bluuebunny/crossref_metadata_2025 huggingface dataset:
The efficacy and adverse events of conventional and second-generation androgen receptor inhibitors for castration-resistant prostate cancer: A network meta-analysis
Authors: Zhang Xianlu , Zhang Gejun , Wang Jianfeng , Bi Jianbin
Published: February 2023

Background

Second-generation androgen receptor inhibitors (ARIs) have been developed and approved for treating castration-resistant prostate cancer (CRPC). There is a lack of direct comparison of the therapeutic effects and adverse events between the conventional ARI (bicalutamide) and three second-generation ARIs (enzalutamide, apalutamide and darolutamide).

Methods

Our network meta-analysis evaluated therapeutic effects and adverse events of the conventional ARI (bicalutamide) and the second-generation ARIs in treating CRPC. We systematically searched the Pubmed, Cochrane library and Embase databases for studies published until October 2022 and only randomized clinical trials (RCTs) were included. The progression-free survival, prostate-specific antigen (PSA) progression-free survival, overall survival (PFS/PSA-PFS/OS), PSA response rate and relative adverse events (AEs) of CRPC patients were collected and synthesized. We then performed subgroup analysis. The non-metastatic and metastatic CRPC (nm/mCRPC) observations were analyzed separately. Data analyses were performed using R software (4.2.1) based on Bayesian framework.

Results

6,993 subjects from seven eligible RCTs were analyzed. Enzalutamide, apalutamide and darolutamide were more effective than bicalutamide in treating CRPC, and the performance of darolutamide was slightly worse than the other two second-generation ARIs. Similar adverse events rate were observed among the second-generation ARIs and bicalutamide. Apalutamide showed a slightly higher rate of Grade 3+ AEs, percentages of AE-related drug withdrawals and AE-related mortality. Patients receiving enzalutamide had significantly higher rate of hypertension and fatigue. In subgroup analysis, enzalutamide showed better therapeutic effects compared with bicalutamide in both nmCRPC and mCRPC groups. In nmCRPC group, enzalutamide and apalutamide had more benefits on PFS and PSA-PFS compared with darolutamide. We displayed the probability ranking map of PFS, PSA-PFS, OS, time to cytotoxic chemotherapy, PSA response rate and relative AE outcomes.

Conclusion

The current network meta-analysis indicated that the second-generation ARIs were superior to the conventional ARI, bicalutamide. The three second-generation ARIs showed incomplete equivalence on CRPC treatment. The darolutamide was slightly less effective compared with enzalutamide and apalutamide. The adverse events of apalutamide were worse than the others, but no statistical significance was observed among these vital AEs. All ARIs were generally well-tolerated. These results may provide reference to clinical decision and further direct comparison trials.

Systematic review registration

https://www.crd.york.ac.uk/PROSPERO, identifier CRD42022370842.
The clinical characteristics and gene mutations associated with thyroid hormone resistance syndrome coexisting with pituitary tumors
Authors: Zhao Junyu , Xu Lusi , Li Chunyu , Wang Fei , Liao Lin , Dong Jianjun
Published: February 2023

Aims

Resistance to thyroid hormone (RTH) and pituitary tumors are both rare diseases, and the differential diagnosis of these two diseases is difficult in some cases. There are also patients who have both conditions, making diagnosis more difficult. To better understand this aspect, we analyzed the clinical characteristics and gene mutations of RTH coexisting with pituitary tumors.

Methods

Database retrieval was conducted in the PubMed, Cochrane Library, and SinoMed databases, and the search contents were case reports or case series of patients with RTH coexisting with pituitary tumors. The demographic, clinical manifestations, and imaging characteristics of pituitary tumors and gene mutations were summarized.

Results

Thirteen articles involving 16 patients with RTH coexistent with pituitary tumors, consisting of 13 female patients, one male patient, and two patients with unknown sex, were included. The patients were 10 to 79 years old and most patients were 41-55 years old (43.75%). The 16 patients were from seven different countries and three continents (Asia, the Americas, and Europe). All the patients showed an abnormal secretion of TSH, and five patients underwent transsphenoidal surgery. Finally, four patients were pathologically confirmed to have TSHoma. A total of 11 different mutations occurred at nine amino acid sequence sites (251, 310, 344, 347, 383, 429, 435, 438, and 453). Two different mutations occurred in both the no. 435 and no. 453 amino acid sequences. Fourteen patients provided their treatment histories, and all had undergone different treatment regimens.

Conclusions

Patients with both RTH and pituitary tumors had multiple clinical manifestations and different thyroid functions, imaging characteristics of pituitary tumors, genetic mutations of THRβ, and treatments. However, due to the limited number of cases, the patients were mainly women. Further studies with more cases that focus on the mechanism are still needed.
Integrating single-cell RNA-seq and bulk RNA-seq to construct prognostic signatures to explore the role of glutamine metabolism in breast cancer
Authors: Pei Shengbin , Zhang Pengpeng , Chen Huilin , Zhao Shuhan , Dai Yuhan , Yang Lili , Kang Yakun , Zheng Mingjie , Xia Yiqin , Xie Hui
Published: February 2023

Background

Although breast cancer (BC) treatment has entered the era of precision therapy, the prognosis is good in the case of comprehensive multimodal treatment such as neoadjuvant, endocrine, and targeted therapy. However, due to its high heterogeneity, some patients still cannot benefit from conventional treatment and have poor survival prognoses. Amino acids and their metabolites affect tumor development, alter the tumor microenvironment, play an increasingly obvious role in immune response and regulation of immune cell function, and are involved in acquired and innate immune regulation; therefore, amino acid metabolism is receiving increasing attention.

Methods

Based on public datasets, we carried out a comprehensive transcriptome and single-cell sequencing investigation. Then we used 2.5 Weighted Co-Expression Network Analysis (WGCNA) and Cox to evaluate glutamine metabolism-related genes (GRGs) in BC and constructed a prognostic model for BC patients. Finally, the expression and function of the signature key gene SNX3 were examined by in vitro experiments.

Results

In this study, we constituted a risk signature to predict overall survival (OS) in BC patients by glutamine-related genes. According to our risk signature, BC patients can obtain a Prognostic Risk Signature (PRS), and the response to immunotherapy can be further stratified according to PRS. Compared with traditional clinicopathological features, PRS demonstrated robust prognostic power and accurate survival prediction. In addition, altered pathways and mutational patterns were analyzed in PRS subgroups. Our study sheds some light on the immune status of BC. In in vitro experiments, the knockdown of SNX3, an essential gene in the signature, resulted in a dramatic reduction in proliferation, invasion, and migration of MDA-MB-231 and MCF-7 cell lines.

Conclusion

We established a brand-new PRS consisting of genes associated with glutamine metabolism. It expands unique ideas for the diagnosis, treatment, and prognosis of BC.
Valuing changes in the portfolio of service flows from climate-induced extremes on a linked food, energy, water system (C-FEWS)
Authors: Chang Joseph W. , Ando Amy W. , Chen Mengye
Published: February 2023

Introduction:Recent work examining the impact of climate-change induced extremes on food-energy-water systems (FEWS) estimates the potential changes in physical flows of multiple elements of the systems. Climate adaptation decisions can involve tradeoffs between different system outcomes. Thus, it is important for decision makers to consider the potential changes in monetary value attributed to the observed changes in physical flows from these events, since the value to society of a unit change in an outcome varies widely between thing like food and energy production, water quality, and carbon sequestration.

Methods:We develop a valuation tool (FEWSVT) that applies theoretically sound valuation techniques to estimates changes in value for four parameters within the food-energy-water nexus. We demonstrate the utility of the tool through the application of a case study that analyzes the monetary changes in value of a modelled heat wave scenario relative to historic (baseline) conditions in two study regions in the United States.

Results:We find that food (corn and soybeans) comprises the majority (89%) of total changes in value, as heatwaves trigger physical changes in corn and soybeans yields. We also find that specifying overly simplified and incorrect valuation methods lead to monetary values that largely differ from FEWSVT results that use accepted valuation methods.

Discussion:These results demonstrate the value in considering changes in monetary value instead of just physical flows when making decisions on how to distribute investments and address the many potential impacts of climate change-induced extremes.
Compositional variations in algal organic matter during distinct growth phases in karst water
Authors: Tian Liye , Zhang Zhiwei , Wang Zhikang , Zhang Ping , Xiong Chao , Kuang Ye , Peng Xingyi , Yu Mengxin , Qian Yu
Published: February 2023

Inland surface water plays an important role in global carbon cycling, which responds to transformation between dissolved inorganic carbon (DIC) and dissolved organic carbon (DOC). Studies have shown that algae in karst lakes and reservoirs can convert DIC to organic matter (OM) and form stable carbon sinks via photosynthesis. However, the pathways of conversion of inorganic carbon to organic carbon during algal growth remain unclear and need further investigation. In this study, spectroscopic techniques were applied to investigate the variations in algal organic matter (AOM) composition in the growth metabolism of Chlorella vulgaris and Scenedesmus obliquus under simulated karst water condition. The results showed that algal extracellular organic matter (EOM) contained high DIC concentration during the adaptation phase, which formed the carbon source for algal photosynthesis. In addition, DOC in algae increased after entering the stationary phase, while more OM was released into water. As algal growth proceeded, the amino groups in EOM were consumed to produce more aromatic protein-like material, while more lipid material was produced in intracellular organic matter (IOM). The spectral characterization results could intuitively determine AOM dynamics in different growth stages of algae, which can be used for establishing effective approaches for detecting organic carbon variations and responding to regional carbon cycling in karst water.
The influence of the taphonomically active zone on peat formation: Establishing modern peat analogs to decipher mangrove sub-habitats from historical peats
Authors: Neely Samuel H. , Raymond Anne
Published: February 2023

Mangroves create unique and highly productive wetland communities in intertidal zones of tropical and subtropical coastlines. Despite their many ecosystem services, such as carbon sequestration, mangroves remain threatened by climate change, sea-level rise, and human development. The inclusion of conservation paleobiology and long-term perspectives on how these ecosystems have responded to past environmental change can inform current policy and lead to more effective conservation and restoration management strategies for modern mangrove communities. In South Florida, humified plant debris, or peat, in mangroves provides this historical record. Our research takes a novel paleobiological approach by using plant organ- and taxon-based measures to describe the influence of the taphonomically active zone (TAZ: the zone near the surface of the substrate where taphonomic processes actively formation and degrade accumulated detritus) on the decomposition of mangrove peat with depth. This allows us to understand the taphonomic biases imposed on mangrove peat as it is sequestered into the sedimentological record and provides us with the paleoecological context to better interpret preserved peats and reconstruct past mangrove sub-habitats from peat cores. Accordingly, we collected modern surficial peat cores from two contrasting mangrove sub-habitats in Barnes Sound, FL. These surficial cores were characterized and compared to historical, deep cores from other South Florida mangrove peat deposits. By comparing the proportional abundance of mangrove peat constituents in these samples, we established modern analogs needed to interpret changes in the depositional environment of historical mangrove peats found in sediment cores, which is critical for understanding shoreline responses of mangroves to sea-level rise and anthropogenic change. We demonstrate that (1) leaf mat thickness may be a relative indicator of surficial peat decomposition rates because it correlates with the degree of tidal activity and detritivore access to the leaf litter layer; (2) root percentages are valid tools to differentiate between peats at depth, and can be used as relative indicators for the distance ofin situpeat from shorelines; and (3) organismal signals, such as foraminifera and insect parts, provide a means for deciphering precursor mangrove sub-habitats from sequestered peats.
A review of the genomics of neonatal abstinence syndrome
Authors: Yen Elizabeth , Gaddis Nathan , Jantzie Lauren , Davis Jonathan M.
Published: February 2023

Neonatal abstinence syndrome (NAS) is a constellation of signs of withdrawal occurring after birth following in utero exposure to licit or illicit opioids. Despite significant research and public health efforts, NAS remains challenging to diagnose, predict, and manage due to highly variable expression. Biomarker discovery in the field of NAS is crucial for stratifying risk, allocating resources, monitoring longitudinal outcomes, and identifying novel therapeutics. There is considerable interest in identifying important genetic and epigenetic markers of NAS severity and outcome that can guide medical decision making, research efforts, and public policy. A number of recent studies have suggested that genetic and epigenetic changes are associated with NAS severity, including evidence of neurodevelopmental instability. This review will provide an overview of the role of genetics and epigenetics in short and longer-term NAS outcomes. We will also describe novel research efforts using polygenic risk scores for NAS risk stratification and salivary gene expression to understand neurobehavioral modulation. Finally, emerging research focused on neuroinflammation from prenatal opioid exposure may elucidate novel mechanisms that could lead to development of future novel therapeutics.
Basophils control T cell priming through soluble mediators rather than antigen presentation
Authors: Möbs Christian , Salheiser Martin , Bleise Fabian , Witt Marie , Mayer Johannes U.
Published: February 2023

Basophils play an important role in the development of type 2 immunity and have been linked to protective immunity against parasites but also inflammatory responses in allergic diseases. While typically classified as degranulating effector cells, different modes of cellular activation have been identified, which together with the observation that different populations of basophils exist in the context of disease suggest a multifunctional role. In this review we aim to highlight the role of basophils play in antigen presentation of type 2 immunity and focus on the contribution basophils play in the context of antigen presentation and T cell priming. We will discuss evidence suggesting that basophils perform a direct role in antigen presentation and relate it to findings that indicate cellular cooperation with professional antigen-presenting cells, such as dendritic cells. We will also highlight tissue-specific differences in basophil phenotypes that might lead to distinct roles in cellular cooperation and how these distinct interactions might influence immunological and clinical outcomes of disease. This review thus aims to consolidate the seemingly conflicting literature on the involvement of basophils in antigen presentation and tries to find a resolution to the discussion whether basophils influence antigen presentation through direct or indirect mechanisms.
Repeated injection of multivitamins and multiminerals during the transition period enhances immune response by suppressing inflammation and oxidative stress in cows and their calves
Authors: Somagond Yallappa M. , Alhussien Mohanned Naif , Dang Ajay Kumar
Published: February 2023

Periparturient dairy cows undergo major physiological and metabolic changes as well as immunosuppression, associated with decrease in plasma concentrations of various minerals and vitamins. The present study was conducted to investigate effects of repeated injections of vitamins and minerals on oxidative stress, innate and adaptive immune response in periparturient dairy cows and their offspring. Experiment was carried out on 24 peripartum Karan-Fries cows, randomly divided into four groups (n=6): control, Multi-mineral (MM), Multi-vitamin (MV) and Multi-minerals and Multi-vitamin (MMMV). Five ml of MM (Zinc 40 mg/ml, Manganese 10 mg/ml, Copper 15 mg/ml, Selenium 5 mg/ml) and five ml of MV (Vitamin E 5 mg/ml, Vitamin A 1000 IU/ml, B-Complex 5 mg/ml, and Vitamin D3 500 IU/ml) were injected intramuscularly (IM) to the MM and MV groups. MMMV group cows were injected with both. In all treatment groups, injections and blood sampling were carried out on 30th, 15th, 7th days before and after expected date of parturition and at calving. In calves, blood was collected at calving and on 1, 2, 3, 4, 7, 8, 15, 30 and 45 days post-calving. Colostrum/milk were collected at calving and at days 2, 4, and 8 post-calving. A lower percentage of total neutrophils and immature neutrophils, higher percentage of lymphocytes together with increased phagocytic activity of neutrophils and proliferative capacity of lymphocytes found in blood of MMMV cows/calves. Lower relative mRNA expression of TLRs and CXCRs and higher mRNA expression of GR-α, CD62L, CD11b, CD25 and CD44 found in blood neutrophils of MMMV groups. Total antioxidant capacity was higher, activity of antioxidant enzymes (SOD and CAT), TBARS levels were lower in the blood plasma of treated cows/calves. In both cows/calves, plasma pro-inflammatory cytokines (IL-1α, IL-1β, IL-6, IL-8, IL-17A, IFN-γ and TNF-α) increased, whereas anti-inflammatory cytokines (IL-4 and IL-10) decreased in MMMV groups. Total immunoglobulins increased in colostrum/milk of MMMV injected cows and plasma of their calves. Results indicate that repeated injections of multivitamins and multiminerals to peripartum dairy cows could be a major strategy to improve immune response and decrease in inflammation and oxidative stress in transition dairy cows and their calves.
BMP-6 promotes type 2 immune response during enhancement of rat mandibular bone defect healing
Authors: McColl Logan F. , Chen Xizhao , Solga Michael D. , Schlegel Kailo , Haughey Sean P. , Lobo Peter I. , Fread Kristen , Zunder Eli , Cha Ryan , Park Stephen , Christophel J. Jared , Cui Quanjun , Dighe Abhijit S.
Published: February 2023

Introduction

Bone morphogenetic proteins (BMPs) are used as key therapeutic agents for the treatment of difficult fractures. While their effects on osteoprogenitors are known, little is known about their effects on the immune system.

Methods

We used permutations of BMP-6 (B), vascular endothelial growth factor (V), and Hedgehog signaling pathway activator smoothened agonist (S), to treat a rat mandibular defect and investigated healing outcomes at week 8, in correlation with the cellular landscape of the immune cells in the fracture callus at week 2.

Results

Maximum recruitment of immune cells to the fracture callus is known to occur at week 2. While the control, S, V, and VS groups remained as nonunions at week 8; all BMP-6 containing groups - B, BV, BS and BVS, showed near-complete to complete healing. This healing pattern was strongly associated with significantly higher ratios of CD4 T (CD45+CD3+CD4+) to putative CD8 T cells (CD45+CD3+CD4-), in groups treated with any permutation of BMP-6. Although, the numbers of putative M1 macrophages (CD45+CD3-CD11b/c+CD38high) were significantly lower in BMP-6 containing groups in comparison with S and VS groups, percentages of putative - Th1 cells or M1 macrophages (CD45+CD4+IFN-γ+) and putative – NK, NKT or cytotoxic CD8T cells (CD45+CD4-IFN-γ+) were similar in control and all treatment groups. Further interrogation revealed that the BMP-6 treatment promoted type 2 immune response by significantly increasing the numbers of CD45+CD3-CD11b/c+CD38low putative M2 macrophages, putative - Th2 cells or M2 macrophages (CD45+CD4+IL-4+) cells and putative – mast cells, eosinophils or basophils (CD45+CD4-IL-4+ cells). CD45- non-haematopoietic fractions of cells which encompass all known osteoprogenitor stem cells populations, were similar in control and treatment groups.

Discussion

This study uncovers previously unidentified regulatory functions of BMP-6 and shows that BMP-6 enhances fracture healing by not only acting on osteoprogenitor stem cells but also by promoting type 2 immune response.
Autoantibody repertoire characterization provides insight into the pathogenesis of monogenic and polygenic autoimmune diseases
Authors: Clarke Thomas , Du Pan , Kumar Satyendra , Okitsu Shinji L. , Schuette Mark , An Qi , Zhang Jinyang , Tzvetkov Evgeni , Jensen Mark A. , Niewold Timothy B. , Ferre Elise M. N. , Nardone Julie , Lionakis Michail S. , Vlach Jaromir , DeMartino Julie , Bender Andrew T.
Published: February 2023

Autoimmune diseases vary in the magnitude and diversity of autoantibody profiles, and these differences may be a consequence of different types of breaks in tolerance. Here, we compared the disparate autoimmune diseases autoimmune polyendocrinopathy–candidiasis–ecto-dermal dystrophy (APECED), systemic lupus erythematosus (SLE), and Sjogren’s syndrome (SjS) to gain insight into the etiology of breaks in tolerance triggering autoimmunity. APECED was chosen as a prototypical monogenic disease with organ-specific pathology while SjS and SLE represent polygenic autoimmunity with focal or systemic disease. Using protein microarrays for autoantibody profiling, we found that APECED patients develop a focused but highly reactive set of shared mostly anti-cytokine antibodies, while SLE patients develop broad and less expanded autoantibody repertoires against mostly intracellular autoantigens. SjS patients had few autoantibody specificities with the highest shared reactivities observed against Ro-52 and La. RNA-seq B-cell receptor analysis revealed that APECED samples have fewer, but highly expanded, clonotypes compared with SLE samples containing a diverse, but less clonally expanded, B-cell receptor repertoire. Based on these data, we propose a model whereby the presence of autoreactive T-cells in APECED allows T-dependent B-cell responses against autoantigens, while SLE is driven by breaks in peripheral B-cell tolerance and extrafollicular B-cell activation. These results highlight differences in the autoimmunity observed in several monogenic and polygenic disorders and may be generalizable to other autoimmune diseases.
Adjuvant activity of tubeimosides by mediating the local immune microenvironment
Authors: Han Ziyi , Jin Junjie , Chen Xiangfeng , He Yanfei , Sun Hongxiang
Published: February 2023

Rhizoma Bolbostemmatis, the dry tuber of Bolbostemma paniculatum, has being used for the treatment of acute mastitis and tumors in traditional Chinese medicine. In this study, tubeimoside (TBM) I, II, and III from this drug were investigated for the adjuvant activities, structure-activity relationships (SAR), and mechanisms of action. Three TBMs significantly boosted the antigen-specific humoral and cellular immune responses and elicited both Th1/Th2 and Tc1/Tc2 responses towards ovalbumin (OVA) in mice. TBM I also remarkably facilitated mRNA and protein expression of various chemokines and cytokines in the local muscle tissues. Flow cytometry revealed that TBM I promoted the recruitment and antigen uptake of immune cells in the injected muscles, and augmented the migration and antigen transport of immune cells to the draining lymph nodes. Gene expression microarray analysis manifested that TBM I modulated immune, chemotaxis, and inflammation-related genes. The integrated analysis of network pharmacology, transcriptomics, and molecular docking predicted that TBM I exerted adjuvant activity by interaction with SYK and LYN. Further investigation verified that SYK-STAT3 signaling axis was involved in the TBM I-induced inflammatory response in the C2C12 cells. Our results for the first time demonstrated that TBMs might be promising vaccine adjuvant candidates and exert the adjuvant activity through mediating the local immune microenvironment. SAR information contributes to developing the semisynthetic saponin derivatives with adjuvant activities.
Early-life hyperoxia-induced Flt3L drives neonatal lung dendritic cell expansion and proinflammatory responses
Authors: Cui Tracy X. , Brady Alexander E. , Zhang Ying-Jian , Fulton Christina T. , Goldsmith Adam M. , Popova Antonia P.
Published: February 2023

Premature infants with chronic lung disease, bronchopulmonary dysplasia (BPD), develop recurrent cough and wheezing following respiratory viral infections. The mechanisms driving the chronic respiratory symptoms are ill-defined. We have shown that hyperoxic exposure of neonatal mice (a model of BPD) increases the activated lung CD103+ dendritic cells (DCs) and these DCs are required for exaggerated proinflammatory responses to rhinovirus (RV) infection. Since CD103+ DC are essential for specific antiviral responses and their development depends on the growth factor Flt3L, we hypothesized that early-life hyperoxia stimulates Flt3L expression leading to expansion and activation of lung CD103+ DCs and this mediates inflammation. We found that hyperoxia numerically increased and induced proinflammatory transcriptional signatures in neonatal lung CD103+ DCs, as well as CD11bhi DCs. Hyperoxia also increased Flt3L expression. Anti-Flt3L antibody blocked CD103+ DC development in normoxic and hyperoxic conditions, and while it did not affect the baseline number of CD11bhi DCs, it neutralized the effect of hyperoxia on these cells. Anti-Flt3L also inhibited hyperoxia-induced proinflammatory responses to RV. In tracheal aspirates from preterm infants mechanically-ventilated for respiratory distress in the first week of life levels of FLT3L, IL-12p40, IL-12p70 and IFN-γ were higher in infants who went on to develop BPD and FLT3L levels positively correlated with proinflammatory cytokines levels. This work highlights the priming effect of early-life hyperoxia on lung DC development and function and the contribution of Flt3L in driving these effects.
Longitudinal analysis of DC subsets in patients with ovarian cancer: Implications for immunotherapy
Authors: Mastelic-Gavillet Beatris , Sarivalasis Apostolos , Lozano Leyder Elena , Lofek Sebastien , Wyss Tania , Melero Ignacio , de Vries I. Jolanda M. , Harari Alexandre , Romero Pedro , Kandalaft Lana Elias , Viganó Selena
Published: February 2023

Background

The use of circulating cDC1 to generate anti-cancer vaccines is among the most promising approaches to overcome the limited immunogenicity and clinical efficacy of monocyte-derived DC. However, the recurrent lymphopenia and the reduction of DC numbers and functionality in patients with cancer may represent an important limitation of such approach. In patients with ovarian cancer (OvC) that had received chemotherapy, we previously showed that cDC1 frequency and function were reduced.

Methods

We recruited healthy donors (HD, n=7) and patients with OvC at diagnosis and undergoing interval debulking surgery (IDS, n=6), primary debulking surgery (PDS, n=6) or at relapse (n=8). We characterized longitudinally phenotypic and functional properties of peripheral DC subsets by multiparametric flow cytometry.

Results

We show that the frequency of cDC1 and the total CD141+ DC capacity to take up antigen are not reduced at the diagnosis, while their TLR3 responsiveness is partially impaired in comparison with HD. Chemotherapy causes cDC1 depletion and increase in cDC2 frequency, but mainly in patients belonging to the PDS group, while in the IDS group both total lymphocytes and cDC1 are preserved. The capacity of total CD141+ DC and cDC2 to take up antigen is not impacted by chemotherapy, while the activation capacity upon Poly(I:C) (TLR3L) stimulation is further decreased.

Conclusions

Our study provides new information about the impact of chemotherapy on the immune system of patients with OvC and sheds a new light on the importance of considering timing with respect to chemotherapy when designing new vaccination strategies that aim at withdrawing or targeting specific DC subsets.
Gene expression in Verson’s glands of the fall armyworm suggests their role in molting and immunity
Authors: Koo Jinmo , Chen Xien , Palli Subba Reddy
Published: February 2023

Verson’s glands are segmental pairs of dermal glands attached to the epidermis in lepidopteran larvae. They produce macromolecules during intermolt period and empty them during each molt. Morphological, histochemical, developmental, and protein analysis studies have been conducted to determine the functions of Verson’s glands. However, the exact role of Verson’s glands remains unclear. In our previous study, a strain of transgenic fall armyworm, Spdoptera frugiperda expressing green fluorescence protein (GFP) and Systemic RNA interference defective protein 1 (SID1) from Caenorhabditis elegans was established to improve RNA interference (RNAi) efficiency. Unexpectedly, we found that GFP fluorescence was significantly brighter in Verson’s glands than in other tissues. Also, RNAi efficiency improved more in Verson’s glands than in other tissues. We took advantage of improved RNAi efficiency to explore the function of Verson’s glands. RNA-seq analysis revealed that genes highly expressed in Verson’s glands code for cuticular proteins, molting fluid proteins, hemolymph proteins, and antimicrobial peptides. Injection of dsRNA targeting essential genes, inhibitor of apoptosis (IAP), Actin, and vacuolar-type ATPase (VATPase) interfered with Verson’s glands growth. These results revealed that Verson’s glands may contribute to hemolymph, cuticle, molting fluid, and immune response during molting. This study also provide useful tools for future research in identifying the physiological role of Verson’s glands in lepidopteran insects.
Case report: Applicability of breastfeeding the child of a patient with kidney failure with replacement therapy
Authors: Kondakova Elena V. , Filat’eva Anastasia E. , Lobanova Nadezhda A. , Nagaev Egor I. , Sarimov Ruslan M. , Gudkov Sergey V. , Vedunova Maria V.
Published: February 2023

This case report highlights the benefit or harm of breastfeeding in a patient with Kidney Failure with Replacement Therapy (KFRT) undergoing program hemodialysis. This is a unique clinical case, as pregnancy and successful delivery are rare in this group of females. With a favorable outcome, the possibility of breastfeeding is especially relevant for doctors and the mother. The patient was a 31-year-old female who was diagnosed in 2017 with end-stage renal disease associated with chronic glomerulonephritis. Against the background of hemodialysis, pregnancy, accompanied by polyhydramnios, anemia, and secondary arterial hypertension, occurred in 2021. At 37 weeks, a healthy, full-term baby girl was born, and breastfeeding was started. In this study, we conducted a detailed analysis of toxic substances and immunologically significant proteins using high-tech analysis methods. In addition, we studied different portions of milk before and after hemodialysis at different time intervals. After a wide range of experiments, our study did not reveal an optimal time interval for breastfeeding a baby. Despite the decrease in the level of the major uremic toxins 4 h after the hemodialysis procedure, their level remained high. In addition, the content of nutrients did not reach acceptable limits and the immune status was characterized as pro-inflammatory. In our opinion, breastfeeding is not advisable for this group of patients since the concentration of nutrients is low, and the content of toxic substances exceeds the permissible limits. In this clinical case, the patient decided to stop breastfeeding one month after delivery due to insufficient breast milk and the inability to express it in a certain period of time.
Microbial Cell Factory of Baccatin III Preparation in Escherichia coli by Increasing DBAT Thermostability and in vivo Acetyl-CoA Supply
Authors: Huang Jia-jun , Wei Tao , Ye Zhi-wei , Zheng Qian-wang , Jiang Bing-hua , Han Wen-feng , Ye An-qi , Han Pei-yun , Guo Li-qiong , Lin Jun-fang
Published: February 2023

Given the rapid development of genome mining in this decade, the substrate channel of paclitaxel might be identified in the near future. A robust microbial cell factory with gene dbat, encoding a key rate-limiting enzyme 10-deacetylbaccatin III-10-O-transferase (DBAT) in paclitaxel biosynthesis to synthesize the precursor baccatin III, will lay out a promising foundation for paclitaxel de novo synthesis. Here, we integrated gene dbat into the wild-type Escherichia coli BW25113 to construct strain BWD01. Yet, it was relatively unstable in baccatin III synthesis. Mutant gene dbatS189V with improved thermostability was screened out from a semi-rational mutation library of DBAT. When it was over-expressed in an engineered strain N05 with improved acetyl-CoA generation, combined with carbon source optimization of fermentation engineering, the production level of baccatin III was significantly increased. Using this combination, integrated strain N05S01 with mutant dbatS189V achieved a 10.50-fold increase in baccatin III production compared with original strain BWD01. Our findings suggest that the combination of protein engineering and metabolic engineering will become a promising strategy for paclitaxel production.
A strategy for addicting transgene-free bacteria to synthetic modified metabolites
Authors: Kato Yusuke
Published: February 2023

Biological containment is a safeguard technology to prevent uncontrolled proliferation of “useful but dangerous” microbes. Addiction to synthetic chemicals is ideal for biological containment, but this currently requires introduction of transgenes containing synthetic genetic elements for which environmental diffusion has to be prevented. Here, I designed a strategy for addicting transgene-free bacteria to synthetic modified metabolites, in which the target organism that can neither produce an essential metabolite nor use the extracellularly supplied metabolite, is rescued by a synthetic derivative that is taken up from a medium and converted into the metabolite in the cell. Because design of the synthetic modified metabolite is the key technology, our strategy differs distinctly from conventional biological containment, which mainly depends on genetic manipulation of the target microorganisms. Our strategy is particularly promising for containment of non-genetically modified organisms such as pathogens and live vaccines.
Seasonal variation of microbial community and methane metabolism in coalbed water in the Erlian Basin, China
Authors: Fu Li , Lai Shouchao , Zhou Zhuo , Chen Zhenhong , Cheng Lei
Published: February 2023

Coalbed water is a semi-open system connecting underground coalbeds with the external environment. Microorganisms in coalbed water play an important role in coal biogasification and the carbon cycle. The community assemblages of microorganisms in such a dynamic system are not well understood. Here, we used high-throughput sequencing and metagenomic analysis to investigate microbial community structure and identify the potential functional microorganisms involved in methane metabolism in coalbed water in the Erlian Basin, a preferred low-rank coal bed methane (CBM) exploration and research area in China. The results showed that there were differences in the responses of bacteria and archaea to seasonal variation. Bacterial community structure was affected by seasonal variation but archaea was not. Methane oxidation metabolism dominated by Methylomonas and methanogenesis metabolism dominated by Methanobacterium may exist simultaneously in coalbed water.
Associations between trajectories of cardiovascular risk factor change and cognitive impairment in Chinese elderly: A nationwide cohort study
Authors: Duan Xinyu , Dang Yusong , Kang Chenxi , Rong Peixi , Yan Mingxin , Zhang Shutong , Cui Jing , Zhao Yaling , Chen Fangyao , Zhou Jing , Wang Duolao , Pei Leilei
Published: February 2023

Objectives

This study aimed to investigate the relationship between long-term trajectories of changes in cardiovascular risk factors (CVRFs) and the risk of cognitive impairment among Chinese adults over 60 years old.

Methods

Data were obtained from the Chinese Longitudinal Healthy Longevity Survey 2005–2018. Cognitive function was evaluated longitudinally through the Chinese version of the Mini-Mental State Examination (C-MMSE), and cognitive impairment (C-MMSE ≤23) was used as the main outcome variable. The cardiovascular risk factors, including systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), pulse pressure (PP), and body mass index (BMI), were continuously measured in the follow-up duration. The patterns of trajectories of changes in CVRFs were derived from the latent growth mixture model (LGMM). The Cox regression model was used to evaluate the cognitive impairment hazard ratio (HR) across different CVRF trajectories.

Results

A total of 5,164 participants aged ≥60 years with normal cognitive function at baseline were included in the study. After a median follow-up of 8 years, 2,071 participants (40.1%) developed cognitive impairment (C-MMSE ≤ 23). The four-class trajectories of SBP and BMI were obtained by means of LGMM, and the trajectories of DBP, MAP, and PP were grouped into a three-class subgroup. In the final adjusted Cox model, the lowered SBP [adjusted HR (aHR): 1.59; 95% CI: 1.17–2.16], lowered PP (aHR: 2.64; 95% CI: 1.66–4.19), and progressively obese (aHR: 1.28; 95% CI: 1.02–1.62) and stable slim (aHR: 1.13; 95% CI: 1.02–1.25) were associated with the higher risk of cognitive impairment. Low stable DBP (aHR: 0.80; 95% CI: 0.66–0.96) and elevated PP (aHR: 0.76; 95% CI: 0.63–0.92) decreased the risk for cognitive impairment among participants.

Conclusion

Lowered SBP, lowered PP, progressive obesity, and stable slim increased the risk for cognitive impairment in the Chinese elderly. Low stable DBP and elevated PP were protective against cognitive impairment, but more DBP lowering and ≥25 mmHg growth in PP contributed to a higher risk of cognitive impairment. The findings have important implications for preventing cognitive impairment in elder adults based on the long-term trajectories of changes in CVRFs.
Signature of miRNAs derived from the circulating exosomes of patients with amyotrophic lateral sclerosis
Authors: Cheng Yang-Fan , Gu Xiao-Jing , Yang Tian-Mi , Wei Qian-Qian , Cao Bei , Zhang Yang , Shang Hui-Fang , Chen Yong-Ping
Published: February 2023

Background

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disorder (NDS) with unclear pathophysiology and few therapeutic options. Mutations in SOD1 and C9orf72 are the most common in Asian and Caucasian patients with ALS, respectively. Aberrant (microRNAs) miRNAs found in patients with gene-mutated ALS may be involved in the pathogenesis of gene-specific ALS and sporadic ALS (SALS). The aim of this study was to screen for differentially expressed miRNAs from exosomes in patients with ALS and healthy controls (HCs) and to construct a miRNA-based diagnostic model to classify patients and HCs.

Methods

We compared circulating exosome-derived miRNAs of patients with ALS and HCs using the following two cohorts: a discovery cohort (three patients with SOD1-mutated ALS, three patients with C9orf72-mutated ALS, and three HCs) analyzed by microarray and a validation cohort (16 patients with gene-mutated ALS, 65 patients with SALS, and 61 HCs) confirmed by RT-qPCR. The support vector machine (SVM) model was used to help diagnose ALS using five differentially expressed miRNAs between SALS and HCs.

Results

A total of 64 differentially expressed miRNAs in patients with SOD1-mutated ALS and 128 differentially expressed miRNAs in patients with C9orf72-mutated ALS were obtained by microarray compared to HCs. Of these, 11 overlapping dysregulated miRNAs were identified in both groups. Among the 14 top-hit candidate miRNAs validated by RT-qPCR, hsa-miR-34a-3p was specifically downregulated in patients with SOD1-mutated ALS, while hsa-miR-1306-3p was downregulated in ALS patients with both SOD1 and C9orf72 mutations. In addition, hsa-miR-199a-3p and hsa-miR-30b-5p were upregulated significantly in patients with SALS, while hsa-miR-501-3p, hsa-miR-103a-2-5p, and hsa-miR-181d-5p had a trend to be upregulated. The SVM diagnostic model used five miRNAs as features to distinguish ALS from HCs in our cohort with an area under receiver operating characteristic curve (AUC) of 0.80.

Conclusion

Our study identified aberrant miRNAs from exosomes of SALS and ALS patients with SOD1/C9orf72 mutations and provided additional evidence that aberrant miRNAs were involved in the pathogenesis of ALS regardless of the presence or absence of the gene mutation. The machine learning algorithm had high accuracy in predicting the diagnosis of ALS, shedding light on the foundation for the clinical application of blood tests in the diagnosis of ALS, and revealing the pathological mechanisms of the disease.
Spiral drawing analysis with a smart ink pen to identify Parkinson's disease fine motor deficits
Authors: Toffoli Simone , Lunardini Francesca , Parati Monica , Gallotta Matteo , De Maria Beatrice , Longoni Luca , Dell'Anna Maria Elisabetta , Ferrante Simona
Published: February 2023

Introduction

Since the uptake of digitizers, quantitative spiral drawing assessment allowed gaining insight into motor impairments related to Parkinson's disease. However, the reduced naturalness of the gesture and the poor user-friendliness of the data acquisition hamper the adoption of such technologies in the clinical practice. To overcome such limitations, we present a novel smart ink pen for spiral drawing assessment, intending to better characterize Parkinson's disease motor symptoms. The device, used on paper as a normal pen, is enriched with motion and force sensors.

Methods

Forty-five indicators were computed from spirals acquired from 29 Parkinsonian patients and 29 age-matched controls. We investigated between-group differences and correlations with clinical scores. We applied machine learning classification models to test the indicators ability to discriminate between groups, with a focus on model interpretability.

Results

Compared to control, patients' drawings were characterized by reduced fluency and lower but more variable applied force, while tremor occurrence was reflected in kinematic spectral peaks selectively concentrated in the 4–7 Hz band. The indicators revealed aspects of the disease not captured by simple trace inspection, nor by the clinical scales, which, indeed, correlate moderately. The classification achieved 94.38% accuracy, with indicators related to fluency and power distribution emerging as the most important.

Conclusion

Indicators were able to significantly identify Parkinson's disease motor symptoms. Our findings support the introduction of the smart ink pen as a time-efficient tool to juxtapose the clinical assessment with quantitative information, without changing the way the classical examination is performed.
Digitally embodied lifespan neurocognitive development and Tactile Internet: Transdisciplinary challenges and opportunities
Authors: Li Shu-Chen , Fitzek Frank H. P.
Published: February 2023

Mechanisms underlying perceptual processing and inference undergo substantial changes across the lifespan. If utilized properly, technologies could support and buffer the relatively more limited neurocognitive functions in the still developing or aging brains. Over the past decade, a new type of digital communication infrastructure, known as the “Tactile Internet (TI),” is emerging in the fields of telecommunication, sensor and actuator technologies and machine learning. A key aim of the TI is to enable humans to experience and interact with remote and virtual environments through digitalized multimodal sensory signals that also include the haptic (tactile and kinesthetic) sense. Besides their applied focus, such technologies may offer new opportunities for the research tapping into mechanisms of digitally embodied perception and cognition as well as how they may differ across age cohorts. However, there are challenges in translating empirical findings and theories about neurocognitive mechanisms of perception and lifespan development into the day-to-day practices of engineering research and technological development. On the one hand, the capacity and efficiency of digital communication are affected by signal transmission noise according to Shannon’s (1949) Information Theory. On the other hand, neurotransmitters, which have been postulated as means that regulate the signal-to-noise ratio of neural information processing (e.g., Servan-Schreiber et al., 1990), decline substantially during aging. Thus, here we highlight neuronal gain control of perceptual processing and perceptual inference to illustrate potential interfaces for developing age-adjusted technologies to enable plausible multisensory digital embodiments for perceptual and cognitive interactions in remote or virtual environments.
Using an appetitive operant conditioning paradigm to screen rats for tinnitus induced by intense sound exposure: Experimental considerations and interpretation
Authors: Hayes Sarah H. , Beh Krystal , Typlt Marei , Schormans Ashley L. , Stolzberg Daniel , Allman Brian L.
Published: February 2023

In an effort to help elucidate the neural mechanisms underlying tinnitus in humans, researchers have often relied on animal models; a preclinical approach which ultimately required that behavioral paradigms be designed to reliably screen animals for tinnitus. Previously, we developed a two-alternative forced-choice (2AFC) paradigm for rats that allowed for the simultaneous recording of neural activity at the very moments when they were reporting the presence/absence of tinnitus. Because we first validated our paradigm in rats experiencing transient tinnitus following a high-dose of sodium salicylate, the present study now sought to evaluate its utility to screen for tinnitus caused by intense sound exposure; a common tinnitus-inducer in humans. More specifically, through a series of experimental protocols, we aimed to (1) conduct sham experiments to ensure that the paradigm was able to correctly classify control rats as not having tinnitus, (2) confirm the time course over which the behavioral testing could reliably be performed post-exposure to assess chronic tinnitus, and (3) determine if the paradigm was sensitive to the variable outcomes often observed after intense sound exposure (e.g., hearing loss with our without tinnitus). Ultimately, in accordance with our predictions, the 2AFC paradigm was indeed resistant to false-positive screening of rats for intense sound-induced tinnitus, and it was able to reveal variable tinnitus and hearing loss profiles in individual rats following intense sound exposure. Taken together, the present study documents the utility of our appetitive operant conditioning paradigm to assess acute and chronic sound-induced tinnitus in rats. Finally, based on our findings, we discuss important experimental considerations that will help ensure that our paradigm is able to provide a suitable platform for future investigations into the neural basis of tinnitus.