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).

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.

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.

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.

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.

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.

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.

Effect of PT symmetry on nonlinear waves for three-wave interaction models in the quadratic nonlinear media.

We study the three-wave interaction that couples an electromagnetic pump wave to two frequency down-converted daughter waves in a quadratic optical crystal and PT-symmetric potentials. PT symmetric potentials are shown to modulate stably nonlinear modes in two kinds of three-wave interaction models. The first one is a spatially extended three-wave interaction system with odd gain-and-loss distribution in the channel. Modulated by the PT-symmetric single-well or multi-well Scarf-II potentials, the system is numerically shown to possess stable soliton solutions. Via adiabatical change of system parameters, numerical simulations for the excitation and evolution of nonlinear modes are also performed. The second one is a combination of PT-symmetric models which are coupled via three-wave interactions. Families of nonlinear modes are found with some particular choices of parameters. Stable and unstable nonlinear modes are shown in distinct families by means of numerical simulations. These results will be useful to further investigate nonlinear modes in three-wave interaction models.

Weak-light vector rogue waves, breathers, and their Stern-Gerlach deflection via electromagnetically induced transparency.

We propose a scheme for generating and manipulating vector (or two-component) optical rogue waves using Akhmediev and Kuznetsov-Ma breathers in a coherent atomic system with an M-type five-level configuration via electromagnetically induced transparency (EIT). We show that the propagation velocity of these nonlinear excitations can be reduced to 10-4c and their generation power can be lowered to microwatts. We also show that the motion trajectories of the two polarization components in these excitations can be deflected significantly by using a transversal gradient magnetic field, similar to the Stern-Gerlach effect of an atomic beam. We find that the deflection angle can reach to 10-4 radian within the propagation distance of only several centimeters; at variance with the atomic Stern-Gerlach effect, the deflection angle can be made different for different polarization components and may be actively adjusted in a controllable way. The results obtained may have promising applications, including the precise measurement of gradient magnetic fields.

Thermal analysis of optical reference cavities for low sensitivity to environmental temperature fluctuations.

The temperature stability of optical reference cavities is significant in state-of-the-art ultra-stable narrow-linewidth laser systems. In this paper, the thermal time constant and thermal sensitivity of reference cavities are analyzed when reference cavities respond to environmental perturbations via heat transfer of thermal conduction and thermal radiation separately. The analysis as well as simulation results indicate that a reference cavity enclosed in multiple layers of thermal shields with larger mass, higher thermal capacity and lower emissivity is found to have a larger thermal time constant and thus a smaller sensitivity to environmental temperature perturbations. The design of thermal shields for reference cavities may vary according to experimentally achievable temperature stability and the coefficient of thermal expansion of reference cavities. A temperature fluctuation-induced length instability of reference cavities as low as 6 × 10(-16) on a day timescale can be achieved if a two-layer thermal shield is inserted between a cavity with the coefficient of thermal expansion of 1 × 10(-10) /K and an outer vacuum chamber with temperature fluctuation amplitude of 1 mK and period of 24 hours.

Localization of light in a parity-time-symmetric quasi-periodic lattice.

We address the propagation of light in a parity-time (PT) symmetric quasi-periodic optical lattice. We show that the PT-symmetry breaking threshold of the system depends on the relative strength of two simple lattices forming quasi-periodic structure. The increase of the imaginary part of such structure leads to a dynamical phase transition from delocalization to re-localization for all eigenmodes. The nontrivial interplay between PT-symmetry breaking and the delocalization-localization transition in the system opens new prospects for the manipulation of dynamical evolution of light beams.

PT-symmetric coupler with a coupling defect: soliton interaction with exceptional point.

We study the interaction of a soliton in a parity-time (PT) symmetric coupler which has local perturbation of the coupling constant. This defect does not change the PT-symmetry of the system, but locally can achieve the exceptional point. We found that the symmetric solitons after interaction with the defect either transform into breathers or blow up. The dynamics of antisymmetric solitons are more complex, showing domains of successive broadening of the beam and of the beam splitting in two outward propagating solitons, in addition to the single breather generation and blowup. All the effects are preserved when the coupling strength in the center of the defect deviates from the exceptional point. If the coupling is strong enough, the only observable outcome of the soliton-defect interaction is the generation of the breather.

Tunable nonlinear double-core PT-symmetric waveguides.

We propose a scheme for creating a tunable, highly nonlinear defect in a one-dimensional photonic crystal with an embedded atomic cell filled by a mixture of two isotopes of three-level atoms. The defect creates an effective double-core waveguide. The induced refractive index for a probe field can be made parity-time (PT) symmetric by means of a proper combination of a control field and a Stark field; hence the complex defect potential obtained contains double-well real and linear imaginary parts. We also show that it is possible to form various stable nonlinear defect modes supported by the focusing nonlinearity of the system.

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.

Subluminal and superluminal terahertz radiation in metamaterials with electromagnetically induced transparency.

We propose a scheme to design a new type of optical metamaterial that can mimic the functionality of four-state atomic systems of N-type energy-level configuration with electromagnetically induced transparency (EIT). We show that in such metamaterial a transition from a single EIT to a double EIT of terahertz radiation may be easily achieved by actively tuning the intensity of the infrared pump field or passively tuning the geometrical parameters of resonator structures. In addition, the group velocity of the terahertz radiation can be varied from subluminal to superluminal by changing the pump field intensity. The scheme suggested here may be used to construct chip-scale slow and fast light devices and to realize rapidly responded switching of terahertz radiation at room temperature.