright green. Aliquots containing nearly all living bovine sperm were prepared using glass wool/Sephadex filtration to remove dead and damaged cells. A portion of this filtered sample was killed by unprotected freeze‐thawing and used to provide mixed aliquots containing known ratios of living and dead sperm. Flow cytometry was used to assess the green and red fluorescence of these mixtures. The percentages of living sperm, as determined by the log of green fluorescence, were 85.1, 68.8, 39.8, 20.7, and 1.4 for ratios of 100:0,75:25,50:50,25:75, and 0:100 of the filtered, killed mixtures. Also, bovine semen was diluted 1:60 in HEPES‐0.1% bovine serum albumin and incubated for 0,3,6, and 24 hours at 36°C to assess changes in cell viability. As ceN death occurred during this incubation period, a relatively rapid transition of staining from green to red occurred as sperm died. Three replicates of cryopreserved sperm from six bulls were also examined using SYBR‐14 and PI to assess the proportion of living and dead cells. Flow cytometric analyses of these samples, which had been processed and stored in homogenized milk, indicated that this stain combination was useful in assessing the quality of cryopreserved sperm. The combination of SYBR‐14 and PI was determined to be an effective tool for assessing the viability of fresh or cryopreserved sperm.
Testosterone Feedback on Gonadotropin Secretion and Gene Expression in Transgenic Mice Expressing Human Growth Hormone Gene
Authors: TANG KECHUN , BARTKE ANDRZEJ , GARDINER CATHERINE S. , WAGNER THOMAS E. , YUN‡ JEUNG S.
Published: October 2023

ABSTRACT: To determine the effects of testosterone on the regulation of gonadotropins in metallothionein‐1/human growth hormone (MT/hGH) transgenic mice, basal and gonadotropin‐releasing hormone (GnRH)‐stimulated luteinizing hormone (LH) and follicle‐stimulating hormone (FSH) release from incubated pituitaries, as well as pituitary content of LH, FSH, and mRNA for their respective β subunits, were measured in normal and transgenic males that were injected with testosterone propionate (5 μg/g body weight; 24 hours before autopsy), injected with oil vehicle, castrated for 10 days, or sham operated. In normal (non‐transgenic) males, exogenous testosterone induced the expected suppression, and castration induced the expected stimulation of various parameters of gonadotropin synthesis and release. In contrast, in testosterone‐treated and in castrated MT/hGH transgenic mice the release of LH and the pituitary levels of LH‐β mRNA did not differ from the corresponding values measured in vehicle‐injected and sham‐operated transgenic controls. Pituitary LH content was elevated in testosterone‐treated MT/hGH transgenic mice but was not changed in castrated transgenic males. The changes in pituitary levels of FSH and FSH‐β mRNA and in FSH release in MT/hGH transgenic mice in response to testosterone and castration were different from the changes in LH and LH‐β mRNA in the same mice, but similar to the changes of FSH and FSH‐β message produced in normal mice by identical treatments. We suggest that hGH expression attenuates the effects of testosterone on the mechanisms controlling LH release, with less influence on testosterone regulation of LH synthesis. These effects of hGH expression appear to be selective for LH, without influencing the FSH control system.
Comparative Effects of Two Different Delivery Systems on Gonadotropin‐releasing Hormone (GnRH) Antagonist‐induced Suppression of Gonadotropins and Testosterone in Man
Authors: SALAMEH W. , BHASIN S. , STEINER B. S. , McADAMS L. A. , PETERSON M. , RIVIER J. E. , VALE W. W. , SWERDLOFF R. S.
Published: October 2023

ABSTRACT: The Nal‐Glu gonadotropin‐releasing hormone (GnRH) antagonist, when given in daily subcutaneous (SC) doses of 5 mg or higher, maximally suppresses serum luteinizing hormone (LH) and follicle‐stimulating hormone (FSH) levels to near undetectable levels and induces azoospermia in normal men; lower doses (1.5 and 3.0 mg) are less effective. Cost and convenience are important considerations in contraceptive development. Studies with GnRH agonists suggest that constant delivery is more effective in suppressing gonadal function than equal doses by single daily injection. In this study, we examined whether the constant infusion (CI) of a submaximal suppressive dose (1.5 mg) of Nal‐Glu would be more effective in suppressing the pituitary‐gonadal axis than its repeated single daily injections (SDI). This (1.5 mg) dose was selected because the 5 mg dose given once daily SC for 21 days led to maximal suppression of LH, FSH, and testosterone (T) levels, whereas 1.5 mg once daily for 21 days gave only partial suppression. It was felt that if continuous infusion was considerably more effective than intermittent administration of this submaximal dose, then the development of long‐acting sustained release delivery systems for contraceptives based on GnRH antagonist analogs would allow both reduced cost and enhanced convenience. One and a half mg of Nal‐Glu was administered SC either as a SDI or CI over 24 hours for 21 days to two groups of five normal men. Three measurements of serum LH, FSH, and T were performed before antagonist injection and 1, 2, 4, 8, 12, 16, and 24 hours after Nal‐Glu injection on days 0, 1, 7, 21. Frequent blood sampling at 10‐minute intervals over an 8‐hour period was carried out for analysis of immunoreactive LH (iLH) pulses on day 0 (control day) and the last treatment day (day 21). In addition, pooled samples for LH, FSH, and T were obtained on days 0, 1, 4, 7, 10, 14, 16, and 21. The SDI regimen suppressed mean serum iLH to a nadir of 6.2 ± 1.3 IU/L (mean ± SEM) on day 1, and serum T to 14.4 ± 3.9 nmol/L (mean ± SEM) on day 7. Detailed sampling on subsequent days revealed that the suppressive effect on iLH lasted for a limited number of hours. There was no significant suppression of serum iFSH. The Cl regimen did not suppress serum iLH, iFSH, or T on any of the days sampled. These data do not support the contention that constant delivery of the Nal‐Glu antagonist is more effective in suppressing the hypothalamic pituitary‐gonadal axis (HPG) than its daily injection. Although small differences in the efficacy of the two regimens may not have been detected because of relatively small sample size, it is unlikely that these small differences would have any practical significance in terms of the cost or the amount of antagonist needed to be loaded into a long‐term sustained release delivery system.
Atrial Natriuretic Peptide (ANP) as a Stimulus of the Human Acrosome Reaction and a Component of Ovarian Follicular Fluid: Correlation of Follicular ANP Content with In Vitro Fertilization Outcome
Authors: ANDERSON ROBERT A. , FEATHERGILL KENNETH A. , DRISDEL RENALDO C. , RAWLINS RICHARD G. , MACK STEPHEN R. , ZANEVELD LOURENS J. D.
Published: October 2023

ABSTRACT: Atrial natriuretic peptides (ANPs) from several species induced the human acrosome reaction. The maximal response was highest for human ANP (18.6% above unstimulated or baseline values) and decreased progressively for peptides derived from animals lower on the phylogenetic scale. ANP concentrations required for a half‐maximal effect in noncapacitated spermatozoa ranged from 0.07 to 0.38 nM. ANP induced the acrosome reaction in capacitated spermatozoa, but the concentration required was higher than in noncapacitated cells. The response in noncapacitated spermatozoa was independent of added extracellular Ca2+ and was completely inhibited by 1 μM LY83583 (inhibits particulate guanylate cyclase). However, 10 μM Nω‐nitro‐L‐arginine (inhibits soluble guanylate cyclase) had no effect. ANP (80 pM) and 3 μM 1,2‐dihexanoyl‐sn‐glycerol each induced a nearly half‐maximal acrosome reaction. Added in combination, they produced no increased response, suggesting antagonism. Follicular fluid had variable levels of immunoreactive ANP. Average ANP content was nearly zero in samples that contained no oocyte at the time of aspiration but was higher (6.9 ± 90% confidence limits = 1.67–28.72 pM) in follicular fluid containing oocytes that did not fertilize in vitro. Highest concentrations of ANP were present in follicular fluid containing oocytes that fertilized in vitro (72.8 ± 90% confidence limits = 38.1–139.1 pM). These data suggest that noncapacitated spermatozoa can acrosome react without added extracellular Ca2+ in response to an extracellular ligand. Also, human spermatozoa appear to contain receptors for ANP similar to those found in other cell types. The ANP content of follicular fluid might partly explain the ability of follicular fluid to induce the acrosome reaction.
Protein3D: Enabling analysis and extraction of metal‐containing sites from the Protein Data Bank with molSimplify
Authors: Edholm Freya , Nandy Aditya , Reinhardt Clorice R. , Kastner David W. , Kulik Heather J.
Published: October 2023

Metalloenzymes catalyze a wide range of chemical transformations, with the active site residues playing a key role in modulating chemical reactivity and selectivity. Unlike smaller synthetic catalysts, a metalloenzyme active site is embedded in a larger protein, which makes interrogation of electronic properties and geometric features with quantum mechanical calculations challenging. Here we implement the ability to fetch crystallographic structures from the Protein Data Bank and analyze the metal binding sites in the program molSimplify. We show the usefulness of the newly created protein3D class to extract the local environment around non‐heme iron enzymes containing a two histidine motif and prepare 372 structures for quantum mechanical calculations. Our implementation of protein3D serves to expand the range of systems molSimplify can be used to analyze and will enable high‐throughput study of metal‐containing active sites in proteins.
Genetic counseling clinic model expansion: Impact on access for general genetics clinic
Authors: Doberstein Rachel , Pilipenko Valentina , Pulda Kathleen , Wusik Katie , Spaeth Christine G.
Published: October 2023

Cincinnati Children's Hospital Medical Center (CCHMC) implemented a Genetic Counseling Clinic (GCC), where the appointment for a general genetics indication is conducted solely by a genetic counselor (GC). We conducted a retrospective chart review of 211 patient encounters scheduled in the GCC between January 1, 2022 and June 30, 2022 and collected patient demographics, wait time, appointment characteristics, referral indication, and clinical recommendations. To study impact on patient access, we compared patient demographics and appointment characteristics with 912 patient encounters scheduled in the General Genetics Clinic with a geneticist during the same time period. We found that there were not significant differences in patient demographics scheduled in the GCC as compared with the General Genetics Clinic with the exception of insurance type, where patients scheduled in the GCC were more likely to have private insurance. Patients scheduled in the GCC had a significantly shorter wait time, were more likely to complete their appointment, were more often new to the genetics division, and were more likely to be seen via telehealth (audio plus video or audio‐only) as compared with patients scheduled in the General Genetics Clinic. The most common indications for patients scheduled in the GCC were post‐test counseling (36.0%) followed by pre‐test counseling and coordination of testing (22.3%), and first‐line testing for autism, intellectual disability, and developmental delay (13.7%). Completed appointments in the GCC often resulted in the GC ordering genetic testing (67.5%). After genetic testing results were received, most patients (72.7%) did not require subsequent follow‐up with the genetics division, thereby reducing burden to the medical genetics team. Our GCC increased access to genetic services and allowed GCs and clinical geneticists to better work at the top of their scope of practice.
The Ritter reaction of N‐(hydroxymethyl)saccharin with nitriles
Authors: de Oliveira Marllon Nascimento , de Mattos Marcio C. S.
Published: October 2023

The development of the Ritter reaction of N‐(hydroxymethyl)saccharin with nitriles for the synthesis of N‐[(saccharinyl)methyl]amides is reported. The success of this reaction relies on an operationally simple procedure and on the use of inexpensive reagents. The present method enables access to a variety of saccharin scaffolds of potential interest in medicinal chemistry in moderate to high yields. Furthermore, the scalability of this reaction was demonstrated by a multigram‐scale transformation, without any loss of efficiency.
Right–Left Ventricular Interdependence in Repaired Tetralogy of Fallot Patients With Right Ventricular Heart Failure
Authors: Jiang Li , Li Yuan , Huang Shan , Han Pei‐Lun , Yan Wei‐Feng , Fang Han , Yang Zhi‐Gang
Published: October 2023

Background

Patients with repaired tetralogy of Fallot (rTOF) continue to face a heightened risk of deteriorating cardiac function, and quantitative techniques of cardiac MRI‐derived cardiac structure and function provide an opportunity to explore the causes and mechanisms of cardiac deterioration.

Purpose

To explore right–left ventricular interdependence in rTOF patients before and after the onset of right ventricular (RV) heart failure.

Study Type

Retrospective.

Population

One hundred eighteen rTOF patients (21.85 [16.74, 29.20] years, 58 females) and 34 controls (23.5 [21, 26.5] years, 17 females) that underwent cardiac MRI were analyzed, with rTOF patients being further subdivided into those with preserved RV function (N = 54) and those that experienced RV heart failure (N = 64).

Field Strength/Sequence

3.0 T/balanced steady‐state free precession sequence.

Assessment

RV, left ventricular (LV), and septal strain; RV and LV volume.

Statistical Tests

Chi‐squared tests or Fisher's exact test, One‐way ANOVAs with Bonferroni's post hoc test, Pearson/Spearman correlation, and multivariate backward linear regression analysis. A two‐tailed P < 0.05 was deemed as the significance threshold.

Results

The MRI‐derived RV, LV, and septal strain decreased sequentially in controls, patients with preserved RV function, and patients with RV heart failure, with a good intra‐observer (0.909–0.964) and inter‐observer (0.879–0.937) agreement. Correlations between LV and RV strain were found to change sequentially with RV function and were the closest in rTOF patients with RV heart failure (r = −0.270 to 0.506). Correlations between RV volume and septal strain was variable in controls (r = 0.483 to −0.604), patients with preserved RV function (r = −0.034 to −0.295), and patients with RV heart failure (r = −0.026 to 0.500). Multivariate analyses revealed that the RV longitudinal strain was independently correlated with LV strain in three directions in rTOF patients with RV heart failure (Radial −0.70 [−1.33, −0.06]; Circumferential 0.44 [0.17, 0.72]; Longitudinal 0.54 [0.26, 0.81]).

Data Conclusion

In rTOF patients, the coupling between RV volume and septal strain was broken during RV function compensation, and the adverse effect of RV on LV deformation was highest in patients with RV heart failure.

Evidence Level

4

Technical Efficacy

Stage 5
Cartilaginous endplates: A comprehensive review on a neglected structure in intervertebral disc research
Authors: Crump Katherine B. , Alminnawi Ahmad , Bermudez‐Lekerika Paola , Compte Roger , Gualdi Francesco , McSweeney Terence , Muñoz‐Moya Estefano , Nüesch Andrea , Geris Liesbet , Dudli Stefan , Karppinen Jaro , Noailly Jérôme , Le Maitre Christine , Gantenbein Benjamin
Published: October 2023

The cartilaginous endplates (CEP) are key components of the intervertebral disc (IVD) necessary for sustaining the nutrition of the disc while distributing mechanical loads and preventing the disc from bulging into the adjacent vertebral body. The size, shape, and composition of the CEP are essential in maintaining its function, and degeneration of the CEP is considered a contributor to early IVD degeneration. In addition, the CEP is implicated in Modic changes, which are often associated with low back pain. This review aims to tackle the current knowledge of the CEP regarding its structure, composition, permeability, and mechanical role in a healthy disc, how they change with degeneration, and how they connect to IVD degeneration and low back pain. Additionally, the authors suggest a standardized naming convention regarding the CEP and bony endplate and suggest avoiding the term vertebral endplate. Currently, there is limited data on the CEP itself as reported data is often a combination of CEP and bony endplate, or the CEP is considered as articular cartilage. However, it is clear the CEP is a unique tissue type that differs from articular cartilage, bony endplate, and other IVD tissues. Thus, future research should investigate the CEP separately to fully understand its role in healthy and degenerated IVDs. Further, most IVD regeneration therapies in development failed to address, or even considered the CEP, despite its key role in nutrition and mechanical stability within the IVD. Thus, the CEP should be considered and potentially targeted for future sustainable treatments.
Simultaneous determination and pharmacokinetics study of three triterpenoid saponins in rat plasma by ultra‐high‐performance liquid chromatography tandem mass‐spectrometry after oral administration of Astragalus Membranaceus leaf extract
Authors: Wang Zhibin , Borjigin Gilwa , Zhang Mingyu , Yang Chunjuan , Wang Zhenyue , Kuang Haixue
Published: October 2023

A selective and sensitive ultra‐high‐performance liquid chromatography‐tandem mass spectrometry method was developed and validated for the determination of three triterpenoid saponins isolated from Astragalus membranaceus leaf extract. In this article, a method for simultaneous determination of Huangqiyenin A, Huangqiyenin E, and Huangqiyenin K was established for the first time. The method was successfully applied to the pharmacokinetic study of Astragalus membranaceus leaf extract after oral administration. Liquid–liquid extraction was applied to plasma sample preparation. Multiple reaction monitoring mode with an electrospray ion source in positive electrospray ionization was chosen to quantify the analytes. Chromatographic separation was performed on a Waters HSS T3 column, using gradient elution with a mobile phase composed of acetonitrile and 5 mM ammonium acetate/water. The pharmacokinetic results showed that all three compounds had the characteristics of rapid absorption‐slow metabolism trend. The time of maximum plasma concentration of Huangqiyenin A is higher than Huangqiyenin E and Huangqiyenin K. And the maximum plasma concentration of Huangqiyenin A is higher as well.

The pharmacokinetic results revealed the pharmacokinetic characteristics of the three analytes in rat plasma, which could provide a helpful reference for the further study of Astragalus membranaceus leaf extract.
Dynamic capabilities and asset orchestration
Authors: Kodama Mitsuru
Published: October 2023

In recent years, the theory of dynamic capabilities (DC) has become more sophisticated and has become a framework for sustainable growth through strategic innovation in companies. The “asset orchestration” function, a core concept of DC, connects various types of knowledge (assets) in an entrepreneurial manner and realizes the recombination, modification, and transformation of existing knowledge (assets) for the purpose of developing new businesses, new products, and so forth. However, the dynamic mechanism of such asset orchestration is largely unclarified in previous studies. This paper derives a dynamic theoretical model of asset orchestration and the components of DC necessary for companies to respond to the uncertainty of business environments and the speed of environmental change. Using the findings of the derived theoretical model, this paper analyzes in‐depth case studies of Taiwan Semiconductor Manufacturing Company, which is currently attracting worldwide attention as a core company in the semiconductor industry, to verify the validity of the theoretical model.
Methylation of ESR1 promoter induced by SNAI2–DNMT3B complex promotes epithelial–mesenchymal transition and correlates with poor prognosis in ERα‐positive breast cancers
Authors: Li Ji‐Wei , Deng Qiu‐Min , Zhu Jian‐Ling , Min Wei , Hu Xiao‐Yi , Yu Chen Hong‐ , Luo Zhong , Lin Lin‐Ling , Wei Xiao‐Long , Zhang Yong‐Qu , Lou Kang‐Liang , Gao Yi‐Yang , Zhang Guo‐Jun , Bai Jing‐Wen
Published: October 2023

Estrogen receptor α (ERα) serves as an essential therapeutic predictor for breast cancer (BC) patients and is regulated by epigenetic modification. Abnormal methylation of cytosine phosphoric acid guanine islands in the estrogen receptor 1 (ESR1) gene promoter could silence or decrease ERα expression. In ERα‐negative BC, we previously found snail family transcriptional repressor 2 (SNAI2), a zinc‐finger transcriptional factor, recruited lysine‐specific demethylase 1 to the promoter to transcriptionally suppress ERα expression by demethylating histone H3 lysine 4 dimethylation (H3K4me2). However, the role of SNAI2 in ERα‐positive BC remains elusive. In this study, we observed a positive correlation between SNAI2 and ESR1 methylation, and SNAI2 promoted ESR1 methylation by recruiting DNA methyltransferase 3 beta (DNMT3B) rather than DNA methyltransferase 1 (DNMT1) in ERα‐positive BC cells. Subsequent enrichment analysis illustrated that ESR1 methylation is strongly correlated with cell adhesion and junction. Knocking down DNMT3B could partially reverse SNAI2 overexpression‐induced cell proliferation, migration, and invasion. Moreover, high DNMT3B expression predicted poor relapse‐free survival and overall survival in ERα‐positive BC patients. In conclusion, this study demonstrated the novel mechanisms of the ESR1 methylation mediated with the SNAI2/DNMT3B complex and enhanced awareness of ESR1 methylation's role in promoting epithelial–mesenchymal transition in BC.
Copper and Diabetes: Current Research and Prospect
Authors: Chang Wenguang , Li Peifeng
Published: October 2023

Copper is an essential trace metal for normal cellular functions; a lack of copper is reported to impair the function of important copper‐binding enzymes, while excess copper could lead to cell death. Numerous studies have shown an association between dietary copper consumption or plasma copper levels and the incidence of diabetes/diabetes complications. And experimental studies have revealed multiple signaling pathways that are triggered by copper shortages or copper overload in diabetic conditions. Moreover, studies show that treated with copper chelators improve vascular function, maintain copper homeostasis, inhibit cuproptosis, and reduce cell toxicity, thereby alleviating diabetic neuropathy, retinopathy, nephropathy, and cardiomyopathy. However, the mechanisms reported in these studies are inconsistent or even contradictory. This review summarizes the precise and tight regulation of copper homeostasis processes, and discusses the latest progress in the association of diabetes and dietary copper/plasma copper. Further, the study pays close attention to the therapeutic potential of copper chelators and copper in diabetes and its complications, and hopes to provide new insight for the treatment of diabetes.
Parent‐child agreement on children's psychopathology and the impact of parental depression
Authors: Löchner Johanna , Hämmerle Stephanie , Ghezih Sarah , Starman‐Wöhrle Kornelija , Schulte‐Körne Gerd , Platt Belinda
Published: October 2023

Background

Parental depression increases children's risk of mental illness and may simultaneously impair the detection of children's symptoms. Here we investigate the nature of parent‐child agreement of children's psychopathology in children of parents with current (cMD) versus remitted (rMD) major depression.

Methods

Baseline data from 100 parent‐child dyads including healthy children aged 8–17 (M = 11.89, SD = 2.83) and their parents with a history of depression were analysed. The presence of sub‐clinical psychopathology (yes/no) in children was assessed using semi‐structured diagnostic interviews with child and parent (K‐DIPS). Self‐ (YSR) and parent‐report (CBCL) questionnaires were used to measure the severity of symptoms. Parent‐child agreement was calculated using Chi‐square tests and Cohen's kappa respectively. We compared whether agreement differed between children of parents with cMD (n = 52) versus rMD (n = 48).

Results

In the interviews parents more frequently reported sub‐clinical child psychopathology than the children themselves (χ2 1,100 = 4.63, p < 0.001, d = 0.59). This pattern characterised parents with cMD (χ2 1,52 = 7.99, p = 0.005; κ = 0.582) but not rMD (χ2 1,48 = 000, p = 0.686; κ = −0.010), a difference which was statistically significant (z = 3.14, p < 0.001, d = 0.66).

Conclusion

Since agreement between parents and children about the severity of children's symptoms was particularly poor in families where parents were currently depressed, parental mental illness should be taken into account when assessing youth psychopathology.
Quantifying adverse events: The burden is on us!
Authors: Claytor Benjamin , Li Yuebing
Published: October 2023

See article on pages 32–39 in this issue.
Skeletal muscle injury in COVID infection: Frequency and patterns
Authors: Rajput Saurabh Singh , Aghoram Rajeswari , Wadwekar Vaibhav , Nanda Nivedita
Published: October 2023

Introduction/Aims

Little is known about skeletal muscle injury with coronavirus disease 2019 (COVID‐19). We estimate the frequency and explore the patterns of skeletal muscle injury in acute COVID‐19.

Methods

A cohort of COVID patients with mild to moderate symptoms were evaluated in a COVID‐designated hospital between May and December 2021 and followed for 2 weeks. Skeletal muscle injury was assessed according to creatine kinase (CK) levels, Manual Muscle Test‐8 (MMT‐8) score, and the Health Assessment Questionnaire (HAQ) score. Injury was defined as CK >200 IU/L with an MMT‐8 score < 76. The association between such injury and severity and outcomes were evaluated using cross‐tabulations.

Results

Two hundred fifty participants with a mean age of 50.2 years (SD: 17.2) were included. One hundred nine (43.6%) were women; 84 (34%) developed severe disease. Median CK levels were 91 IU/L (IQR 56–181). [Correction added on 17 November 2023, after first online publication: In the preceding sentence, the IQR was corrected from ‘56,181’.] Patients with weakness on the MMT‐8 (n = 247, 98.8%) and disability on the HAQ (n = 107; 42.8%) were common. Neck flexor muscles were prominently affected. Skeletal muscle injury was seen in 22.4% (95% CI: 17.4–28.1). There was no significant association between skeletal muscle injury and maximal severity of illness or short‐term outcomes. Disability increased over 14 days in most survivors (n = 172, 72.3%) and this was not seen in those with mild disease (OR: 0.4, 95% CI: 0.22–0.70).

Discussion

Skeletal muscle injury appears to be common in people presenting with mild to moderate COVID infection.
Adipocyte retinoic acid receptor α prevents obesity and steatohepatitis by regulating energy expenditure and lipogenesis
Authors: Cassim Bawa Fathima N. , Hu Shuwei , Gopoju Raja , Shiyab Amy , Mongan Kai , Xu Yanyong , Pan Xiaoli , Clark Alyssa , Wang Hui , Zhang Yanqiao
Published: October 2023

Objective

The adipose tissue–liver axis is a major regulator of the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Retinoic acid signaling plays an important role in development and metabolism. However, little is known about the role of adipose retinoic acid signaling in the development of obesity‐associated NAFLD. In this work, the aim was to investigate whether and how retinoic acid receptor alpha (RARα) regulated the development of obesity and NAFLD.

Methods

RARα expression in adipose tissue of db/db or ob/ob mice was determined. Rarαfl/fl mice and adipocyte‐specific Rarα−/− (RarαAdi−/−) mice were fed a chow diet for 1 year or high‐fat diet (HFD) for 20 weeks. Primary adipocytes and primary hepatocytes were co‐cultured. Metabolic regulation and inflammatory response were characterized.

Results

RARα expression was reduced in adipose tissue of db/db or ob/ob mice. RarαAdi−/− mice had increased obesity and steatohepatitis (NASH) when fed a chow diet or HFD. Loss of adipocyte RARα induced lipogenesis and inflammation in adipose tissue and the liver and reduced thermogenesis. In the co‐culture studies, loss of RARα in adipocytes induced inflammatory and lipogenic programs in hepatocytes.

Conclusions

The data demonstrate that RARα in adipocytes prevents obesity and NASH via inhibiting lipogenesis and inflammation and inducing energy expenditure.
Experimental and Theoretical Investigations of MAPbX3‐Based Perovskites (X=Cl, Br, I) for Photovoltaic Applications
Authors: Mehra Sonali , Pandey Rahul , Madan Jaya , Sharma Rajnish , Goswami Lalit , Gupta Govind , Singh Vidya Nand , Srivastava Avanish Kumar , Sharma Shailesh Narain
Published: October 2023

This work mainly focuses on synthesizing and evaluating the efficiency of methylammonium lead halide‐based perovskite (MAPbX3; X=Cl, Br, I) solar cells. We used the colloidal Hot‐injection method (HIM) to synthesize MAPbX3 (X=Cl, Br, I) perovskites using the specific precursors and organic solvents under ambient conditions. We studied the structural, morphological and optical properties of MAPbX3 perovskites using XRD, FESEM, TEM, UV‐Vis, PL and TRPL (time‐resolved photoluminescence) characterization techniques. The particle size and morphology of these perovskites vary with respect to the halide variation. The MAPbI3 perovskite possesses a low band gap and low carrier lifetime but delivers the highest PCE among other halide perovskite samples, making it a promising candidate for solar cell technology. To further enrich the investigations, the conversion efficiency of the MAPbX3 perovskites has been evaluated through extensive device simulations. Here, the optical constants, band gap energy and carrier lifetime of MAPbX3 were used for simulating three different perovskite solar cells, namely I, Cl or Br halide‐based perovskite solar cells. MAPbI3, MAPbBr3 and MAPbCl3 absorber layer‐based devices showed ~13.7 %, 6.9 % and 5.0 % conversion efficiency. The correlation between the experimental and SCAPS simulation data for HIM‐synthesized MAPBX3‐based perovskites has been reported for the first time.
Structural, optical, and dielectric characteristics of chitosan/hydroxypropyl cellulose‐modified copper vanadate nanoparticles
Authors: Al‐kalali N. A. , Abdelghany A. M. , Bin Anooz S. , Abdelaziz M. , Oraby A. H.
Published: October 2023

Chitosan (Cs) and hydroxypropyl cellulose (HPC) blend films were created and incorporated with copper vanadate nanoparticles. The films were characterized using various techniques, including x‐ray diffraction (XRD), attenuated total reflectance‐Fourier transform infrared (ATR‐FTIR), TEM, SEM, UV/vis spectroscopy, dielectric properties, and AC conductivity. The XRD analysis showed that the prepared films had amorphous characteristics. FT‐IR spectra indicated interactions between the Cs/HPC virgin polymers and copper vanadate nanoparticles. TEM analysis showed that the most prevalent size range of the nanoparticles was 20–60 nm. SEM micrographs revealed surface homogeneity at lower copper vanadate nanoparticle contents but increased inhomogeneity with higher contents. The prepared films showed a decrease in the optical energy gap and an increase in refractive index with increasing copper vanadate nanoparticle content. Copper vanadate nanoparticles enhance AC conductivity in Cs/HPC polymer blend. Dielectric analysis proved the suitability of the films for electroactive polymer applications.

Highlights

The casting process was used to prepare Cs/HPC—copper vanadate NPs films.

XRD shows increased amorphousness post‐addition of copper vanadate NPs.

SEM images revealed an increase in inhomogeneity with higher contents of copper vanadate NPs.

The optical band gap decreased as the content of copper vanadate NPs increased.

Copper vanadate nanoparticles greatly improve electrical conductivity and relaxation time.
Film formation kinetics of polystyrene latex‐based nanocomposites with a broad particle size distribution
Authors: Demirbay Barış
Published: October 2023

The present study article aims to clarify the effect of colloidal polystyrene (PS) latexes with a broad particle size distribution on film formation kinetics of multi‐walled carbon nanotube (MWCNT)‐added polymer nanocomposites by considering theoretical film formation models. Experimentally, light transmitted from nanocomposite films, each having different weight fractions of MWCNT, was recorded at different annealing temperatures via UV–Visible spectrophotometry. Optical data set was then theoretically elaborated by taking into account void closure and Prager‐Tirrell models. Activation energies of viscous flow (ΔH) and backbone motion for reptating PS chains (ΔEB), minimum film formation (T0) and healing (Th) temperatures were then computed from optical data. Experimental results revealed that ΔH required for void closure phenomenon remained unaffected by both nanofiller and size distribution of latexes. On the other hand, it was found that ΔEB for backbone motion promoted upon the addition of nano‐fillers into latex particles. Our experimental findings suggested that film formation from MWCNT‐added latex films with a broad particle size distribution mainly originates from void closure mechanism since ΔH for viscous flow suppresses ΔEB acquired for backbone motion of repeating PS chains to a great extent.

Highlights

A broad size distribution effect of PS on film formation was investigated.

Voids closure and Prager‐Tirrell models were applied to spectroscopic data.

Activation energy of viscous flow is unaffected by size distribution of PS.

Latex film formation with varying size distribution stems from void closure.
The efficacy of transcranial direct current stimulation on upper extremity motor function after stroke: A systematic review and comparative meta‐analysis of different stimulation polarities
Authors: Navarro‐López Víctor , del‐Valle‐Gratacós Manuel , Carratalá‐Tejada María , Cuesta‐Gómez Alicia , Fernández‐Vázquez Diego , Molina‐Rueda Francisco
Published: October 2023

Background

The efficacy of transcranial direct current stimulation (tDCS) has been studied extensively. The cathodic (c‐tDCS), anodic (a‐tDCS), and bihemispheric stimulation have demonstrated efficacy in the management of the paretic upper extremity (UE) after stroke, but it has not been determined which stimulation polarity has, so far, shown the best results.

Objective

To evaluate the available evidence to determine which tDCS polarity has the best results in improving UE motor function after stroke.

Methods

PubMed, PEDro, Web of Science, EMBASE, and SCOPUS databases were searched. Different Medical Subject Headings (MeSH) terms were combined for the search strategy, to cover all studies that performed a comparison between different tDCS configurations focused on UE motor rehabilitation in people with lived experience of stroke.

Results

Fifteen studies remained for qualitative analysis and 12 for quantitative analysis. Non‐significant differences with a 95% confidence interval (CI) were obtained for c‐tDCS versus a‐tDCS (g = 0.10, 95% CI = −0.13; 0.33, p = .39, N = 292), for a‐tDCS versus bihemispheric (g = 0.02, 95% CI = −0.46; 0.42, p = .93, N = 81), and for c‐tDCS versus bihemispheric (g = 0.09, 95% CI = −0.84; .66, p = .73, N = 100). No significant differences between the subgroups of the meta‐analysis were found.

Conclusions

The results of the present meta‐analysis showed no evidence that a stimulation polarity is superior to the others in the rehabilitation of UE motor function after stroke. A non‐significant improvement trend was observed toward c‐tDCS compared to a‐tDCS.
Exercise as a behavioral approach to improve mood in persons with traumatic brain injury
Authors: Wender Carly L. A. , Ray LaShawnna N. , Sandroff Brian M. , Krch Denise
Published: October 2023

Mood disturbance is a common, long‐term, negative consequence of traumatic brain injury (TBI) that is insufficiently addressed by most traditional treatment modalities. A large body of evidence supports the efficacy of exercise training (ET) to broadly improve mood, as measured most often by the Profile of Mood States (POMS). However, this behavioral approach is not used nearly enough in the TBI population, and when it is, mood is rarely measured. This scoping review will evaluate the use of POMS as a mood measure in TBI research and to establish a rationale for using ET as a behavioral approach to broadly improve mood in persons with TBI.
Excited‐state tautomerization of cytidine in water solution when exposed to UVC light
Authors: Cherneva Tsvetina D. , Todorova Mina M. , Bakalska Rumyana I. , Shterev Ivan G. , Horkel Ernst , Delchev Vassil B.
Published: October 2023

The irradiation of water solution of cytidine with UVC light showed that the compound participates in a tautomerism following the kinetics of a first‐order reaction. The PIDA mechanism showed that the proton detachments in the tautomers of cytidine occur through the repulsive 1πσ* excited states and lead to conical intersections S0/S1, whose structures were optimized. More probable is the IRC mechanism, which proceeds along 1nπ* excited state reaction paths. This mechanism includes a water molecule as a catalyst, which assists the phototransformation of amino‐oxo tautomer of cytidine into imino‐hydroxy one.
Molecular wrench activity of DNA helicases: Keys to modulation of rapid kinetics in DNA repair
Authors: Wettasinghe Ashan P. , Seifi Melodee O. , Bravo Marco , Adams Austen C. , Patel Aman , Lou Monica , Kahanda Dimithree , Peng Hao‐Che , Stelling Allison L. , Fan Li , Slinker Jason D.
Published: October 2023

DNA helicase activity is essential for the vital DNA metabolic processes of recombination, replication, transcription, translation, and repair. Recently, an unexpected, rapid exponential ATP‐stimulated DNA unwinding rate was observed from an Archaeoglobus fulgidus helicase (AfXPB) as compared to the slower conventional helicases from Sulfolobus tokodaii, StXPB1 and StXPB2. This unusual rapid activity suggests a “molecular wrench” mechanism arising from the torque applied by AfXPB on the duplex structure in transitioning from open to closed conformations. However, much remains to be understood. Here, we investigate the concentration dependence of DNA helicase binding and ATP‐stimulated kinetics of StXPB2 and AfXPB, as well as their binding and activity in Bax1 complexes, via an electrochemical assay with redox‐active DNA monolayers. StXPB2 ATP‐stimulated activity is concentration‐independent from 8 to 200 nM. Unexpectedly, AfXPB activity is concentration‐dependent in this range, with exponential rate constants varying from seconds at concentrations greater than 20 nM to thousands of seconds at lower concentrations. At 20 nM, rapid exponential signal decay ensues, linearly reverses, and resumes with a slower exponential decay. This change in AfXPB activity as a function of its concentration is rationalized as the crossover between the fast molecular wrench and slower conventional helicase modes. AfXPB‐Bax1 inhibits rapid activity, whereas the StXPB2‐Bax1 complex induces rapid kinetics at higher concentrations. This activity is rationalized with the crystal structures of these complexes. These findings illuminate the different physical models governing molecular wrench activity for improved biological insight into a key factor in DNA repair.
Pediatric model‐based dose optimization using a pooled exposure–response safety analysis for nivolumab and nivolumab plus ipilimumab combination in melanoma
Authors: Du Shengnan , Zhao Yue , Hu Zheyi , Liu Sihang , Roy Amit , Shen Jun , Zhu Li , Hamuro Lora
Published: October 2023

An exposure–response (E–R) safety analysis was conducted across adult and pediatric (<18 years) studies to evaluate the potential impact of higher nivolumab and/or ipilimumab exposures in adolescents (≥12 to <18 years) versus adults with melanoma using the approved adult dosing regimens for nivolumab alone or in combination with ipilimumab. Data from 3507 patients across 15 studies were used to examine the relationship between nivolumab–ipilimumab daily average exposure and time to grade 2+ immune‐mediated adverse events (gr2+ IMAEs). Results from the E–R safety model showed ipilimumab, but not nivolumab, exposure to be a statistically significant predictor of gr2+ IMAEs. Significant covariates included sex (41% higher risk for women than men), line of therapy (19% higher for first‐line than later‐line), and treatment setting (26% lower for adjuvant than advanced melanoma). Younger age and lower body weight (BW) were each associated with a lower risk of gr2+ IMAEs (hazard ratio [HR]: 0.830 for 15‐year‐olds versus 60‐year‐olds and 0.84 for BW 52 kg versus 75 kg). For adolescents with melanoma treated with nivolumab in the advanced or adjuvant settings, these results are supportive of nivolumab flat dosing regimens for adolescents greater than or equal to 40 kg and BW‐based dosing for adolescents less than 40 kg. These results also support adult weight‐based dosing regimens for nivolumab plus ipilimumab in adolescents with advanced melanoma. This analysis suggests that although higher exposures are predicted in adolescents with lower weight compared with adults, there is no predicted immune‐mediated safety risk when treated with the approved adult dosing of nivolumab with/without ipilimumab.
Frequentist and Bayesian tolerance intervals for setting specification limits for left‐censored gamma distributed drug quality attributes
Authors: Montes Richard O.
Published: October 2023

Tolerance intervals from quality attribute measurements are used to establish specification limits for drug products. Some attribute measurements may be below the reporting limits, that is, left‐censored data. When data has a long, right‐skew tail, a gamma distribution may be applicable. This paper compares maximum likelihood estimation (MLE) and Bayesian methods to estimate shape and scale parameters of censored gamma distributions and to calculate tolerance intervals under varying sample sizes and extents of censoring. The noninformative reference prior and the maximal data information prior (MDIP) are used to compare the impact of prior choice. Metrics used are bias and root mean square error for the parameter estimation and average length and confidence coefficient for the tolerance interval evaluation. It will be shown that Bayesian method using a reference prior overall performs better than MLE for the scenarios evaluated. When sample size is small, the Bayesian method using MDIP yields conservatively too wide tolerance intervals that are unsuitable basis for specification setting. The metrics for all methods worsened with increasing extent of censoring but improved with increasing sample size, as expected. This study demonstrates that although MLE is relatively simple and available in user‐friendly statistical software, it falls short in accurately and precisely producing tolerance limits that maintain the stated confidence depending on the scenario. The Bayesian method using noninformative prior, even though computationally intensive and requires considerable statistical programming, produces tolerance limits which are practically useful for specification setting. Real‐world examples are provided to illustrate the findings from the simulation study.
Protective mechanism of Paeonol on central nervous system
Authors: Wu Rui , Liu Yanfang , Zhang Fang , Dai Shu , Xue Xinyan , Peng Cheng , Li Yan , Li Yunxia
Published: October 2023

Cerebrovascular diseases involve neuronal damage, resulting in degenerative neuropathy and posing a serious threat to human health. The discovery of effective drug components from natural plants and the study of their mechanism are a research idea different from chemical synthetic medicines. Paeonol is the main active component of traditional Chinese medicine Paeonia lactiflora Pall. It widely exists in many medicinal plants and has pharmacological effects such as anti‐atherosclerosis, antiplatelet aggregation, anti‐oxidation, and anti‐inflammatory, which keeps generally used in the treatment of cardiovascular and cerebrovascular diseases. Based on the therapeutic effects of Paeonol for cardiovascular and cerebrovascular diseases, this article reviewed the pharmacological effects of Paeonol in Alzheimer's disease, Parkinson's disease, stroke, epilepsy, diabetes encephalopathy, and other neurological diseases, providing a reference for the research of the mechanism of Paeonol in central nervous system diseases.
Biliothorax in a patient with unresectable cholangiocarcinoma
Authors: Valero Sara , Copoví Àlison , Boira Ignacio , Sancho‐Chust Jose N. , Esteban Violeta , de la Paz Alejandro , Chiner Eusebi
Published: October 2023

Biliothorax is a rare but serious condition, as the presence of bile is damaging and can lead to empyema. Here, we report a case of a 51‐year‐old man recently diagnosed with unresectable cholangiocarcinoma, admitted to the hospital for malignant obstructive jaundice. After interventional management of biliary obstruction, the patient developed a significant right pleural effusion compatible with biliothorax, successfully managed with pleural drainage and antibiotic therapy. Resolution was possible with a conservative approach: biliary decompression, chest tube drainage and antibiotics.