Extrafollicular PD-1highCXCR5-CD4+ T cells participate in local immunoglobulin production in nasal polyps.

BACKGROUND: Local immunoglobulin hyperproduction is observed in nasal polyps (NPs) with and without ectopic lymphoid tissues (eLTs). OBJECTIVE: Our aim was to identify the T-cell subsets involved in local immunoglobulin production independent of eLTs in NPs. METHODS: The localization, abundance, and phenotype of CD4+ T-cell subsets were studied by immunofluorescence, flow cytometry, and single-cell RNA sequencing. Purified nasal T-cell subsets were cultured with autologous peripheral naive B cells to explore their function. Programmed death ligand 1 and programmed death ligand 2 expression in NPs was investigated by immunofluorescence staining and flow cytometry. RESULTS: Accumulation of PD-1highCXCR5-CD4+ T cells outside lymphoid aggregates was found in NPs. Nasal PD-1highCXCR5-CD4+ T cells were characterized by a unique phenotype that was related to B-cell help and tissue residency and distinct from PD-1-/intCXCR5- and CXCR5+ CD4+ T cells in NPs as well as PD-1highCXCR5highCD4+ follicular helper T cells in tonsils. Compared with the frequencies of PD-1highCXCR5-CD4+ T cells and their IFN-γ+, IL-17A+, and IL-21+ subsets in the control inferior turbinate tissues, the frequencies of these cells and their subsets were increased in both eosinophilic and noneosinophilic NPs, whereas the frequencies of the IL-4+ and IL-4+IL-21+ subsets were increased only in eosinophilic NPs. Nasal PD-1highCXCR5-CD4+ T cells induced immunoglobulin production from B cells in a potency comparable to that induced by tonsillar follicular helper T cells. PD-1highCXCR5-CD4+ T-cell frequencies were correlated with IgE levels in eosinophilic NPs. PD-L1 and PD-L2 suppressed the function of PD-1highCXCR5-CD4+ T cells, and their levels were reduced in NPs. PD-1highCXCR5-CD4+ T-cell abundance was associated with the postsurgical relapse of NPs. CONCLUSION: PD-1highCXCR5-CD4+ T cells participate in local immunoglobulin production independent of eLTs in NPs.

Ammonia nitrogen recovery from biogas slurry by SCP production using Candida utilis.

The safe and robust yeast Candida utilis was employed for nitrogen recovery as single cell protein from biogas slurry. The maximum biomass of 6.2 g/L with protein content of 53.5% was produced in batch cultivation with glucose as the carbon source, C/N ratio of 3:1, NH4+-N concentration of 3000 mg/L, initial pH of 8.0, and the addition of 0.35% (w/v) Na2HPO4. It was speculated that C. utilis can grow well with free ammonia below 197 mg/L. In fed-batch fermentation, a biomass of 14.8 g/L was obtained, and the maintenance of aerobic conditions was critical to improving the production of single cell protein. The sterilized and non-sterilized biogas slurry can be used as an effective pH regulator. The obtained single cell protein was a nutritious, safe, and reliable protein source. This study provides novel insights into nitrogen recovery via C. utilis as a single cell protein from biogas slurry.

Therapeutic monoclonal antibodies and clinical laboratory tests: When, why, and what is expected?

BACKGROUND: We herein provide an overview of the clinical laboratory tests that should be performed before, during and after using therapeutic monoclonal antibodies (mAbs) and the clinical laboratory tests that may be affected by mAbs. METHODS: The labels of FDA-approved therapeutic mAbs were downloaded from DailyMed (the official website for drug labels) and were used as the sources of data for this review. RESULTS: It was found that most of the labels provided information relevant to the clinical laboratory tests, including the tests needed before mAbs treatment to check the patients' background status and to identify potentially sensitive patients, the tests needed during or after the treatment to evaluate the patients' response, and the mAbs that may lead to false positive or negative results for clinical laboratory tests. CONCLUSIONS: The present findings will be of interest to physicians, laboratory scientists, those involved in drug development and surveillance and individuals making health care policy.

FDA-approved drugs that are spermatotoxic in animals and the utility of animal testing for human risk prediction.

PURPOSE: This study reviews FDA-approved drugs that negatively impact spermatozoa in animals, as well as how these findings reflect on observations in human male gametes. METHODS: The FDA drug warning labels included in the DailyMed database and the peer-reviewed literature in the PubMed database were searched for information to identify single-ingredient, FDA-approved prescription drugs with spermatotoxic effects. RESULTS: A total of 235 unique, single-ingredient, FDA-approved drugs reported to be spermatotoxic in animals were identified in the drug labels. Forty-nine of these had documented negative effects on humans in either the drug label or literature, while 31 had no effect or a positive impact on human sperm. For the other 155 drugs that were spermatotoxic in animals, no human data was available. CONCLUSION: The current animal models are not very effective for predicting human spermatotoxicity, and there is limited information available about the impact of many drugs on human spermatozoa. New approaches should be designed that more accurately reflect the findings in men, including more studies on human sperm in vitro and studies using other systems (ex vivo tissue culture, xenograft models, in silico studies, etc.). In addition, the present data is often incomplete or reported in a manner that prevents interpretation of their clinical relevance. Changes should be made to the requirements for pre-clinical testing, drug surveillance, and the warning labels of drugs to ensure that the potential risks to human fertility are clearly indicated.

Automatic online detection of atrial fibrillation based on symbolic dynamics and Shannon entropy.

BACKGROUND: Atrial fibrillation (AF) is the most common and debilitating abnormalities of the arrhythmias worldwide, with a major impact on morbidity and mortality. The detection of AF becomes crucial in preventing both acute and chronic cardiac rhythm disorders. OBJECTIVE: Our objective is to devise a method for real-time, automated detection of AF episodes in electrocardiograms (ECGs). This method utilizes RR intervals, and it involves several basic operations of nonlinear/linear integer filters, symbolic dynamics and the calculation of Shannon entropy. Using novel recursive algorithms, online analytical processing of this method can be achieved. RESULTS: Four publicly-accessible sets of clinical data (Long-Term AF, MIT-BIH AF, MIT-BIH Arrhythmia, and MIT-BIH Normal Sinus Rhythm Databases) were selected for investigation. The first database is used as a training set; in accordance with the receiver operating characteristic (ROC) curve, the best performance using this method was achieved at the discrimination threshold of 0.353: the sensitivity (Se), specificity (Sp), positive predictive value (PPV) and overall accuracy (ACC) were 96.72%, 95.07%, 96.61% and 96.05%, respectively. The other three databases are used as testing sets. Using the obtained threshold value (i.e., 0.353), for the second set, the obtained parameters were 96.89%, 98.25%, 97.62% and 97.67%, respectively; for the third database, these parameters were 97.33%, 90.78%, 55.29% and 91.46%, respectively; finally, for the fourth set, the Sp was 98.28%. The existing methods were also employed for comparison. CONCLUSIONS: Overall, in contrast to the other available techniques, the test results indicate that the newly developed approach outperforms traditional methods using these databases under assessed various experimental situations, and suggest our technique could be of practical use for clinicians in the future.

Effects of pomegranate (Punica granatum L.) peel on the growth performance and intestinal microbiota of broilers challenged with Escherichia coli.

The effects of pomegranate peel on the growth performance, intestinal morphology, and the cecal microbial community were investigated in broilers challenged with avian pathogenic Escherichia coli (APEC) O78. A total of 240 one-day-old chicks (120 males and 120 females) were randomly and evenly allotted into 4 treatment groups (each with 6 biological replicates each of 10 chicks), i.e., negative control (NC), positive control (PC), and 2 experimental groups treated with 0.2% fermented pomegranate peel (FP) and 0.2% unfermented pomegranate peel (UFP), respectively, with PC, FP, and UFP groups challenged with APEC O78 (5 × 108 CFU) on day 14. Results showed that the challenge of APEC O78 decreased the body weight (BW) and average daily gain (ADG) of broilers from 1 to 28 d (P < 0.01). These broilers exhibited more pathological conditions in the heart and liver and higher mortality rates in 28 d compared to the NC group. Diet supplemented with pomegranate peel (either fermented or unfermented) significantly increased BW, ADG, and the villus height/crypt depth ratio (VCR) of small intestine in 28 d compared to the NC group (P < 0.05). Results of the taxonomic structure of the gut microbiota showed that compared to the NC group, the APEC challenge significantly decreased the relative abundance of Bacteroidetes and increased the relative abundance of Firmicutes (P < 0.01). Compared to the PC group, the relative abundance of Ruminococcus_torques_group in FP group was increased, while the relative abundance of Alistipes was decreased. In summary, our study showed that the dietary supplementation of pomegranate peel could maintain the intestinal microbiota at a state favorable to the host, effectively reduce the abnormal changes in the taxonomic structure of the intestinal microbiota, and improve the growth performance in broilers treated with APEC.

Comparative Analysis of Six Chloroplast Genomes in Chenopodium and Its Related Genera (Amaranthaceae): New Insights into Phylogenetic Relationships and the Development of Species-Specific Molecular Markers.

Species within the genus Chenopodium hold significant research interest due to their nutritional richness and salt tolerance. However, the morphological similarities among closely related species and a dearth of genomic resources have impeded their comprehensive study and utilization. In the present research, we conduct the sequencing and assembly of chloroplast (cp) genomes from six Chenopodium and related species, five of which were sequenced for the first time. These genomes ranged in length from 151,850 to 152,215 base pairs, showcased typical quadripartite structures, and encoded 85 protein-coding genes (PCGs), 1 pseudogene, 37 tRNA genes, and 8 rRNA genes. Compared with the previously published sequences of related species, these cp genomes are relatively conservative, but there are also some interspecific differences, such as inversion and IR region contraction. We discerned 929 simple sequence repeats (SSRs) and a series of highly variable regions across 16 related species, predominantly situated in the intergenic spacer (IGS) region and introns. The phylogenetic evaluations revealed that Chenopodium is more closely related to genera such as Atriplex, Beta, Dysphania, and Oxybase than to other members of the Amaranthaceae family. These lineages shared a common ancestor approximately 60.80 million years ago, after which they diverged into distinct genera. Based on InDels and SNPs between species, we designed 12 pairs of primers for species identification, and experiments confirmed that they could completely distinguish 10 related species.

The synergistic effect of rumen cellulolytic bacteria and activated carbon on thermophilic digestion of cornstalk.

To explore the bioaugmentation of rumen cellulolytic bacteria (RCB) and activated carbon (AC) on thermophilic digestion of cornstalk, biochemical methane potential tests were carried out. Adding RCB or AC can improve methane production, while simultaneous existence of AC (10 g/L) and RCB (5%) obtained the best performance. The maximum cellulose degradation rate, methane production rate and methane yield were 66.92%, 32.2 L/(kgVS·d), and 144.9 L/kgVS, which increased by 30.23%, 51.17%, and 20.35% compared with control group. The cellulolytic and fermentative bacteria (Hydrogenispora), syntrophic acetate-oxidizing bacteria (norank_o_MBA03), and hydrogenotrophic Methanothermobacter were crucial for thermophilic digestion of cornstalk. The enhancement of AC was due to the enrichment of Hydrogenispora and Methanothermobacter, while RCB can increase the abundance of cellulolytic bacteria (Halocella and norank_o_M55-D21) and mixotrophic Methanosarcina. The synergetic effect of AC and RCB owing to the enriched cellulolytic bacteria, the enhanced syntrophic acetate oxidation and the concentrated carbon metabolic flow to methane.

The need for contraception in patients taking prescription drugs: a review of FDA warning labels, duration of effects, and mechanisms of action.

Introduction: This review provides a guide for the rational use of prescription drugs in patients of reproductive age. Areas covered: A comprehensive retrieval of the labels of FDA-approved drugs was performed to identify drugs where the label recommends contraceptive use during and/or after treatment. The acquired data were analyzed and organized into a table. Contraception was recommended or mandated for 268 single-ingredient drugs. These could be divided into four main categories, with many having effects across several categories: 177 drugs required contraception because they were associated with pregnancy loss or stillbirth, 177 drugs were associated with teratogenesis, 136 were associated with non-teratogenic adverse peri- or postnatal effects on the fetus (e.g. low birth weight), and 44 were associated with decreased efficacy of contraception or a change in ovulatory cycle. We also discuss the period of time contraception is required, as well as the known or hypothesized reasons for the reproductive toxicity of these agents. Expert opinion: We have provided a comprehensive overview of the FDA-approved drugs where the warning labels currently stipulate that contraception should be used. Although other references are available for clinicians, this review provides a useful source of information regarding the single-ingredient prescription drugs that may affect the outcome of pregnancy. This information is particularly relevant for researchers, as it provides an overview of the different drugs with reproductive toxicity, and because it highlights the specific needs for future research. In particular, more work (especially epidemiological studies) is needed to clarify the clinical relevance of these findings, most of which were obtained through animal studies.

Targeting BCR-ABL+ stem/progenitor cells and BCR-ABL-T315I mutant cells by effective inhibition of the BCR-ABL-Tyr177-GRB2 complex.

Treatment of BCR-ABL+ human leukemia has been significantly improved by ABL tyrosine kinase inhibitors (TKIs), but they are not curative for most patients and relapses are frequently associated with BCR-ABL mutations, warranting new targets for improved treatments. We have now demonstrated that protein expression of human estrogen receptor alpha 36 (ERα36), an alternative splicing variant of human estrogen receptor alpha 66 (ERα66), is highly increased in TKI-insensitive CD34+ chronic myeloid leukemia (CML) cells and BCR-ABL-T315I mutant cells, and is abnormally localized in plasma membrane and cytoplasm. Interestingly, new pre-clinically-validated analogs of Icaritin (SNG162 and SNG1153), which target abnormal ERα36 activity, inhibit cell growth and induce apoptosis of BCR-ABL+ leukemic cells, particularly BCR-ABL-T315I mutant cells. A combination of SNG inhibitors and TKI selectively eliminates treatment-naïve TKI-insensitive stem/progenitor cells while sparing healthy counterparts. Oral TKI dasatinib combined with potent SNG1153 inhibitor effectively eliminates infiltrated BCR-ABL+ blast cells and enhances survival of mice. Importantly, a unique mechanism of SNG inhibition was uncovered by demonstrating a marked interruption of the BCR-ABLTyr177-GRB2 interaction, leading to inhibition of the downstream RAS/MAPK pathway. This new combination therapy may lead to more effective disease eradication, especially in patients at high risk of TKI resistance and disease progression.

Synthesis and biological evaluation of novel compounds related to 1-arylnaphthalene lignans and isoquinolines.

Novel compounds designed as hybrids of 1-arylnaphthalene lignans with isoquinoline alkaloids were prepared and evaluated for their cytotoxicities on human tumor cell lines, such as A549, Hela, PC-3, CNE, BEL-7404, and KB. Some of the synthetic compounds exhibited their IC50 values on selected cell lines at 10(-6) M scale. The preliminary CoMFA molecular-modelling studies of these synthetic analogues were also performed.

A Real-Time Atrial Fibrillation Detection Algorithm Based on the Instantaneous State of Heart Rate.

Atrial fibrillation (AF), the most frequent cause of cardioembolic stroke, is increasing in prevalence as the population ages, and presents with a broad spectrum of symptoms and severity. The early identification of AF is an essential part for preventing the possibility of blood clotting and stroke. In this work, a real-time algorithm is proposed for accurately screening AF episodes in electrocardiograms. This method adopts heart rate sequence, and it involves the application of symbolic dynamics and Shannon entropy. Using novel recursive algorithms, a low-computational complexity can be obtained. Four publicly-accessible sets of clinical data (Long-Term AF, MIT-BIH AF, MIT-BIH Arrhythmia, and MIT-BIH Normal Sinus Rhythm Databases) were used for assessment. The first database was selected as a training set; the receiver operating characteristic (ROC) curve was performed, and the best performance was achieved at the threshold of 0.639: the sensitivity (Se), specificity (Sp), positive predictive value (PPV) and overall accuracy (ACC) were 96.14%, 95.73%, 97.03% and 95.97%, respectively. The other three databases were used for independent testing. Using the obtained decision-making threshold (i.e., 0.639), for the second set, the obtained parameters were 97.37%, 98.44%, 97.89% and 97.99%, respectively; for the third database, these parameters were 97.83%, 87.41%, 47.67% and 88.51%, respectively; the Sp was 99.68% for the fourth set. The latest methods were also employed for comparison. Collectively, results presented in this study indicate that the combination of symbolic dynamics and Shannon entropy yields a potent AF detector, and suggest this method could be of practical use in both clinical and out-of-clinical settings.

Validation of new and existing decision rules for the estimation of beat-to-beat pulse transit time.

Pulse transit time (PTT) is a pivotal marker of vascular stiffness. Because the actual PTT duration in vivo is unknown and the complicated variation in waveform may occur, the robust determination of characteristic point is still a very difficult task in the PTT estimation. Our objective is to devise a method for real-time estimation of PTT duration in pulse wave. It has an ability to reduce the interference caused by both high- and low-frequency noise. The reproducibility and performance of these methods are assessed on both artificial and clinical pulse data. Artificial data are generated to investigate the reproducibility with various signal-to-noise ratios. For all artificial data, the mean biases obtained from all methods are less than 1 ms; collectively, this newly proposed method has minimum standard deviation (SD, <1 ms). A set of data from 33 participants together with the synchronously recorded continuous blood pressure data are used to investigate the correlation coefficient (CC). The statistical analysis shows that our method has maximum values of mean CC (0.5231), sum of CCs (17.26), and median CC (0.5695) and has the minimum SD of CCs (0.1943). Overall, the test results in this study indicate that the newly developed method has advantages over traditional decision rules for the PTT measurement.