bluuebunny/crossref_metadata_2025 huggingface dataset:
Megakaryocytes respond during sepsis and display innate immune cell behaviors
Authors: Frydman Galit H. , Ellett Felix , Jorgensen Julianne , Marand Anika L. , Zukerberg Lawrence , Selig Martin K. , Tessier Shannon N. , Wong Keith H. K. , Olaleye David , Vanderburg Charles R. , Fox James G. , Tompkins Ronald G. , Irimia Daniel
Published: March 2023

Megakaryocytes (MKs) are precursors to platelets, the second most abundant cells in the peripheral circulation. However, while platelets are known to participate in immune responses and play significant functions during infections, the role of MKs within the immune system remains largely unexplored. Histological studies of sepsis patients identified increased nucleated CD61+ cells (MKs) in the lungs, and CD61+ staining (likely platelets within microthrombi) in the kidneys, which correlated with the development of organ dysfunction. Detailed imaging cytometry of peripheral blood from patients with sepsis found significantly higher MK counts, which we predict would likely be misclassified by automated hematology analyzers as leukocytes. Utilizing in vitro techniques, we show that both stem cell derived MKs (SC MKs) and cells from the human megakaryoblastic leukemia cell line, Meg-01, undergo chemotaxis, interact with bacteria, and are capable of releasing chromatin webs in response to various pathogenic stimuli. Together, our observations suggest that MK cells display some basic innate immune cell behaviors and may actively respond and play functional roles in the pathophysiology of sepsis.
Lymphocyte-to-C reactive protein ratio as novel inflammatory marker for predicting outcomes in hemodialysis patients: A multicenter observational study
Authors: Chen Xinpan , Guo Wang , Diao Zongli , Huang Hongdong , Liu Wenhu
Published: March 2023

Background

Patients undergoing hemodialysis experience inflammation, which is associated with a higher risk of mortality. The lymphocyte-to-C reactive protein ratio (LCR) is a novel marker of inflammation that has been shown to predict mortality in patients with malignant cancer. However, the utility of LCR has not been evaluated in patients undergoing hemodialysis.

Methods

We performed a multi-center cohort study of 3,856 patients who underwent hemodialysis as part of the Beijing Hemodialysis Quality Control and Improvement Project between 1 January 2012 and December 2019. The relationship between LCR and all-cause mortality was assessed using a restricted cubic spline model and a multivariate Cox regression model. An outcome-oriented method was used to determine the most appropriate cut-off value of LCR. Subgroup analysis was also performed to evaluate the relationships of LCR with key parameters.

Results

Of the 3,856 enrolled patients, 1,581 (41%) were female, and their median age was 62 (53, 73) years. Over a median follow-up period of 75.1 months, 1,129 deaths occurred. The mortality rate for the patients after 60 months was 38.1% (95% confidence interval (CI) 36%–40.1%), resulting in a rate of 93.41 events per 1,000 patient-years. LCR showed an L-shaped dose-response relationship with all-cause mortality. The optimal cut-off point for LCR as a predictor of mortality in hemodialysis patients was 1513.1. An LCR of ≥1513.1 could independently predict mortality (hazard ratio 0.75, 95% CI 0.66–0.85, P<0.001).

Conclusions

Baseline LCR was found to be an independent prognostic biomarker in patients undergoing hemodialysis. Implying that it should be a useful means of improving patient prognosis and judging the timing of appropriate interventions in routine clinical practice.
The role of hyaluronan in renal cell carcinoma
Authors: Jin Chenchen , Zong Yunfeng
Published: March 2023

Renal cell carcinoma (RCC) is associated with high mortality rates worldwide and survival among RCC patients has not improved significantly in the past few years. A better understanding of the pathogenesis of RCC can enable the development of more effective therapeutic strategies against RCC. Hyaluronan (HA) is a glycosaminoglycan located in the extracellular matrix (ECM) that has several roles in biology, medicine, and physiological processes, such as tissue homeostasis and angiogenesis. Dysregulated HA and its receptors play important roles in fundamental cellular and molecular biology processes such as cell signaling, immune modulation, tumor progression and angiogenesis. There is emerging evidence that alterations in the production of HA regulate RCC development, thereby acting as important biomarkers as well as specific therapeutic targets. Therefore, targeting HA or combining it with other therapies are promising therapeutic strategies. In this Review, we summarize the available data on the role of abnormal regulation of HA and speculate on its potential as a therapeutic target against RCC.
Knowledge mapping of global trends for myasthenia gravis development: A bibliometrics analysis
Authors: Jiang Fan , Su Yue , Chang Ting
Published: March 2023

Background

Myasthenia gravis (MG) is an autoimmune disease with acquired neuromuscular junction transmission disorders. In the last two decades, various pathogenesis, application of immunosuppressive agents, and targeted immunotherapy have been significant events. However, extracting the most critical information from complex events is very difficult to guide clinical work. Therefore, we used bibliometrics to summarize and look forward.

Methods

Science Citation Index Expanded (SCI-E) from the Web of Science Core Collection (WoSCC) database was identified as a source of material for obtaining MG-related articles. Scimago Graphica, CiteSpace, VOSviewer, and bibliometrix were utilized for bibliometric analysis. Knowledge network graphs were constructed and visualized; countries, institutions, authors, journals, references, and keywords were evaluated. In addition, GraphPad Prism and Microsoft Excel 365 were applied for statistical analysis.

Results

As of October 25, 2022, 9,970 original MG-related articles were used for the bibliometric analysis; the cumulative number of citations to these articles was 236,987, with an H-index of 201. The United States ranked first in terms of the number of publications (2,877) and H-index (134). Oxford has the highest H-index (67), and Udice French Research University has the highest number of publications (319). The author with the highest average number of citations (66.19), publications (151), and H-index (53) was Vincent A. 28 articles have remained in an explosive period of citations. The final screening yielded predictive keywords related to clinical trials and COVID-19.

Conclusion

We conducted a bibliometric analysis of 9,970 original MG-related articles published between 1966 and 2022. Ultimately, we found that future MG research hotspots include two major parts: (1) studies directly related to MG disease itself: clinical trials of various targeted biological agents; the relationship between biomarkers and therapeutic decisions, pathogenesis and outcome events, ultimately serving individualized management or precision therapy; (2) studies related to MG and COVID-19: different variants of COVID-19 (e.g., Omicron) on MG adverse outcome events; assessment of the safety of different COVID-19 vaccines for different subtypes of MG.
The colonic interleukin-19 aggravates the dextran sodium sulfate/stress-induced comorbidities due to colitis and anxiety
Authors: Li Qiongyu , Meng Fantao , Ma Xiangxian , Sun Zhe , Dai Juanjuan , Liu Jing , Li Dan , Cong Peijia , Xu Ruixue , Zhao Di , Wang Wentao , Wang Dan , Liu Cuilan , Wang Faxiang , Li Chen , Lian Haifeng
Published: March 2023

Comorbidities due to inflammatory bowel disease (IBD) and anxiety are commonly acknowledged; however, their underlying basis is unclear. In the current study, we first conducted a clinical retrospective analysis to identify the enhancive incidence rate of IBD before or after the epidemic of Corona Virus Disease 2019 (COVID-19), with higher Generalized Anxiety Disorder-7 (GAD-7), as well as poorer Gastrointestinal Quality of Life Index (GIQLI). Then, the dextran sodium sulfate (DSS) and chronic unpredictable stress (CUS)-induced IBD and anxiety comorbid models were established with the correlational relations between symptoms of IBD and anxiety-related behaviors. We found dysfunctional up-regulation of a new inflammatory factor interleukin (IL)-19 in the colon of DSS/CUS treated mice. Overexpression of IL-19 in colon induced anxious phenotypes, and accelerated the anxious condition and symptoms of colitis in the DSS/CUS model by promoting the expression of inducible nitric oxide synthase (iNOS), IL-1β, and IL-6 pro-inflammatory factors, and activating signal transducer and activator of transcription 3 (STAT3) signaling pathway in the colon. Furthermore, overexpression of IL-19 in the colon also reduced the expression levels of brain-derived neurotrophic factor (BDNF), extracellular signal-regulated kinase (ERK), and cAMP-response element binding protein (CREB) signaling pathways activity in the hippocampus. These results suggest that IL-19 was a pivotal player in DSS/CUS-induced comorbidities of colitis and anxiety with different signaling pathways for the colon and hippocampus, which provides a candidate gene to explore the pathophysiology of comorbidities due to colitis and anxiety.
Potential interactions between diatoms and bacteria are shaped by trace element gradients in the Southern Ocean
Authors: Sterling Alexa R. , Holland Laura Z. , Bundy Randelle M. , Burns Shannon M. , Buck Kristen N. , Chappell P. Dreux , Jenkins Bethany D.
Published: March 2023

The growth of diatoms in the Southern Ocean, especially the region surrounding the West Antarctic Peninsula, is frequently constrained by low dissolved iron and other trace metal concentrations. This challenge may be overcome by mutualisms between diatoms and co-occurring associated bacteria, in which diatoms produce organic carbon as a substrate for bacterial growth, and bacteria produce siderophores, metal-binding ligands that can supply diatoms with metals upon uptake as well as other useful secondary compounds for diatom growth like vitamins. To examine the relationships between diatoms and bacteria in the plankton (diatom) size class (> 3 µm), we sampled both bacterial and diatom community composition with accompanying environmental metadata across a naturally occurring concentration gradient of macronutrients, trace metals and siderophores at 21 stations near the West Antarctic Peninsula (WAP). Offshore Drake Passage stations had low dissolved iron (0.33 ± 0.15 nM), while the stations closer to the continental margin had higher dissolved iron (5.05 ± 1.83 nM). A similar geographic pattern was observed for macronutrients and most other trace metals measured, but there was not a clear inshore-offshore gradient in siderophore concentrations. The diatom and bacteria assemblages, determined using 18S and 16S rDNA sequencing respectively, were similar by location sampled, and variance in both assemblages was driven in part by concentrations of soluble reactive phosphorous, dissolved manganese, and dissolved copper, which were all higher near the continent. Some of the most common diatom sequence types observed wereThalassiosiraandFragilariopsis, and bacteria in the plankton size fraction were most commonly Bacteroidetes and Gammaproteobacteria. Network analysis showed positive associations between diatoms and bacteria, indicating possiblein situmutualisms through strategies such as siderophore and vitamin biosynthesis and exchange. This work furthers the understanding of how naturally occurring gradients of metals and nutrients influence diatom-bacteria interactions. Our data suggest that distinct groups of diatoms and associated bacteria are interacting under different trace metal regimes in the WAP, and that diatoms with different bacterial partners may have different modes of biologically supplied trace metals.
Temperature sensitivity of oxygen demand varies as a function of organic matter source
Authors: Szewczyk Curtis J. , Smith Erik M. , Benitez-Nelson Claudia R.
Published: March 2023

Dissolved oxygen (DO) impairment within coastal waters is widespread and rising temperatures may exacerbate low DO levels by enhancing organic matter (OM) degradation. Here, the temperature sensitivity of OM degradation was investigated as DO decay rates determined during standard five-day biochemical oxygen demand (BOD) measurements conducted under different incubation temperatures. Sampling was conducted in the Waccamaw River watershed, South Carolina, a blackwater river with extensive forested wetland that also receives drainage from stormwater detention ponds associated with coastal development, thus providing different sources of contrasting OM composition. Temperature sensitivities were measured as Q10 temperature coefficients, which define how DO decay rates change with 10 degrees of warming. The average Q10 value for the wetland sites (2.14 ± 0.41) was significantly greater (p < 0.05) than those measured in either the River (1.49 ± 0.36) or stormwater ponds (1.41 ± 0.21). Furthermore, using Intergovernmental Panel on Climate Change intermediate-to-very high temperature estimates for 2100 of +2.7 – 4.4°C, average predicted increases in DO decay rates for wetlands (~22-39%) are more than double the River (~11-18%) and stormwater pond rates (~9-16%). Our findings for inland, coastal waters agree with previous results for soils, suggesting that temperature sensitivities are variable across sites and increase with more complex, lower quality OM. Future modeling scenarios of DO utilization must therefore consider the influence of OM heterogeneity and the temperature sensitivity response of OM degradation across sources and region to better predict how climate change may impact oxygen impairment in aquatic ecosystems.
Vessel sound causes hearing loss for hummingbird bobtail squid (Euprymna berryi)
Authors: Putland Rosalyn L. , Mooney T. Aran , Mensinger Allen F.
Published: March 2023

Anthropogenic activity and its associated sounds have been shown to incur adverse effects on the behaviour and physiology of a wide range of aquatic taxa, from marine mammals to fishes. Yet, little is known about how invertebrates detect and respond to anthropogenic sound. The hummingbird bobtail squid (Euprymna berryi) has a short lifespan (< 6 months), grows to sexual maturity around 90 days post hatching and its small size (< 5 cm mantle length) makes the species an ideal candidate to examine potential effects of sound exposure under laboratory conditions. Hearing and behavioural observations were made before, during and after 15 minutes of vessel sound playback, and aural sensitivity curves were determined using auditory evoked potentials. A significant decrease in relative ventilation rate was observed during and post sound exposure. Auditory sensitivity before and after vessel sound exposure was also examined for three different ages: juveniles, mid- and late adults. Baseline audiograms indicated that there was a decrease in aural sensitivity with age. All three age groups showed similar, significantly decreased hearing sensitivity following sound exposure, however auditory sensitivity recovered within two hours. Globally, anthropogenic sounds have become louder and more persistent, therefore there may be limited time for these animals to recover from sound exposure. Given their ecological and economic importance, cephalopods should be considered in management and policy on underwater noise owing to potential adverse effects of anthropogenic sound on behaviour and physiology.
Enhanced performance of planar perovskite solar cells by doping the SnO2 electron transport layer with guanidinium chloride
Authors: Ye Jiajiu , Li Yuze , Medjahed Asma Aicha , Pouget Stéphanie , Aldakov Dmitry , Liu Yueli , Reiss Peter
Published: March 2023

Tin (IV) oxide is a highly promising electron transport layer (ETL) for lead halide perovskite solar cells due to its high conductivity, transparency, wide band gap, and the possibility of low-temperature processing. Nonetheless, charge carrier recombination processes at the SnO2/perovskite interface diminish the device performance. Here, we demonstrate that SnO2 doping with guanidine hydrochloride (G-SnO2) leads to efficient surface passivation and a larger band offset between the ETL and the perovskite layer, resulting in reduced voltage losses and faster electron transfer. Moreover, G-SnO2 facilitates the growth of highly crystalline perovskite layers. Consequently, a power conversion efficiency of up to 23.48% and a high open-circuit voltage of 1.18 V are obtained in solar cells incorporating the G-SnO2 ETL. These devices also exhibited negligible hysteresis and maintained more than 96% of their initial power conversion efficiency after 1,250 h exposure to the air without encapsulation.
The comparison of gasless and traditional robot-assisted transvaginal natural orifice transluminal endoscopic surgery in hysterectomy
Authors: Mei Youwen , He Li , Zhang Qiang , Chen Ying , Zheng Jiafeng , Xiao Xinyu , Lin Yonghong
Published: March 2023

Study objective

To describe the surgical technique and compare the operative outcomes of gasless and traditional robot-assisted transvaginal natural orifice transluminal endoscopic surgery (GR-vNOTES vs. TR-vNOTES) in hysterectomy.

Methods

The patients undergoing hysterectomy via GR-vNOTES or TR-vNOTES between February 2020 and January 2022 in our hospital were included. Clinical data regarding patient demographics, operative time, blood loss, complications, and postoperative hospital stays were collected and analyzed.

Results

Five cases underwent hysterectomy via GR-vNOTES, and nine cases via TR-vNOTES. The baseline demographics and operative outcomes were not significantly different in GR-vNOTES and TR-vNOTES groups. There was no conversion to multiport robotic laparoscopy, conventional laparoscopy or laparotomy. No complications were seen in both groups, except two cases had fever postoperatively in the TR-vNOTES group. For those with early stage cervical/endometrial cancer, no recurrence or metastasis was observed in the follow-up of six months.

Conclusion

Both GR-vNOTES and TR-vNOTES were feasible and safe for hysterectomy. GR-vNOTES was a promising alternative to TR-vNOTES in hysterectomy.
Nitrate reductase enzymes in alga Chattonella subsalsa are regulated by environmental cues at the translational and post-translational levels
Authors: Wang Yanfei , Johnson Gretchen I. , Postles Anna , Coyne Kathryn J.
Published: March 2023

Nitrate reductase (NR) catalyzes the rate-limiting step in nitrate assimilation. Plant and algal NRs have a highly conserved domain architecture but differ in regulation. In plants, NR activity is regulated by reversible phosphorylation and subsequent binding of 14-3-3 proteins at a conserved serine residue. Algal NRs typically lack 14-3-3 binding motifs, which have only recently been identified in a few algal species. Previous research indicates that the alga, Chattonella subsalsa, possesses a novel NR, NR2-2/2HbN (NR2), which incorporates a 2/2 hemoglobin domain. A second NR (NR3) in C. subsalsa lacks the cytochrome b5 (heme-Fe) domain but includes a putative binding motif for 14-3-3 proteins. The expression of NR2 and NR3 genes indicates that NR2 transcript abundance was regulated by light, nitrogen source, and temperature, while NR3 transcript levels were only regulated by light. Here, we measured total NR activity in C. subsalsa and the potential for regulation of NR activity by putative 14-3-3 binding proteins. Results indicate that NR activity in C. subsalsa was regulated by light, nitrogen source, and temperature at the translational level. NR activity was also regulated by endogenous rhythm and temperature at the post-translational level, supporting the hypothesis that NR3 is regulated by 14-3-3 binding proteins. Together with a previous report describing the regulation of NR gene expression in C. subsalsa, results suggest that C. subsalsa responds to environmental conditions by differential regulation of NRs at transcriptional, translational, and post-translational levels. This flexibility may provide a competitive advantage for this species in the environment. To date, this is the first report which provides evidence for the potential post-translational regulation of NR by 14-3-3 proteins in algal species and suggests that regulatory mechanisms for NR activity may be shared between plants and some algal species.
Microbiome analysis revealed distinct microbial communities occupying different sized nodules in field-grown peanut
Authors: Hossain Md Shakhawat , DeLaune Paul B. , Gentry Terry J.
Published: March 2023

Legume nodulation is the powerhouse of biological nitrogen fixation (BNF) where host-specific rhizobia dominate the nodule microbiome. However, other rhizobial or non-rhizobial inhabitants can also colonize legume nodules, and it is unclear how these bacteria interact, compete, or combinedly function in the nodule microbiome. Under such context, to test this hypothesis, we conducted 16S-rRNA based nodule microbiome sequencing to characterize microbial communities in two distinct sized nodules from field-grown peanuts inoculated with a commercial inoculum. We found that microbial communities diverged drastically in the two types of peanut nodules (big and small). Core microbial analysis revealed that the big nodules were inhabited by Bradyrhizobium, which dominated composition (>99%) throughout the plant life cycle. Surprisingly, we observed that in addition to Bradyrhizobium, the small nodules harbored a diverse set of bacteria (~31%) that were not present in big nodules. Notably, these initially less dominant bacteria gradually dominated in small nodules during the later plant growth phases, which suggested that native microbial communities competed with the commercial inoculum in the small nodules only. Conversely, negligible or no competition was observed in the big nodules. Based on the prediction of KEGG pathway analysis for N and P cycling genes and the presence of diverse genera in the small nodules, we foresee great potential of future studies of these microbial communities which may be crucial for peanut growth and development and/or protecting host plants from various biotic and abiotic stresses.
Diversity characteristics of arbuscular mycorrhizal fungi communities in the soil along successional altitudes of Helan Mountain, arid, and semi-arid regions of China
Authors: Yan Peixuan , Hou Hui , Lv Yingze , Zhang Haiying , Li Jia , Shao Leilei , Xie Qinmi , Liang Yongliang , Li Jingyao , Ni Xilu
Published: March 2023

Introduction

Arbuscular mycorrhizal fungi (AMF) perform a vital role in terrestrial ecosystems.

Methods

To investigate the diversity of AMF communities on the western slope of Helan Mountain at different altitudes and their influence factors, high-throughput sequencing was used to study the structure and diversity of soil AMF communities under different environments and their interrelationships between AMF and environmental factors.

Results

The results revealed that there were significant differences (p < 0.05) in the physical and chemical properties of the soil along the different altitudes. A total of 1,145 OTUs were obtained by high-throughput sequencing, belonging to 1 phylum, 4 class, 6 orders, 13 families, 18 genera and 135 species, with the dominant genus being Glomus, which accounted for 75.27% of the relative abundance of the community. Soil AMF community structure was shown to be variable at the generic level according to NMDS analysis. Correlation analysis showed that soil pH, water content (WC), organic matter (OM), available K, available P and N were significantly correlated with AMF community diversity and species abundance (p < 0.05, p < 0.01). Based on redundancy analysis (RDA) and Monte Carlo test results, soil pH, WC and OM had highly significant effects (p < 0.01) on AMF community diversity and species abundance.

Discussion

This study investigates the relationship between AMF community structure and diversity and soil physicochemical properties at different elevations on the western slope of Helan Mountain, which is of great significance to the study of the Helan Mountain ecosystem.
Predicting β-lactam susceptibility from the genome of Streptococcus pneumoniae and other mitis group streptococci
Authors: Eriksen Helle Brander , Fuursted Kurt , Jensen Anders , Jensen Christian Salgård , Nielsen Xiaohui , Christensen Jens Jørgen , Shewmaker Patricia , Rebelo Ana Rita , Aarestrup Frank Møller , Schønning Kristian , Slotved Hans-Christian ,   the One Day in Denmark (ODiD) Consortium
Published: March 2023

Introduction

For Streptococcus pneumoniae, β-lactam susceptibility can be predicted from the amino acid sequence of the penicillin-binding proteins PBP1a, PBP2b, and PBP2x. The combination of PBP-subtypes provides a PBP-profile, which correlates to a phenotypic minimal inhibitory concentration (MIC). The non-S. pneumoniae Mitis-group streptococci (MGS) have similar PBPs and exchange pbp-alleles with S. pneumoniae. We studied whether a simple BLAST analysis could be used to predict phenotypic susceptibility in Danish S. pneumoniae isolates and in internationally collected MGS.

Method

Isolates with available WGS and phenotypic susceptibility data were included. For each isolate, the best matching PBP-profile was identified by BLAST analysis. The corresponding MICs for penicillin and ceftriaxone was retrieved. Category agreement (CA), minor-, major-, and very major discrepancy was calculated. Genotypic-phenotypic accuracy was examined with Deming regression.

Results

Among 88 S. pneumoniae isolates, 55 isolates had a recognized PBP-profile, and CA was 100% for penicillin and 98.2% for ceftriaxone. In 33 S. pneumoniae isolates with a new PBP-profile, CA was 90.9% (penicillin) and 93.8% (ceftriaxone) using the nearest recognized PBP-profile. Applying the S. pneumoniae database to non-S. pneumoniae MGS revealed that none had a recognized PBP-profile. For Streptococcus pseudopneumoniae, CA was 100% for penicillin and ceftriaxone in 19 susceptible isolates. In 33 Streptococcus mitis isolates, CA was 75.8% (penicillin) and 86.2% (ceftriaxone) and in 25 Streptococcus oralis isolates CA was 8% (penicillin) and 100% (ceftriaxone).

Conclusion

Using a simple BLAST analysis, genotypic susceptibility prediction was accurate in Danish S. pneumoniae isolates, particularly in isolates with recognized PBP-profiles. Susceptibility was poorly predicted in other MGS using the current database.
Therapeutic developments for SARS-CoV-2 infection—Molecular mechanisms of action of antivirals and strategies for mitigating resistance in emerging variants in clinical practice
Authors: Săndulescu Oana , Apostolescu Cătălin Gabriel , Preoțescu Liliana Lucia , Streinu-Cercel Adrian , Săndulescu Mihai
Published: March 2023

This article systematically presents the current clinically significant therapeutic developments for the treatment of COVID-19 by providing an in-depth review of molecular mechanisms of action for SARS-CoV-2 antivirals and critically analyzing the potential targets that may allow the selection of resistant viral variants. Two main categories of agents can display antiviral activity: direct-acting antivirals, which act by inhibiting viral enzymes, and host-directed antivirals, which target host cell factors that are involved in steps of the viral life cycle. We discuss both these types of antivirals, highlighting the agents that have already been approved for treatment of COVID-19, and providing an overview of the main molecules that are currently in drug development. Direct-acting antivirals target viral enzymes that are essential in the viral life cycle. Three direct-acting antivirals are currently in use: two are nucleoside analogs that inhibit the RNA-dependent RNA polymerase of SARS-CoV-2, i.e., remdesivir and molnupiravir, and the third one, nirmatrelvir/ritonavir, is an inhibitor of SARS-CoV-2 main protease. The potential for induction of viral resistance is discussed for each of these antivirals, along with their clinical activity on each of the SARS-CoV-2 variants and sublineages that have been dominant over the course of the pandemic, i.e., Alpha, Delta, as well as Omicron and its sublineages BA.1, BA.2, BA.5, BQ.1 and XBB. Host-directed antivirals are currently in preclinical or clinical development; these agents target host cell enzymes that are involved in facilitating viral entry, replication, or virion release. By blocking these enzymes, viral replication can theoretically be effectively stopped. As no SARS-CoV-2 host-directed antiviral has been approved so far, further research is still needed and we present the host-directed antivirals that are currently in the pipeline. Another specific type of agents that have been used in the treatment of COVID-19 are neutralizing antibodies (NAbs). Their main binding site is the spike protein, and therefore their neutralization activity is influenced by mutations occurring in this region. We discuss the main changes in neutralization activity of NAbs for the most important dominant SARS-CoV-2 variants. Close monitoring of emerging variants and sublineages is still warranted, to better understand the impact of viral mutations on the clinical efficiency of antivirals and neutralizing antibodies developed for the treatment of COVID-19.
Differences in peripheral and central metabolites and gut microbiome of laying hens with different feather-pecking phenotypes
Authors: Wang Chao , Li Yaling , Wang Haoliang , Li Miao , Rong Jinsheng , Liao Xindi , Wu Yinbao , Wang Yan
Published: March 2023

Background

Feather pecking (FP) is a maladaptive behavior in laying hens that is associated with numerous physiological traits, including those involving the central neurotransmitter system and the immune system, which have been identified in many species as being regulated by the gut microbiota via the “microbiota-gut-brain” (MGB) axis. Yet, it is unknown whether and how gut microbiota influences FP by regulating multiple central neurotransmission systems and immune system.

Methods

This study was measured the prevalence of severe FP (SFP) in the commercial layer farm. The chicken flock with the highest frequency of SFP were selected for FP phenotype identification. Nontargeted metabolomics was performed to investigated the differences in the peripheral and central metabolites and 16S rDNA sequencing was performed to investigated the differences in gut microbiome of laying hens with different FP phenotypes. Correlation analysis was performed to determine the potential mechanism by which the disturbed gut microbiota may modulate host physiology and behavior.

Results

The results showed that pullets (12 weeks of age) showed significantly higher SFP frequencies than chicks (6 weeks of age) and adults (22 weeks of age; p < 0.05). Compared to neutrals (N), peckers (P) exhibited the stress-induced immunosuppression with the increased plasma levels of corticosterone and norepinephrine, and the decreased plasma levels of IgA, IL-1, IL-6 and tumor necrosis factor α (p < 0.05). In the cecum, the relative abundances of Bacteroides and Gemmiger were higher in the P group, while Roseburia, Ruminococcus2, Anaerostipes, Lachnospiracea_incertae_sedis and Methanobrevibacter were more enriched in the N group. Moreover, increased plasma levels of L-tryptophan, beta-tyrosine and L-histidine were found in the P group (p < 0.05). Notably, in the P group, hippocampal levels of L-tryptophan, xanthurenic acid, L-histidine and histamine were improved and showed a positive association with L-glutamic acid levels. Plasma levels of L-tryptophan, beta-tyrosine and L-histidine were both positively correlated with Bacteroides abundance but negatively correlated with Methanobrevibacter abundance.

Conclusion

Overall, these findings suggest that the development of FP may be affected by the gut microbiota, which regulates the central glutamatergic nerve system by altering the metabolism of tryptophan, histidine and tyrosine.
PROT-ON: A structure-based detection of designer PROTein interface MutatiONs
Authors: Koşaca Mehdi , Yılmazbilek İrem , Karaca Ezgi
Published: March 2023

The mutation-induced changes across protein-protein interfaces have often been observed to lead to severe diseases. Therefore, several computational tools have been developed to predict the impact of such mutations. Among these tools, FoldX and EvoEF1 stand out as fast and accurate alternatives. Expanding on the capabilities of these tools, we have developed the PROT-ON (PROTein-protein interface mutatiONs) framework, which aims at delivering the most critical protein interface mutations that can be used to design new protein binders. To realize this aim, PROT-ON takes the 3D coordinates of a protein dimer as an input. Then, it probes all possible interface mutations on the selected protein partner with EvoEF1 or FoldX. The calculated mutational energy landscape is statistically analyzed to find the most enriching and depleting mutations. Afterward, these extreme mutations are filtered out according to stability and optionally according to evolutionary criteria. The final remaining mutation list is presented to the user as the designer mutation set. Together with this set, PROT-ON provides several residue- and energy-based plots, portraying the synthetic energy landscape of the probed mutations. The stand-alone version of PROT-ON is deposited at https://github.com/CSB-KaracaLab/prot-on. The users can also use PROT-ON through our user-friendly web service http://proton.tools.ibg.edu.tr:8001/ (runs with EvoEF1 only). Considering its speed and the range of analysis provided, we believe that PROT-ON presents a promising means to estimate designer mutations.
Molecular imaging of HER2 receptor: Targeting HER2 for imaging and therapy in nuclear medicine
Authors: Miladinova Daniela
Published: March 2023

Targeting HER 2 for imaging and therapy in nuclear medicine has been used with a special emphasis on developing more powerful radiopharmaceuticals. Zirconium-89 plays an essential role in immune PET imaging so was used labeled with anti-HER2 antibody (Trastuzumab and Pertuzumab). Also there were attempts with other PET tracers as Cuprum-64 and Galium-68, as well as SPECT radiopharmaceuticals Indium-111 and Technetium- 99m. Regarding antibody pharmacokinetic that is not quite appropriate for imaging acquisition, several smaller molecules with shorter residence times have been developed. These molecules called nanobody, affibody, minibody do not compromize HER2 receptor affinity and specificity. Excess of Trastuzumab do not block the affinity of labeled affibodies. Silica nanoparticles have been conjugated to anti-HER2 antibodies to enable targeting of HER2 expressing cells with potential of drug delivery carry for antitumor agents and b(beta) or a(alfa) emitting radioisotopes commonly used for radionuclide therapy, as Iodine-131, Lutetium-177, Yttrium-90, Rhenium-188 and Thorium-277.
Targeting macrophages in atherosclerosis using nanocarriers loaded with liver X receptor agonists: A narrow review
Authors: Yang Tong-Mei , Miao Miao , Yu Wen-Qian , Wang Xue , Xia Fang-Jie , Li Yan-Jie , Guo Shou-Dong
Published: March 2023

Macrophages are involved in the whole process of atherosclerosis, which is characterized by accumulation of lipid and inflammation. Presently, clinically used lipid-lowering drugs cannot completely retard the progress of atherosclerosis. Liver X receptor (LXR) plays a key role in regulation of lipid metabolism and inflammation. Accumulating evidence have demonstrated that synthetic LXR agonists can significantly retard the development of atherosclerosis. However, these agonists induce sever hypertriglyceridemia and liver steatosis. These side effects have greatly limited their potential application for therapy of atherosclerosis. The rapid development of drug delivery system makes it possible to delivery interested drugs to special organs or cells using nanocarriers. Macrophages express various receptors which can recognize and ingest specially modified nanocarriers loaded with LXR agonists. In the past decades, a great progress has been made in this field. These macrophage-targeted nanocarriers loaded with LXR agonists are found to decrease atherosclerosis by reducing cholesterol accumulation and inflammatory reactions. Of important, these nanocarriers can alleviate side effects of LXR agonists. In this article, we briefly review the roles of macrophages in atherosclerosis, mechanisms of action of LXR agonists, and focus on the advances of macrophage-targeted nanocarriers loaded with LXR agonists. This work may promote the potential clinical application of these nanocarriers.
Emotional and sensory dysregulation as a possible missing link in attention deficit hyperactivity disorder: A review
Authors: Grossman Anna , Avital Avi
Published: March 2023

Attention Deficit Hyperactivity Disorder (ADHD) is a common developmental disorder affecting 5-7% of adults and children. We surveyed the literature to examine ADHD through three pillars: developmental characteristics, symptomatology, and treatment strategies. Firstly, in terms of developmental characterstics, early life stress may increase the risk of developing ADHD symptoms according to animal models’ research. Secondly, the current core symptoms of ADHD are comprised of inattention, hyperactivity, and impulsivity. However, the up-to-date literature indicates individuals with ADHD experience emotional and sensory dysregulation as well, which early-life stress may also increase the risk of. Finally, we discuss the therapeutic benefits of methylphenidate on both the current core ADHD symptoms and the sensory and emotional dysregulation found in those with ADHD. In summation, we surveyed the recent literature to analyze (i) the potential role of early-life stress in ADHD development, (ii) the involvement of emotional and sensory dysregulation in ADHD symptomatology and finally, (iii) the therapeutic intervention with methylphenidate, aiming to reduce the potential effect of early life stress in ADHD, and mainly emotional and sensory dysregulation. The apparent but currently less recognized additional symptoms of emotional and sensory dysregulation in ADHD call for further investigation of these possible causes and thus increasing treatments efficacy in individuals with ADHD.
Identification of co-expressed central genes and transcription factors in atherosclerosis-related intracranial aneurysm
Authors: Zhang Quan , Liu Hengfang , Zhang Min , Liu Fang , Liu Tiantian
Published: March 2023

Background

Numerous clinical studies have shown that atherosclerosis is one of the risk factors for intracranial aneurysms. Calcifications in the intracranial aneurysm walls are frequently correlated with atherosclerosis. However, the pathogenesis of atherosclerosis-related intracranial aneurysms remains unclear. This study aims to investigate this mechanism.

Methods

The Gene Expression Omnibus (GEO) database was used to download the gene expression profiles for atherosclerosis (GSE100927) and intracranial aneurysms (GSE75436). Following the identification of the common differentially expressed genes (DEGs) of atherosclerosis and intracranial aneurysm, the network creation of protein interactions, functional annotation, the identification of hub genes, and co-expression analysis were conducted. Thereafter, we predicted the transcription factors (TF) of hub genes and verified their expressions.

Results

A total of 270 common (62 downregulated and 208 upregulated) DEGs were identified for subsequent analysis. Functional analyses highlighted the significant role of phagocytosis, cytotoxicity, and T-cell receptor signaling pathways in this disease progression. Eight hub genes were identified and verified, namely, CCR5, FCGR3A, IL10RA, ITGAX, LCP2, PTPRC, TLR2, and TYROBP. Two TFs were also predicted and verified, which were IKZF1 and SPI1.

Conclusion

Intracranial aneurysms are correlated with atherosclerosis. We identified several hub genes for atherosclerosis-related intracranial aneurysms and explored the underlying pathogenesis. These discoveries may provide new insights for future experiments and clinical practice.
Plasma biomarkers for diagnosis of Alzheimer's disease and prediction of cognitive decline in individuals with mild cognitive impairment
Authors: Kivisäkk Pia , Carlyle Becky C. , Sweeney Thadryan , Trombetta Bianca A. , LaCasse Kathryn , El-Mufti Leena , Tuncali Idil , Chibnik Lori B. , Das Sudeshna , Scherzer Clemens R. , Johnson Keith A. , Dickerson Bradford C. , Gomez-Isla Teresa , Blacker Deborah , Oakley Derek H. , Frosch Matthew P. , Hyman Bradley T. , Aghvanyan Anahit , Bathala Pradeepthi , Campbell Christopher , Sigal George , Stengelin Martin , Arnold Steven E.
Published: March 2023

Background

The last few years have seen major advances in blood biomarkers for Alzheimer's Disease (AD) with the development of ultrasensitive immunoassays, promising to transform how we diagnose, prognose, and track progression of neurodegenerative dementias.

Methods

We evaluated a panel of four novel ultrasensitive electrochemiluminescence (ECL) immunoassays against presumed CNS derived proteins of interest in AD in plasma [phosphorylated-Tau181 (pTau181), total Tau (tTau), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP)]. Two sets of banked plasma samples from the Massachusetts Alzheimer's Disease Research Center's longitudinal cohort study were examined: A longitudinal prognostic sample (n = 85) consisting of individuals with mild cognitive impairment (MCI) and 4 years of follow-up and a cross-sectional sample (n = 238) consisting of individuals with AD, other neurodegenerative diseases (OND), and normal cognition (CN).

Results

Participants with MCI who progressed to dementia due to probable AD during follow-up had higher baseline plasma concentrations of pTau181, NfL, and GFAP compared to non-progressors. The best prognostic discrimination was observed with pTau181 (AUC = 0.83, 1.7-fold increase) and GFAP (AUC = 0.83, 1.6-fold increase). Participants with autopsy- and/or biomarker verified AD had higher plasma levels of pTau181, tTau and GFAP compared to CN and OND, while NfL was elevated in AD and further increased in OND. The best diagnostic discrimination was observed with pTau181 (AD vs CN: AUC = 0.90, 2-fold increase; AD vs. OND: AUC = 0.84, 1.5-fold increase) but tTau, NfL, and GFAP also showed good discrimination between AD and CN (AUC = 0.81–0.85; 1.5–2.2 fold increase).

Conclusions

These new ultrasensitive ECL plasma assays for pTau181, tTau, NfL, and GFAP demonstrated diagnostic utility for detection of AD. Moreover, the absolute baseline plasma levels of pTau181 and GFAP reflect cognitive decline over the next 4 years, providing prognostic information that may have utility in both clinical practice and clinical trial populations.
Fecal microbiota transplantation in Parkinson's disease—A randomized repeat-dose, placebo-controlled clinical pilot study
Authors: DuPont Herbert L. , Suescun Jessika , Jiang Zhi-Dong , Brown Eric L. , Essigmann Heather T. , Alexander Ashley S. , DuPont Andrew W. , Iqbal Tehseen , Utay Netanya S. , Newmark Michael , Schiess Mya C.
Published: March 2023

Background and purpose

The intestinal microbiome plays a primary role in the pathogenesis of neurodegenerative disorders and may provide an opportunity for disease modification. We performed a pilot clinical study looking at the safety of fecal microbiota transplantation (FMT), its effect on the microbiome, and improvement of symptoms in Parkinson's disease.

Methods

This was a randomized, double-blind placebo-controlled pilot study, wherein orally administered lyophilized FMT product or matching placebo was given to 12 subjects with mild to moderate Parkinson's disease with constipation twice weekly for 12 weeks. Subjects were followed for safety and clinical improvement for 9 additional months (total study duration 12 months).

Results

Fecal microbiota transplantation caused non-severe transient upper gastrointestinal symptoms. One subject receiving FMT was diagnosed with unrelated metastatic cancer and was removed from the trial. Beta diversity (taxa) of the microbiome, was similar comparing placebo and FMT groups at baseline, however, for subjects randomized to FMT, it increased significantly at 6 weeks (p = 0.008) and 13 weeks (p = 0.0008). After treatment with FMT, proportions of selective families within the phylum Firmicutes increased significantly, while proportion of microbiota belonging to Proteobacteria were significantly reduced. Objective motor findings showed only temporary improvement while subjective symptom improvements were reported compared to baseline in the group receiving FMT. Constipation, gut transient times (NS), and gut motility index (p = 0.0374) were improved in the FMT group.

Conclusions

Subjects with Parkinson's disease tolerated multi-dose-FMT, and experienced increased diversity of the intestinal microbiome that was associated with reduction in constipation and improved gut transit and intestinal motility. Fecal microbiota transplantation administration improved subjective motor and non-motor symptoms.

Clinical trial registration

ClinicalTrial.gov, identifier: NCT03671785.
Dietary protection against the visual and motor deficits induced by experimental autoimmune encephalomyelitis
Authors: Zyla-Jackson Katarzyna , Walton Dorothy A. , Plafker Kendra S. , Kovats Susan , Georgescu Constantin , Brush Richard S. , Tytanic Madison , Agbaga Martin-Paul , Plafker Scott M.
Published: March 2023

Introduction

Five to eight percent of the world population currently suffers from at least one autoimmune disorder. Despite multiple immune modulatory therapies for autoimmune demyelinating diseases of the central nervous system, these treatments can be limiting for subsets of patients due to adverse effects and expense. To circumvent these barriers, we investigated a nutritional intervention in mice undergoing experimental autoimmune encephalomyelitis (EAE), a model of autoimmune-mediated demyelination that induces visual and motor pathologies similar to those experienced by people with multiple sclerosis (MS).

Methods

EAE was induced in female and male mice and the impact of limiting dietary carbohydrates by feeding a ketogenic diet (KD) enriched in medium chain triglycerides (MCTs), alpha-linolenic acid (an omega-3 fatty acid), and fiber was evaluated in both a preventive regimen (prior to immunization with MOG antigen) and an interventional regimen (following the onset of symptoms). Motor scores were assigned daily and visual acuity was measured using optokinetic tracking. Immunohistochemical analyses of optic nerves were done to assess inflammatory infiltrates and myelination status. Fatty acid and cytokine profiling from blood were performed to evaluate systemic inflammatory status.

Results

The KD was efficacious when fed as a preventive regimen as well as when initiated as an interventional regimen following symptom onset. The KD minimally impacted body weight during the experimental time course, increased circulating ketones, prevented motor and ocular deficits, preserved myelination of the optic nerve, and reduced infiltration of immune cells to optic nerves. The KD also increased anti-inflammatory-associated omega-3 fatty acids in the plasma and reduced select cytokines in the circulation associated with EAE-mediated pathological inflammation.

Discussion

In light of ongoing clinical trials using dietary strategies to treat people with MS, these findings support that a KD enriched in MCTs, omega-3 fatty acids, and fiber promotes a systemic anti-inflammatory milieu and ameliorates autoimmune-induced demyelinating visual and motor deficits.