Process Development of a Macrocyclic Peptide Inhibitor of PD-L1.

This article outlines the process development leading to the manufacture of 800 g of BMS-986189, a macrocyclic peptide active pharmaceutical ingredient. Multiple N-methylated unnatural amino acids posed challenges to manufacturing due to the lability of the peptide to cleavage during global side chain deprotection and precipitation steps. These issues were exacerbated upon scale-up, resulting in severe yield loss and necessitating careful impurity identification, understanding the root cause of impurity formation, and process optimization to deliver a scalable synthesis. A systematic study of macrocyclization with its dependence on concentration and pH is presented. In addition, a side chain protected peptide synthesis is discussed where the macrocyclic protected peptide is extremely labile to hydrolysis. A computational study explains the root cause of the increased lability of macrocyclic peptide over linear peptide to hydrolysis. A process solution involving the use of labile protecting groups is discussed. Overall, the article highlights the advancements achieved to enable scalable synthesis of an unusually labile macrocyclic peptide by solid-phase peptide synthesis. The sustainability metric indicates the final preparative chromatography drives a significant fraction of a high process mass intensity (PMI).

Clinical manifestations and outcomes of otitis media with effusion in adult patients following Omicron infection in China.

This study investigates the clinical features and therapeutic outcomes of otitis media with effusion (OME) in adults following infection with the Omicron variant of coronavirus disease 2019 (COVID-19), in the context of China ending its "Zero-COVID-19" policy. Conducted as a multicenter, retrospective analysis at two medical institutions in Eastern China from December 2022 to February 2023, the study included patients with confirmed Omicron infection who were diagnosed with OME within two months, adhering to guidelines from the American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF). Data on demographics, time from infection to OME manifestation, associated symptoms, and treatment outcomes were collected. Among 68 patients (73 affected ears) with OME post-Omicron infection, common symptoms included cough and nasal obstruction (69.1%). All reported ear fullness, with 86.8% experiencing hearing loss. Tympanic bullae were observed in 72.6% during otoscopy, and most tympanometry results showed a B-type tympanogram (80.0%). An integrated treatment strategy led to an 83.6% cure rate, although 8.2% experienced relapse within 2-3 months. Our findings highlight OME as a prevalent ear complication associated with COVID-19 during the Omicron pandemic, underscoring the necessity for further investigation into its complexities. While the integrated treatment approach proved effective, the 8.2% post-treatment recurrence rate underscores the importance of ongoing monitoring and signals an urgent need for more comprehensive research.

The silent reservoir? SARS-CoV-2 detection in the middle ear effusion of patients with Otitis media with effusion after omicron infection.

PURPOSE: This multicenter, prospective study is designed to investigate whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is present in the Middle Ear Effusion (MEE) of patients developing Otitis Media with Effusion (OME) subsequent to an Omicron infection. The objective is to elucidate any potential association between the virus and the condition. METHODS: This study, conducted from January to June 2023, spanned the Otolaryngology departments of two medical institutions in Eastern China. Patients manifesting OME subsequent to Omicron infection from both hospitals were subjected to comprehensive otolaryngological assessments, including pure-tone audiometry (PTA), tympanometry, otoscopic examination, and nasopharyngolaryngoscopy. Subsequently, MEE samples extracted from these patients were analyzed through RT-PCR to detect SARS-CoV-2. RESULTS: In this study, 23 patients (32-84 years; 57.5 ± 14.8 mean age; 47.8 % male) presented OME in 25 ears post-Omicron infection, with 21 (91.3 %) exhibiting unilateral symptoms. The median duration from infection to MEE sampling was 21 days (IQR: 25-46; range: 11-150). Predominantly, 64.0 % exhibited Type B tympanograms, and fluid accumulation was observed in 88.0 % of ears. SARS-CoV-2 was detected in 3 MEE samples (12.0 %), with cycle threshold values ranging between 25.65 and 33.30. CONCLUSIONS: Our study highlights the potential effects of COVID-19 on the middle ear, suggesting a link between SARS-CoV-2 and OME onset. The virus, a significant contributor to OME, is detectable in the MEE nearly a month post-Omicron infection, indicating a potential alteration in OME treatment strategies and a risk of recurrence, emphasizing the necessity for otolaryngologist vigilance.

Giant nonlocal Kerr nonlinearity and polaritonic solitons in a Rydberg-dressed Bose-Einstein condensate.

We present a scheme to generate nonlocal optical Kerr nonlinearity and polaritonic solitons via matter-wave superradiance in a Rydberg-dressed Bose-Einstein condensate (BEC). We show that the polariton spectrum of the scattered field generated by the superradiance is changed significantly due to the existence of the long-range Rydberg-Rydberg interaction between atoms, i.e. it has a roton-maxon form; moreover, the BEC structure factor displays a strong dependence on the Rydberg-dressing, which can be tuned in a controllable way. We also show that such a Rydberg-dressed BEC system can support a giant nonlocal optical Kerr nonlinearity, and hence allow the formation and stable propagation of polaritonic solitons, which have ultraslow propagation velocity and ultralow generation power. The results reported here are useful to understand the unique properties of Rydberg-dressing in BECs and have potential applications in optical information processing and transmission.

Matter-wave solitons in an array of spin-orbit-coupled Bose-Einstein condensates.

We investigate matter-wave solitons in a binary Bose-Einstein condensate (BEC) with spin-orbit (SO) coupling, loaded in a one-dimensional (1D) deep optical lattice and a three-dimensional anisotropic magnetic trap, which creates an array of elongated sub-BECs with transverse tunneling. We show that the system supports 1D continuous and discrete solitons localized in the longitudinal (along the array) and the transverse (across the array) directions, respectively. In addition, such solitons are always unpolarized in the zero-momentum state but polarized in finite-momentum states. We also show that the system supports stable two-dimensional semidiscrete solitons, including single- and multiple-peaked ones, localized in both the longitudinal and transverse directions. Stability diagrams for single-peaked semidiscrete solitons in different parameter spaces are identified. The results reported here are beneficial not only for understanding the physical property of SO-coupled BECs but also for generating new types of matter-wave solitons.

Soliton molecules and their scattering by a localized P T-symmetric potential in atomic gases.

We propose a physical scheme to study the formation of optical soliton molecules (SMs), consisting of two solitons bound together with a π-phase difference, and the scattering of SMs by a localized parity-time (P T)-symmetric potential. In order to stabilize SMs, we apply an additional space-dependent magnetic field to introduce a harmonic trapping potential for the two solitons and balance the repulse interaction induced by the π-phase difference between them. On the other hand, a localized complex optical potential obeying P T symmetry can be created through an incoherent pumping and spatial modulation of the control laser field. We investigate the scattering of optical SMs by the localized P T-symmetric potential, which exhibits evident asymmetric behavior and can be actively controlled by changing the incident velocity of SMs. Moreover, the P T symmetry of the localized potential, together with the interaction between two solitons of the SM, can also have a significant effect on the SM scattering behavior. The results presented here may be useful for understanding the unique properties of SMs and have potential applications in optical information processing and transmission.

Unraveling the Strong Fluorescence Enhancement of HPBI Molecules by ZIF-8 Colloidal Suspensions via Adsorption Analysis.

Enhancing the fluorescence of organic dye by colloidal particles is one of the most promising routes to optimize fluorescence detection. However, in addition to metallic particles, which serve as the most frequently used particles and have been found to employ the plasmonic resonance to provide strong fluorescence enhancement, neither new types of colloidal particles nor new fluorescence mechanisms have been intensively explored in recent years. In this work, strongly enhanced fluorescence was observed when 2-(2-hydroxyphenyl)-1H-benzimidazole (HPBI) molecules were simply mixed with zeolitic imidazolate framework-8 (ZIF-8) colloidal suspensions. Moreover, the enhancement factor ΔI = IHPBI+ZIF-8/IHPBI does not increase accordingly with the increasing amount of HPBI. To find out how the strong fluorescence was triggered and affected by the amount of HPBI, multiple techniques were applied to analyze the adsorption behavior. By combining analytical ultracentrifugation with first-principles calculations, we proposed that HPBI molecules were adsorbed onto the surface of ZIF-8 particles coordinatively and electrostatically, depending on the concentration of HPBI molecules. The coordinative adsorption would result in a new kind of fluorescence emitter. The new fluorescence emitters tend to distribute on the outer surface of ZIF-8 particles periodically. The distance between each fluorescence emitter is fixed and much smaller than the wavelength of the excitation light. Thus, it can be concluded that collective spontaneous emission might be triggered.

Correlation of lipoprotein lipase gene polymorphism and mRNA expression with intramuscular fat content in Baicheng-Oil chicken.

Lipoprotein lipase (LPL) was often taken as a candidate gene for investigating fat metabolism. However, there are few studies on the effect of LPL on intramuscular fat (IMF) deposition in Baicheng oil chicken (BOC) and Three-yellow Chicken (TYC). In this study, we studied the relationship between polymorphism and messenger RNA (mRNA) expression of LPL with IMF deposition in the chest muscle (CM) and leg muscle (LM) of TYC and BOC. Sixty TYCs and 60 BOCs were raised from 1 d and slaughtered by avascularization at their slaughtering age. IMF contents of the CM and LM in the BOC were markedly higher than those in the TYC. Three genotypes following AA, AB and BB were found by the method of polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). The synonymous mutation C12315T was detected. The content of IMF with the AA genotype was significantly higher than the AB genotype in the LM of TYC. The mRNA expression both of CM and LM in BOC was prominently higher than those in TYC, and there was a positive significant correlation between LM and CM in both BOC and TYC. These results suggested that the SNPs polymorphism and mRNA expression of the LPL gene might be helpful for selective breeding in IMF of the chicken.

Application of Smartphone Otoscope in Telemedicine in Rural Medical Consortium in Eastern China in the COVID-19 Era.

Purpose: This study aimed to evaluate the effectiveness of smartphone otoscope telemedicine in the rural medical consortium in East China in the COVID-19 era. Methods: This prospective study was conducted within a rural medical consortium that provides health care services by integrating medical resources in the same area. When a patient visited primary health care (PHC) for ear diseases, the PHC provider used a smartphone otoscope to examine the patient's external ear canal and eardrum, and then sent photos or videos of the patient's ear to the otolaryngologist at the lead hospital via WeChat group. The otolaryngologist provided remote diagnosis and management recommendations to the PHC provider. The following data were recorded: age and gender, outpatient diagnosis, disease duration, sides, duration of treatment, telemedicine visits, treatment outcomes, patient satisfaction, and PHC providers' self-evaluation score. Results: A total of 83 patients were included in the study, including 43 males and 40 females, with a mean age of 44.6 ± 19.7 years (range 3-83 years). The duration of treatment for these patients was 14.0 (7,14) days. PHC visits were 2.2 ± 1.1 times (range: 1-7 times). Telemedicine visits ranged from 1 to 5, with a mean of 1.8 ± 0.9. Among of patients, 62 (74.7%) were cured, 21 (25.3%) improved, and 0 (0%) were ineffective. Sixty-five patients (78.3%) were very satisfied, 16 (19.3%) patients were somewhat satisfied, and two patients (2.4%) were dissatisfied. Based on the self-reported helpfulness, the primary health care providers assessed telemedicine as very helpful (n = 63, 75.9%), helpful (n = 20, 24.1%), and unhelpful (n = 0, 0%). Conclusions: Smartphone otoscope telemedicine in the medical consortium can effectively improve the ability of rural PHC providers to diagnose and treat ear diseases, save time and costs for patients, and improve patient satisfaction.

P(III) vs P(V): A P(V) Reagent for Thiophosphoramidate Linkages and Application to an Asymmetric Synthesis of a Cyclic Dinucleotide STING Agonist.

A highly stereoselective synthesis of a cyclic dinucleotide (CDN) STING agonist containing two chiral thiophosphoramidate linkages is described. These rare yet key functional groups were, for the first time, installed efficiently and with high diastereoselectivity using a specially designed P(V) reagent. By utilizing this strategy, the CDN was prepared in greater than 16-fold higher yield than the prior P(III) approach, with fewer hazardous reagents and chromatographic purifications.

Fluorescence of CoTPP Mediated by the Plasmon-Exciton Coupling Effect in the Tunneling Junction.

CoTPP, as a common hypsoporphyrin, is usually not a luminescent molecule because of the open-shell Co ion. In this paper, well-defined multilayer CoTPP molecules self-assembled on Au(111) surface are characterized layer by layer with scanning tunneling microscope (STM) induced luminescence. By using the highly localized STM tunneling current, we not only investigate the influence of bias polarity on the amplitude of distinct plasmonic emission resulted from the interaction between the metal substrate and the metal ions but also first obtain the light emission from the hypsoporphyrins in the tunneling junction. The density-matrix method and the combined approach of classical electrodynamics and first-principles calculation are used to explain the mechanism of the light emission. These findings may expand the underlying physics of plasmon-exciton coupling in STM nanocavity and reveal a new possible path to overcome the fluorescent potential of hypsoporphyrins by the intense localized electric fields.

Telemedicine for ear diseases with the smartphone otoscopes via WeChat in the COVID-19 era.

PURPOSE: This study aimed to evaluate the outcomes and satisfaction of ear patients who participated in the smartphone otoscopes telemedicine via WeChat. METHODS: Patients in this study included newly diagnosed outpatients and online patients who did not undergo an outpatient diagnosis. Patients performed regular ear self-examinations, took pictures at home using their smartphone endoscopes, and submitted images to a WeChat community. Otolaryngologist gave timely online feedback. All of the following data were recorded: patients age and gender, disease duration, outpatient diagnosis, side, telemedicine duration, number of telemedicine visits, outcomes, satisfaction. RESULTS: A total of 74 patients were included in the study, including 39 males and 35 females, with an average age of 31.1 ± 13.7 years (range 4-55 years). Of these patients, 68 were outpatients, and 6 directly participated in telemedicine online. The patient's disease duration ranged from 1 day to 15 days, with an average of 4.0 ± 3.0 days. The mean duration was 8.1 days (range: 3-21 days) for telemedicine. The mean number of visits was 2.7 times (range: 2-6 times) for telemedicine. 68 (91.9%) of the 74 patients were cured, 6 (8.1%) were improved, and 0 (0%) were ineffective. Almost all patients were pleased with the telemedicine service, 71.9 0% were very satisfied (n = 62), 28.10% were very satisfied (n = 11), and 0% were dissatisfied (n = 0). CONCLUSIONS: Smartphone otoscopes telemedicine can decrease outpatient follow-up, reduce the risk of cross-infection, increase telemedicine accuracy, and improve patient satisfaction. It is worthy of clinical application in the COVID-19 era.

The casein kinase 2α promotes the occurrence polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a complicated reproductive endocrine disease characterized by hyperandrogenism, polycystic ovaries, and anovulation. Previous studies have revealed that androgen receptors (ARs) are strongly associated with hyperandrogenism and abnormalities in folliculogenesis in patients with PCOS. However, the kinases responsible for androgen receptor activity, especially in granulosa cells, and the role of casein kinase 2α (CK2α) specifically in the pathogenesis of PCOS, remain unknown. Here, we show that both CK2α protein and mRNA levels were higher in luteinized granulosa cells of patients with PCOS compared with non-PCOS, as well as in the ovarian tissues of mice with a dehydroepiandrosterone-induced PCOS-like phenotype, compared with controls. In addition, CK2α not only interacted with AR in vivo and in vitro, but it also phosphorylated and stabilized AR, triggering AR and ovulation related genes excessive expression. CK2α also promoted cell proliferation in the KGN cell line and inhibited apoptosis. Collectively, the finding highlighted that the CK2α-AR axis probably caused the etiology of the PCOS. Thus, CK2α might be a promising clinical therapeutic target for PCOS treatment.

A revised Ladevèze criteria for carbon fiber reinforced laminated plates.

All parameters of revised Ladevèze failure criterion in Table 1 were determined based on mechanical tests which mainly include quasi-static tensile experiments, quasi-static compressive experiments, quasi-static tensile cyclic loading experiments, the dynamic tensile experiments, dynamic compressive experiments, quasi-static and dynamic inter-laminar shear experiments. The quasi-static experiments were performed using an electronic universal testing machine with a maximum load capacity of 10KN, and the split Hopkinson pressure bar (SHPB) and split Hopkinson tension bar (SHTB) were employed in dynamic experiments. In addition, the parameters of traditional orthogonal anisotropic model and cohesive layer for the laminated plates are listed in Table 2.

Association of A-FABP gene polymorphism and mRNA expression with intramuscular fat content (IMF) in Baicheng-You chicken.

This study aims to assess the association of polymorphisms and mRNA expression of adipocyte-type fatty acid-binding protein (A-FABP) with intramuscular fat (IMF) in the breast muscle (BM) and leg muscle (LM) of Baicheng-You chickens (BYCs). A total of 180 chickens, including sixty black Baicheng-You chickens (BBYCs), sixty silky Baicheng-You chickens (SBYCs) and sixty white Baicheng-You chickens (WBYCs), were reared from 1 to 120 day. A polymerase chain reaction-single-strand conformation polymorphism strategy (PCR-SSCP) was used to detect the polymorphism of the A-FABP gene in the first exon, and the C51T silent mutational site was found. The IMF content with the AA genotype was significantly higher than that with the AG genotype (p = 0.0473) in the LM of WBYC. Thus, this site could be taken as a molecular marker in selecting a higher IMF content of LM in WBYC. A-FABP gene mRNA expression in the BM and LM of BYCs was detected, and a significant positive correlation was observed in the LM of WBYC. These findings provide fundamental data that might be useful in further study of the role of the A-FABP gene in IMF content and fatty metabolism in chickens.

Prenatal exposure to testosterone induces cardiac hypertrophy in adult female rats through enhanced Pkcδ expression in cardiac myocytes.

High circulating androgen in women with polycystic ovary syndrome (PCOS) may increase the risk of cardiovascular disease in offspring. The aim of the present study is to investigate whether maternal androgen excess in the rat PCOS model would lead to cardiac hypertrophy in offspring. Maternal testosterone propionate (maternal-TP)-treated adult female offspring displayed cardiac hypertrophy associated with local high cardiac dihydrotestosterone (DHT). The molecular markers of cardiac hypertrophy along with androgen receptor (AR) and PKCδ, were increased in the Maternal-TP group. Treatment of primary neonatal rat ventricular cardiomyocytes (NRCMs) and H9c2 cells with DHT significantly increased cell size and upregulated PKCδ expression, which could be attenuated by AR antagonist. Treatment with phorbol 12-myristate 13-acetate (PMA), a PKC activator, significantly increased cell size and upregulated myh7 level. Rottlerin, that may inhibit PKCδ, significantly reduced the hypertrophic effect of DHT and PMA on NRCMs and H9c2 cells. Chromatin immunoprecipitation revealed that AR could bind to Pkcδ promoter. Our results indicate that prenatal exposure to testosterone may induce cardiac hypertrophy in adult female rats through enhanced Pkcδ expression in cardiac myocytes.

Unlocking P(V): Reagents for chiral phosphorothioate synthesis.

Phosphorothioate nucleotides have emerged as powerful pharmacological substitutes of their native phosphodiester analogs with important translational applications in antisense oligonucleotide (ASO) therapeutics and cyclic dinucleotide (CDN) synthesis. Stereocontrolled installation of this chiral motif has long been hampered by the systemic use of phosphorus(III) [P(III)]-based reagent systems as the sole practical means of oligonucleotide assembly. A fundamentally different approach is described herein: the invention of a P(V)-based reagent platform for programmable, traceless, diastereoselective phosphorus-sulfur incorporation. The power of this reagent system is demonstrated through the robust and stereocontrolled synthesis of various nucleotidic architectures, including ASOs and CDNs, via an efficient, inexpensive, and operationally simple protocol.

Fullerol improves seed germination, biomass accumulation, photosynthesis and antioxidant system in Brassica napus L. under water stress.

Carbon nanoparticles are widely studied for affecting crop production in agriculture. Considering their potential threats to the crops, especially under drought stress, is important for carbon nanoparticle application. However, the influence of polyhydroxy fullerene-fullerol on drought tolerance at the physiological and molecular levels in Brassica napus remains unclear. In the present study, different doses of fullerol were applied to seeds or leaves of B. napus subjected to water stress. The results showed that water stress significantly reduced the seed germination, aboveground dry weight, and photosynthesis, whereas it increased the abscisic acid (ABA) concentration, reactive oxygen species (ROS) accumulation, levels of non-enzymatic substances, and activities of antioxidant enzymes in B. napus. Priming with fullerol at 10 and 100 mg L-1 in seeds exhibited a significant promotional effect on seed germination under 15% polyethylene glycol treatment. Moreover, foliar application of fullerol raised the aboveground dry weight and photosynthesis in B. napus seedlings under soil drying. Compared with soil drying alone, the accumulation of ROS was repressed, which was concomitant with higher concentrations of non-antioxidant substances and increased activities of antioxidant enzymes in leaves of seedlings exposed to fullerol at specific concentrations addition with water shortage. Fullerol treatments at 1-100 mg L-1 dramatically increased the leaf ABA level and induced ABA biosynthesis by down-regulating the expression of the ABA catabolic gene CYP707A3 under drought. It is concluded that exogenous fullerol with seed priming or foliar application can stimulate growth in B. napus when water-stressed. The increased antioxidant ability that collectively detoxified ROS improved the drought tolerance in B. napus seedlings under foliar-applied fullerol treatment.

5-aminolevulinic acid improves salt tolerance mediated by regulation of tetrapyrrole and proline metabolism in Brassica napus L. seedlings under NaCl stress.

5-aminolevulinic acid (ALA), a key biosynthetic precursor of tetrapyrroles, is vital for plant growth and adaptation to stress environments. Although exogenous ALA could enhance photosynthesis and biomass accumulation in plants under stress conditions, the underlying physiological and molecular mechanisms governed by ALA in promoting salt tolerance in Brassica napus L. are not yet clearly understood. In the present study, exogenous ALA with the concentration of 30 mg L-1 was applied to the leaves of B. napus seedlings subjected to 200 mM NaCl. The results showed that NaCl stress decreased the photosynthesis, biomass accumulation, and levels of chlorophyll and heme with the reduction of the concentrations of intermediates including ALA, protoporphyrin IX (Proto IX), Mg-Proto IX, and Pchlide in the tetrapyrrole (chlorophyll and heme) biosynthetic pathway. The transcript levels of genes encoding ALA-associated enzymes and genes encoding Mg-chelatase in the chlorophyll biosynthetic branch were down-regulated, while the expression levels of genes encoding Fe-chelatase in the heme branch were not significantly altered by NaCl stress. Foliar application with ALA enhanced the aboveground biomass, net photosynthetic rate, activities of antioxidant enzymes, accumulation of chlorophyll and heme, and concentrations of intermediates related to chlorophyll and heme biosynthesis in B. napus under 200 mM NaCl. The expression of most genes mentioned above remained constant in ALA-treated plants in comparison with non-ALA-treated plants under NaCl stress. Additionally, exogenous ALA synchronously induced the proline concentration and up-regulated the expression of genes P5CS and ProDH encoding proline metabolic enzymes in the NaCl treatment. These findings suggested that ALA improved salt tolerance through promoting the accumulation of chlorophyll and heme resulting from the increase of intermediate levels in the tetrapyrrole biosynthetic pathway, along with enhancing the proline accumulation in B. napus.