bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Endotypes of Hospitalized COVID-19 Patients
Authors: Ranard Benjamin L. , Megjhani Murad , Terilli Kalijah , Doyle Kevin , Claassen Jan , Pinsky Michael R. , Clermont Gilles , Vodovotz Yoram , Asgari Shadnaz , Park Soojin
Published: November 2021

Background: Characterization of coronavirus disease 2019 (COVID-19) endotypes may help explain variable clinical presentations and response to treatments. While risk factors for COVID-19 have been described, COVID-19 endotypes have not been elucidated.

Objectives: We sought to identify and describe COVID-19 endotypes of hospitalized patients.

Methods: Consensus clustering (using the ensemble method) of patient age and laboratory values during admission identified endotypes. We analyzed data from 528 patients with COVID-19 who were admitted to telemetry capable beds at Columbia University Irving Medical Center and discharged between March 12 to July 15, 2020.

Results: Four unique endotypes were identified and described by laboratory values, demographics, outcomes, and treatments. Endotypes 1 and 2 were comprised of low numbers of intubated patients (1 and 6%) and exhibited low mortality (1 and 6%), whereas endotypes 3 and 4 included high numbers of intubated patients (72 and 85%) with elevated mortality (21 and 43%). Endotypes 2 and 4 had the most comorbidities. Endotype 1 patients had low levels of inflammatory markers (ferritin, IL-6, CRP, LDH), low infectious markers (WBC, procalcitonin), and low degree of coagulopathy (PTT, PT), while endotype 4 had higher levels of those markers.

Conclusions: Four unique endotypes of hospitalized patients with COVID-19 were identified, which segregated patients based on inflammatory markers, infectious markers, evidence of end-organ dysfunction, comorbidities, and outcomes. High comorbidities did not associate with poor outcome endotypes. Further work is needed to validate these endotypes in other cohorts and to study endotype differences to treatment responses.
Glacial Ice Age Shapes Microbiome Composition in a Receding Southern European Glacier
Authors: Garcia-Lopez Eva , Moreno Ana , Bartolomé Miguel , Leunda Maria , Sancho Carlos , Cid Cristina
Published: November 2021

Glaciers and their microbiomes are exceptional witnesses of the environmental conditions from remote times. Climate change is threatening mountain glaciers, and especially those found in southern Europe, such as the Monte Perdido Glacier (northern Spain, Central Pyrenees). This study focuses on the reconstruction of the history of microbial communities over time. The microorganisms that inhabit the Monte Perdido Glacier were identified using high-throughput sequencing, and the microbial communities were compared along an altitudinal transect covering most of the preserved ice sequence in the glacier. The results showed that the glacial ice age gradient did shape the diversity of microbial populations, which presented large differences throughout the last 2000 years. Variations in microbial community diversity were influenced by glacial conditions over time (nutrient concentration, chemical composition, and ice age). Some groups were exclusively identified in the oldest samples as the bacterial phyla Fusobacteria and Calditrichaeota, or the eukaryotic class Rhodophyceae. Among groups only found in modern samples, the green sulfur bacteria (phylum Chlorobi) stood out, as well as the bacterial phylum Gemmatimonadetes and the eukaryotic class Tubulinea. A patent impact of human contamination was also observed on the glacier microbiome. The oldest samples, corresponding to the Roman Empire times, were influenced by the beginning of mining exploitation in the Pyrenean area, with the presence of metal-tolerant microorganisms. The most recent samples comprise 600-year-old ancient ice in which current communities are living.
The Gene Rearrangement, Loss, Transfer, and Deep Intronic Variation in Mitochondrial Genomes of Conidiobolus
Authors: Nie Yong , Zhao Heng , Wang Zimin , Zhou Zhengyu , Liu Xiaoyong , Huang Bo
Published: November 2021

The genus Conidiobolus s.s. was newly delimited from Conidiobolus s.l. In order to gain insight into its mitochondrial genetic background, this study sequenced six mitochondrial genomes of the genus Conidiobolus s.s. These mitogenomes were all composed of circular DNA molecules, ranging from 29,253 to 48,417 bp in size and from 26.61 to 27.90% in GC content. The order and direction for 14 core protein-coding genes (PCGs) were identical, except for the atp8 gene lost in Conidiobolus chlamydosporus, Conidiobolus polyspermus, and Conidiobolus polytocus, and rearranged in the other Conidiobolus s.s. species. Besides, the atp8 gene split the cox1 gene in Conidiobolus taihushanensis. Phylogenomic analysis based on the 14 core PCGs confirmed that all Conidiobolus s.s. species formed a monophyly in the Entomophthoromycotina lineage. The number and length of introns were the main factors contributing to mitogenomic size, and deep variations and potential transfer were detected in introns. In addition, gene transfer occurred between the mitochondrial and nuclear genomes. This study promoted the understanding of the evolution and phylogeny of the Conidiobolus s.s. genus.
NMR Studies of Tau Protein in Tauopathies
Authors: Kitoka Kristine , Skrabana Rostislav , Gasparik Norbert , Hritz Jozef , Jaudzems Kristaps
Published: November 2021

Tauopathies, including Alzheimer’s disease (AD), are the most troublesome of all age-related chronic conditions, as there are no well-established disease-modifying therapies for their prevention and treatment. Spatio-temporal distribution of tau protein pathology correlates with cognitive decline and severity of the disease, therefore, tau protein has become an appealing target for therapy. Current knowledge of the pathological effects and significance of specific species in the tau aggregation pathway is incomplete although more and more structural and mechanistic insights are being gained using biophysical techniques. Here, we review the application of NMR to structural studies of various tau forms that appear in its aggregation process, focusing on results obtained from solid-state NMR. Furthermore, we discuss implications from these studies and their prospective contribution to the development of new tauopathy therapies.
Effects of Galvanic Vestibular Stimulation on Visual Verticality and Standing Posture Differ Based on the Polarity of the Stimulation and Hemispheric Lesion Side in Patients With Stroke
Authors: Tohyama Takamichi , Kondo Kunitsugu , Otaka Yohei
Published: November 2021

Introduction: There is growing evidence supporting the relationship of vertical misperception and poor balance control with asymmetrical standing posture in patients with stroke. Although the vestibular system has been shown to be responsible for vertical misperception and balance disorders, the effect of galvanic vestibular stimulation (GVS) on both vertical misperception and postural asymmetry after stroke remains elusive. The aim of this study was to investigate the effects of GVS on visual verticality and postural asymmetry after stroke and to clarify whether the effects differ depending on the polarity of the stimulation and hemispheric lesion side.

Methods: We measured the subjective visual vertical (SVV) and body weight distribution on each foot in an upright stance in 24 patients with a hemispheric stroke (10 with a left hemisphere lesion and 14 with a right hemisphere lesion) and nine age-matched healthy controls. During the measurements, bipolar GVS (1.5 mA) was applied over the bilateral mastoid processes in three stimulation conditions: contralesional-anodal and ipsilesional-cathodal vestibular stimulation, ipsilesional-anodal and contralesional-cathodal vestibular stimulation, and no stimulation. To examine whether GVS modulates visual verticality and standing posture, SVV and weight-bearing in the three conditions were analyzed.

Results: During no stimulation, the SVV deviated to the contralesional side in patients with a right hemisphere lesion, while more weight-bearing was observed on the ipsilesional limb than on the contralesional limb in both patient groups than in the controls. The SVV was modulated by reversing the polarity of GVS in all the groups when the cathodal stimulus side was either ipsilateral or contralateral to the lesion while the ipsilesional-cathodal vestibular stimulation reduced weight-bearing asymmetry in only the patients with a right hemisphere lesion.

Conclusions: These findings demonstrate that the effects of GVS on the SVV and standing posture differ depending on the polarity of GVS and the hemispheric lesion side. Patients with a right hemisphere lesion have difficulty maintaining their preferred standing posture under visual verticality modulation evoked by GVS. The application of GVS may clarify whether the vestibular system has neural redundancy after stroke to suppress any effects of the stimulation, including modulation of the visual verticality, on balance.
Differential Effects of Pathological Beta Burst Dynamics Between Parkinson’s Disease Phenotypes Across Different Movements
Authors: Neuville Raumin S. , Petrucci Matthew N. , Wilkins Kevin B. , Anderson Ross W. , Hoffman Shannon L. , Parker Jordan E. , Velisar Anca , Bronte-Stewart Helen M.
Published: November 2021

Background: Resting state beta band (13–30 Hz) oscillations represent pathological neural activity in Parkinson’s disease (PD). It is unknown how the peak frequency or dynamics of beta oscillations may change among fine, limb, and axial movements and different disease phenotypes. This will be critical for the development of personalized closed loop deep brain stimulation (DBS) algorithms during different activity states.

Methods: Subthalamic (STN) and local field potentials (LFPs) were recorded from a sensing neurostimulator (Activa® PC + S, Medtronic PLC.) in fourteen PD participants (six tremor-dominant and eight akinetic-rigid) off medication/off STN DBS during 30 s of repetitive alternating finger tapping, wrist-flexion extension, stepping in place, and free walking. Beta power peaks and beta burst dynamics were identified by custom algorithms and were compared among movement tasks and between tremor-dominant and akinetic-rigid groups.

Results: Beta power peaks were evident during fine, limb, and axial movements in 98% of movement trials; the peak frequencies were similar during each type of movement. Burst power and duration were significantly larger in the high beta band, but not in the low beta band, in the akinetic-rigid group compared to the tremor-dominant group.

Conclusion: The conservation of beta peak frequency during different activity states supports the feasibility of patient-specific closed loop DBS algorithms driven by the dynamics of the same beta band during different activities. Akinetic-rigid participants had greater power and longer burst durations in the high beta band than tremor-dominant participants during movement, which may relate to the difference in underlying pathophysiology between phenotypes.
The Etiology of Auditory Hallucinations in Schizophrenia: From Multidimensional Levels
Authors: Shao Xu , Liao Yanhui , Gu Lin , Chen Wei , Tang Jinsong
Published: November 2021

Enormous efforts have been made to unveil the etiology of auditory hallucinations (AHs), and multiple genetic and neural factors have already been shown to have their own roles. Previous studies have shown that AHs in schizophrenia vary from those in other disorders, suggesting that they have unique features and possibly distinguishable mechanisms worthy of further investigation. In this review, we intend to offer a comprehensive summary of current findings related to AHs in schizophrenia from aspects of genetics and transcriptome, neurophysiology (neurometabolic and electroencephalogram studies), and neuroimaging (structural and functional magnetic resonance imaging studies and transcriptome–neuroimaging association study). Main findings include gene polymorphisms, glutamate level change, electroencephalographic alterations, and abnormalities of white matter fasciculi, cortical structure, and cerebral activities, especially in multiple regions, including auditory and language networks. More solid and comparable research is needed to replicate and integrate ongoing findings from multidimensional levels.
Myelination Deficits in the Auditory Brainstem of a Mouse Model of Fragile X Syndrome
Authors: Lucas Alexandra , Poleg Shani , Klug Achim , McCullagh Elizabeth A.
Published: November 2021

Auditory symptoms are one of the most frequent sensory issues described in people with Fragile X Syndrome (FXS), the most common genetic form of intellectual disability. However, the mechanisms that lead to these symptoms are under explored. In this study, we examined whether there are defects in myelination in the auditory brainstem circuitry. Specifically, we studied myelinated fibers that terminate in the Calyx of Held, which encode temporally precise sound arrival time, and are some of the most heavily myelinated axons in the brain. We measured anatomical myelination characteristics using coherent anti-stokes Raman spectroscopy (CARS) and electron microscopy (EM) in a FXS mouse model in the medial nucleus of the trapezoid body (MNTB) where the Calyx of Held synapses. We measured number of mature oligodendrocytes (OL) and oligodendrocyte precursor cells (OPCs) to determine if changes in myelination were due to changes in the number of myelinating or immature glial cells. The two microscopy techniques (EM and CARS) showed a decrease in fiber diameter in FXS mice. Additionally, EM results indicated reductions in myelin thickness and axon diameter, and an increase in g-ratio, a measure of structural and functional myelination. Lastly, we showed an increase in both OL and OPCs in MNTB sections of FXS mice suggesting that the myelination phenotype is not due to an overall decrease in number of myelinating OLs. This is the first study to show that a myelination defects in the auditory brainstem that may underly auditory phenotypes in FXS.
Disease Duration Influences Gene Expression in Neuromelanin-Positive Cells From Parkinson’s Disease Patients
Authors: Tiklová Katarína , Gillberg Linda , Volakakis Nikolaos , Lundén-Miguel Hilda , Dahl Lina , Serrano Geidy E. , Adler Charles H. , Beach Thomas G. , Perlmann Thomas
Published: November 2021

Analyses of gene expression in cells affected by neurodegenerative disease can provide important insights into disease mechanisms and relevant stress response pathways. Major symptoms in Parkinson’s disease (PD) are caused by the degeneration of midbrain dopamine (mDA) neurons within the substantia nigra. Here we isolated neuromelanin-positive dopamine neurons by laser capture microdissection from post-mortem human substantia nigra samples recovered at both early and advanced stages of PD. Neuromelanin-positive cells were also isolated from individuals with incidental Lewy body disease (ILBD) and from aged-matched controls. Isolated mDA neurons were subjected to genome-wide gene expression analysis by mRNA sequencing. The analysis identified hundreds of dysregulated genes in PD. Results showed that mostly non-overlapping genes were differentially expressed in ILBD, subjects who were early after diagnosis (less than five years) and those autopsied at more advanced stages of disease (over five years since diagnosis). The identity of differentially expressed genes suggested that more resilient, stably surviving DA neurons were enriched in samples from advanced stages of disease, either as a consequence of positive selection of a less vulnerable long-term surviving mDA neuron subtype or due to up-regulation of neuroprotective gene products.
Fructose Induces Visceral Adipose Tissue Inflammation and Insulin Resistance Even Without Development of Obesity in Adult Female but Not in Male Rats
Authors: Kovačević Sanja , Brkljačić Jelena , Vojnović Milutinović Danijela , Gligorovska Ljupka , Bursać Biljana , Elaković Ivana , Djordjevic Ana
Published: November 2021

Introduction: Obesity and related metabolic disturbances are frequently related to modern lifestyle and are characterized by excessive fructose intake. Visceral adipose tissue (VAT) inflammation has a central role in the development of insulin resistance, type 2 diabetes (T2D), and metabolic syndrome. Since sex-related differences in susceptibility and progression of metabolic disorders are not yet fully understood, our aim was to examine inflammation and insulin signaling in VAT of fructose-fed female and male adult rats.

Methods: We analyzed effects of 9-week 10% fructose-enriched diet on energy intake, VAT mass and histology, and systemic insulin sensitivity. VAT insulin signaling and markers of VAT inflammation, and antioxidative defense status were also evaluated.

Results: The fructose diet had no effect on VAT mass and systemic insulin signaling in the female and male rats, while it raised plasma uric acid, increased PPARγ level in the VAT, and initiated the development of a distinctive population of small adipocytes in the females. Also, adipose tissue insulin resistance, evidenced by increased PTP1B and insulin receptor substrate 1 (IRS1) inhibitory phosphorylation and decreased Akt activity, was detected. In addition, fructose stimulated the nuclear accumulation of NFκB, increased expression of proinflammatory cytokines (IL-1β, IL-6, and TNFα), and protein level of macrophage marker F4/80, superoxide dismutase 1, and glutathione reductase. In contrast to the females, the fructose diet had no effect on plasma uric acid and VAT inflammation in the male rats, but less prominent alterations in VAT insulin signaling were observed.

Conclusion: Even though dietary fructose did not elicit changes in energy intake and led to obesity in the females, it initiated the proliferation of small-sized adipocytes capable of storing fats further. In contrast to the males, this state of VAT was accompanied with enhanced inflammation, which most likely contributed to the development of insulin resistance. The observed distinction could possibly originate from sex-related differences in uric acid metabolism. Our results suggest that VAT inflammation could precede obesity and start even before the measurable increase in VAT mass, making it a silent risk factor for the development of T2D. Our results emphasize that adipose tissue dysfunction, rather than its simple enlargement, could significantly contribute to the onset and development of obesity and related metabolic disorders.
Case Report: Tissue Origin Identification for Cancer of Unknown Primary: Gene Expression Profiling Approach
Authors: Pu Xingxiang , Yang Sa , Xu Yan , Chen Bolin , Wang Qianzhi , Gong Qian , Wu Lin
Published: November 2021

The treatment of cancer of unknown primary (CUP) is a huge challenge for clinicians. Gene expression profiling can help identify the tissue origin of tumors by detecting the expression levels of specific genes in tumor tissues. Herein, we report four CUP cases. All of them have been successfully identified with the corresponding primary tumor sites through gene expression profiling analysis. Then all patients received accurate treatment, providing reference to guide therapeutic decisions to treat CUP tumors in the future.
Long-Term Efficacy of Neoadjuvant Concurrent Chemoradiotherapy for Potentially Resectable Advanced Siewert Type II and III Adenocarcinomas of the Esophagogastric Junction
Authors: Tian Yuan , Wang Jun , Qiao Xueying , Zhang Jun , Li Yong , Fan Liqiao , Zhang Zhidong , Zhao Xuefeng , Tan Bibo , Wang Dong , Yang Peigang , Zhao Qun
Published: November 2021

Background

Reports have shown that neoadjuvant concurrent chemoradiotherapy (nCRT) increases the R0 resection rate for patients with Siewert type II or III adenocarcinoma of the gastroesophageal junction (AEG). However, the long-term efficacy of nCRT for AEG patients remains unclear. In this multicenter study, we investigated the long-term results of AEG patients treated with nCRT.

Methods

A total of 149 patients with potentially resectable advanced AEG (T3/4, Nany, M0) were randomly divided into two groups: the nCRT-treated group (treated group) (n = 76) and the surgery group (control group) (n = 73). The primary endpoint was disease-free survival (DFS), and the secondary outcome indexes included the R0 resection rate, HER-2 expression, tumor regression grade (TRG), objective response rate (ORR), disease control rate (DCR), overall survival (OS), and adverse events.

Results

In the treated group, the overall therapeutic efficacy rate was 40.8%, and the pathological complete response (pCR) rate was 16.9%. The rates of patients who underwent R0 resection in the treated and control groups were 97.0% and 87.7%, respectively (p < 0.05). The toxic effects were mainly graded 1–2 in the treated group. The median DFS times in the treated and control groups were 33 and 27 months, respectively (p = 0.08), whereas the median OS times were 39 and 30 months, respectively (p = 0.01). The median DFS times of patients with positive and negative HER-2 expression in the treated group were 13 and 43 months, respectively (p = 0.01), and the median OS times were 27 and 41 months, respectively (p = 0.01).

Conclusion

Surgery after nCRT improved the efficacy of treatment for AEG patients and thus provided a better prognosis.

Clinical Trial Registration

The trial is registered with ClinicalTrials.gov (number NCT01962246).
Paroxysmal Nocturnal Hemoglobinuria in the Context of a Myeloproliferative Neoplasm: A Case Report and Review of the Literature
Authors: Giannotta Juri Alessandro , Fattizzo Bruno , Barcellini Wilma
Published: November 2021

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by intravascular hemolytic anemia and thrombosis and is notoriously associated with aplastic anemia and myelodysplastic syndromes. Rarer associations include myeloproliferative neoplasms (MPNs), which are also burdened by increased thrombotic tendency. The therapeutic management of this rare combination has not been defined so far. Here, we describe a 62-year-old man who developed a highly hemolytic PNH more than 10 years after the diagnosis of MPN. The patient started eculizumab, obtaining good control of intravascular hemolysis but without amelioration of transfusion-dependent anemia. Moreover, we performed a review of the literature regarding the clinical and pathogenetic significance of the association of PNH and MPN. The prevalence of PNH clones in MPN patients is about 10%, mostly in association with JAK2V617F-positive myelofibrosis. Thrombotic events were a common clinical presentation (35% of subjects), sometimes refractory to combined treatment with cytoreductive agents, anticoagulants, and complement inhibitors. The latter showed only partial effectiveness in controlling hemolytic anemia and, due to the paucity of data, should be taken in consideration after a careful risk/benefit evaluation in this peculiar setting.
Fibroblast-Activated Protein Inhibitor PET/CT: Cancer Diagnosis and Management
Authors: Kuyumcu Serkan , Sanli Yasemin , Subramaniam Rathan M.
Published: November 2021

Fibroblast activation protein (FAP), overexpressed on cancer-associated fibroblasts (CAFs), is a novel target for molecular imaging of various tumors. Recently, the development of several small-molecule FAP inhibitors for radiolabeling with 68Ga has resulted in the emergence of studies evaluating its clinical role in cancer imaging. Preliminary findings have demonstrated that, in contrast to radiotracers taking advantage of cancer-specific targets such as PSMA and DOTATATE, FAPs as a target are the most promising that can compete with 18FDG in terms of widespread indications. They also have the potential to overcome the shortcomings of 18FDG, particularly false-positive uptake due to inflammatory or infectious processes, low sensitivity in certain cancer types, and radiotherapy planning. In addition, the attractive theranostic properties may facilitate the treatment of many refractory cancers. This review summarizes the current FAP variants and related clinical studies, focusing on radiopharmacy, dosimetry, and diagnostic and theranostic applications.
The Positivity Rate of IA-2A and ZnT8A in the Chinese Han Population With Type 1 Diabetes Mellitus: Association With rs1143627 and rs1143643 Polymorphisms in the IL1B Gene
Authors: Li Jiaqi , Sun Xiaoxiao , Luo Shuoming , Lin Jian , Xiao Yang , Yu Haibo , Huang Gan , Li Xia , Xie Zhiguo , Zhou Zhiguang
Published: November 2021

Objective: To investigate the association between susceptibility to type 1 diabetes mellitus (T1DM) and polymorphisms (rs1143627 and rs1143643) in the interleukin 1 beta (IL1B) gene in the Chinese Han population.

Methods: The Meso Scale Discovery (MSD) method was used to detect the concentration of IL-1β in 24 T1DM patients and 27 healthy controls. MassARRAY was used to analyze the polymorphisms in the IL1B gene in 510 patients with classic T1DM and 531 healthy controls. The general data of the T1DM patients and healthy controls were compared by the chi-square test and Mann-Whitney U test. The chi-square test and logistic regression were used to analyze the frequency distributions of alleles and genotypes of polymorphisms in the IL1B gene. The Kruskal-Wallis H test and chi-square test were used for the genotype-phenotype analysis of rs1143627 and rs1143643 in the IL1B gene.

Results: ① The concentration of IL-1β in T1DM patients was significantly higher than that in healthy controls. ② rs1143627 and rs1143643 in the IL1B gene were significantly correlated with the positivity rates for IA-2A and ZnT8A; genotype GG at rs1143627 and genotype CC at rs1143643 in the case group showed lower positivity rates for IA-2A and ZnT8A. ③ There was no significant difference in the genotypes or allele frequencies at rs1143627 (GG/GA/AA) or rs1143643 (CC/CT/TT) between the case group and control group (p > 0.05). ④ rs1143627 and rs1143643 were not found to be linked to T1DM susceptibility under different genetic models.

Conclusion: rs1143627 and rs1143643 in the IL1B gene correlate with the positivity rate of IA-2A and ZnT8A in Chinese Han individuals with T1DM.
Screening of a Small Molecule Compound Library Identifies Toosendanin as an Inhibitor Against Bunyavirus and SARS-CoV-2
Authors: Li Shufen , Ye Meidi , Chen Yuanqiao , Zhang Yulan , Li Jiachen , Liu Wei , Li Hao , Peng Ke
Published: November 2021

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne virus causing serious infectious disease with a high case-fatality of up to 50% in severe cases. Currently, no effective drug has been approved for the treatment of SFTSV infection. Here, we performed a high-throughput screening of a natural extracts library for compounds with activities against SFTSV infection. Three hit compounds, notoginsenoside Ft1, punicalin, and toosendanin were identified for displaying high anti-SFTSV efficacy, in which, toosendanin showed the highest inhibition potency. Mechanistic investigation indicated that toosendanin inhibited SFTSV infection at the step of virus internalization. The anti-viral effect of toosendanin against SFTSV was further verified in mouse infection models, and the treatment with toosendanin significantly reduced viral load and histopathological changes in vivo. The antiviral activity of toosendanin was further expanded to another bunyavirus and the emerging SARS-CoV-2. This study revealed a broad anti-viral effect of toosendanin and indicated its potential to be developed as an anti-viral drug for clinical use.
Off-Label Use of Venetoclax in Patients With Acute Myeloid Leukemia: Single Center Experience and Data From Pharmacovigilance Database
Authors: Gozzo Lucia , Vetro Calogero , Brancati Serena , Longo Laura , Vitale Daniela Cristina , Romano Giovanni Luca , Mauro Elisa , Fiumara Paolo Fabio , Maugeri Cinzia , Parisi Marina Silvia , Dulcamare Ilaria , Garibaldi Bruno , Duminuco Andrea , Palumbo Giuseppe Alberto , Di Raimondo Francesco , Drago Filippo
Published: November 2021

The potent oral inhibitor of BCL2, venetoclax (VEN), used to treat adults with chronic lymphocytic leukaemia, has been approved in US for the treatment of naïve patients with acute myeloid leukemia (AML) unfit for intensive chemotherapy and recently in Europe, too. However, the drug has been used for years in combination with hypomethylating agents (HMAs) in patients not eligible to other treatment option, according to the so-called off-label use. We collected real-world data about patients treated with VEN + HMAs in the context of a pharmacovigilance project focused on the evaluation of the safety and effectiveness of drugs used for unapproved indication in Italian hospitals. From March to December 2020, 24 patients started treatment with VEN combined with HMAs. 21 patients have been assessed for response. Eleven (52%) patients reached complete remission (CR), and three patients (14%) CR with partial hematological recovery (CRh), with a median duration of response of 4.5 months (range 0.5–12.5). 19 patients experienced at least 1 adverse drug reaction (ADR), mostly serious, including 3 deaths (9% of ADRs; 12.5% of patients) in febrile neutropenia. Hematological toxicities and infections (cytopenia, neutropenia, febrile neutropenia, sepsis), were the most reported ADRs (84.4%). In general, neutropenic fever occurred more frequently in patients treated with decitabine (7 out of 9, 78%) compared to azacitidine (5 out of 15, 33%; p = 0.03), whereas response assessment did not differ based on used HMA (p = 0.1). These results confirm the benefit-risk profile of VEN in a real-world setting of patients with no adequate therapeutic options.
Co-Administration of Vonoprazan, Not Tegoprazan, Affects the Pharmacokinetics of Atorvastatin in Healthy Male Subjects
Authors: Hwang Sejung , Ko Jae-Wook , Lee Heechan , Kim Seokuee , Kim Bongtae , Song Geun Seog , Kim Jungryul
Published: November 2021

Potassium-competitive acid blocker is a new class of drugs inhibiting gastric acid. It is controversial that vonoprazan showed the inhibitory activities of cytochrome P450 3A4. This study aimed to evaluate the pharmacokinetics (PK) of atorvastatin and safety when atorvastatin was administered alone and co-administered with vonoprazan or tegoprazan. An open-label, multiple-dose, 3-intervention, 4-sequence, 4-period, partial replicate crossover study was conducted, and three interventions were; one is orally administered atorvastatin 40 mg alone once daily for 7 days, another is atorvastatin co-administered with vonoprazan 20 mg, and the other is atorvastatin co-administered with tegoprazan 50 mg. PK blood samples were collected up to 24 h after the last dose, and PK parameters for atorvastatin, 2-hydroxyatorvastatin and atorvastatin lactone were estimated by a non-compartmental method. Safety was evaluated, including adverse events and clinical laboratory tests. A total of 28 subjects completed the study. When atorvastatin was co-administered with vonoprazan, the systemic exposures of atorvastatin and atorvastatin lactone significantly increased, and the metabolic ratio of 2-hydroxyatorvastatin significantly decreased. Hypergastrinemia only occurred when atorvastatin was co-administered with vonoprazan. However, the plasma concentration profiles of atorvastatin, 2-hydroxyatorvastatin and atorvastatin lactone were similar when atorvastatin was administered alone or co-administered with tegoprazan. In conclusion, after multiple doses of atorvastatin co-administered with vonoprazan in healthy subjects, the systemic exposure of atorvastatin and the incidence of hypergastrinemia increased. With tegoprazan, however, those interactions were not observed.
The Protective Effect of Panax notoginseng Mixture on Hepatic Ischemia/Reperfusion Injury in Mice via Regulating NR3C2, SRC, and GAPDH
Authors: Hou Wen , Wei Bao , Liu Hong Sheng
Published: November 2021

Panax notoginseng mixture (PNM) has the characteristics of multicomponent, multitarget, and multieffect, which can cope with the multidirectional and multidimensional complex pathological process caused by hepatic ischemia/reperfusion injury (HIRI). Our animal experiments showed that PNM composed of notoginseng, dogwood, and white peony root could significantly reduce the level of aspartate transaminase and alanine aminotransferase in the blood of mice with HIRI, indicating that this preparation had a protective effect on HIRI in mice. Therefore, on this basis, the molecular mechanism of PNM intervention in HIRI was further explored by network pharmacology. First, target genes corresponding to active components and HIRI were obtained through databases such as TCMSP, Pharm Mapper, Swiss Target Prediction, GeneCards, and so on. All target genes were standardized by Uniprot database, and a total of 291 target genes with their intersection were obtained. Then, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and biological processes (BPs) of 291 target genes were obtained through the online public platform of DAVID. A total of 177 KEGG pathways and 337 BPs were obtained by setting p < 0.01 and false discovery rate <0.05. The network mapping map of components and disease targets was drawn by Cytoscape, and the top 10 Hub target genes related to HIRI were obtained. At the same time, the String database was used to obtain the protein–protein interaction dataset, which was imported into Cytoscape, and the first 10 Hub target genes were obtained. The Hub target genes obtained by the above two methods were molecular docking with their corresponding small molecule compounds through DockThor online tool. The results showed that the docking of paeoniflorin with glyceraldehyde 3-phosphate dehydrogenase (GAPDH), paeoniflorin and loganin with SRC, ginsenoside Rb1 with NR3C2, ursolic acid and oleanolic acid with IL-6, paeoniflorin docking VEGFA, and MMP9. Finally, NR3C2, SRC, and GAPDH were identified as target genes in this study by referring to relevant literature reports. After verification by immunohistochemical experiments, compared with the sham group, the above three target genes were highly expressed in the HIRI group (p < 0.01). Compared with the HIRI group, the expression of three target genes in the PNM + HIRI group was significantly decreased (p < 0.01). The results showed that PNM could protect mouse HIRI by decreasing the expression of NR3C2, SRC, and GAPDH.
Recent Advances in Pharmaceutical Cocrystals: From Bench to Market
Authors: Kumar Bandaru Ravi , Rout Smruti Rekha , Kenguva Gowtham , Gorain Bapi , Alhakamy Nabil A. , Kesharwani Prashant , Dandela Rambabu
Published: November 2021

The pharmacokinetics profile of active pharmaceutical ingredients (APIs) in the solid pharmaceutical dosage forms is largely dependent on the solid-state characteristics of the chemicals to understand the physicochemical properties by particle size, size distribution, surface area, solubility, stability, porosity, thermal properties, etc. The formation of salts, solvates, and polymorphs are the conventional strategies for altering the solid characteristics of pharmaceutical compounds, but they have their own limitations. Cocrystallization approach was established as an alternative method for tuning the solubility, permeability, and processability of APIs by introducing another compatible molecule/s into the crystal structure without affecting its therapeutic efficacy to successfully develop the formulation with the desired pharmacokinetic profile. In the present review, we have grossly focused on cocrystallization, particularly at different stages of development, from design to production. Furthermore, we have also discussed regulatory guidelines for pharmaceutical industries and challenges associated with the design, development and production of pharmaceutical cocrystals with commercially available cocrystal-based products.
Influence of Rock Block Content on Compaction Characteristics of Graded Coarse-Grained Fillers
Authors: Cai Lili , Wang Shengnian , Gao Xinqun , Li Guoyu
Published: November 2021

The bearing capacity, stability, and durability of subgrade are affected by the compaction quality of fillers to a large extent. In this study, samples of graded coarse-grained fillers with different rock block contents were designed and prepared with the aid of an improved continuous gradation equation for coarse-grained soils. Then standard compaction tests of these samples with different water content conditions were conducted to understand the influence of rock block content on the compaction characteristics of graded coarse-grained fillers. Results show that the compaction curve peaks of graded coarse-grained fillers always increase with the rock block content. The maximum dry density of graded coarse-grained fillers increases linearly with the rock block content in approximation, while the optimal water content is the opposite. The optimal water content of graded coarse-grained fillers decreases in nonlinearity with characteristics of rapidly first and then slowly. Two empirical formulas about the rock block content were summarized for predicting the maximum dry density and optimal water content of graded coarse-grained fillers. The results of this study can provide a reference for the engineering application of graded coarse-grained fillers.
Classification of Fibrillation Organisation Using Electrocardiograms to Guide Mechanism-Directed Treatments
Authors: Li Xinyang , Shi Xili , Handa Balvinder S. , Sau Arunashis , Zhang Bowen , Qureshi Norman A. , Whinnett Zachary I. , Linton Nick W. F. , Lim Phang Boon , Kanagaratnam Prapa , Peters Nicholas S. , Ng Fu Siong
Published: November 2021

Background: Atrial fibrillation (AF) and ventricular fibrillation (VF) are complex heart rhythm disorders and may be sustained by distinct electrophysiological mechanisms. Disorganised self-perpetuating multiple-wavelets and organised rotational drivers (RDs) localising to specific areas are both possible mechanisms by which fibrillation is sustained. Determining the underlying mechanisms of fibrillation may be helpful in tailoring treatment strategies. We investigated whether global fibrillation organisation, a surrogate for fibrillation mechanism, can be determined from electrocardiograms (ECGs) using band-power (BP) feature analysis and machine learning.

Methods: In this study, we proposed a novel ECG classification framework to differentiate fibrillation organisation levels. BP features were derived from surface ECGs and fed to a linear discriminant analysis classifier to predict fibrillation organisation level. Two datasets, single-channel ECGs of rat VF (n = 9) and 12-lead ECGs of human AF (n = 17), were used for model evaluation in a leave-one-out (LOO) manner.

Results: The proposed method correctly predicted the organisation level from rat VF ECG with the sensitivity of 75%, specificity of 80%, and accuracy of 78%, and from clinical AF ECG with the sensitivity of 80%, specificity of 92%, and accuracy of 88%.

Conclusion: Our proposed method can distinguish between AF/VF of different global organisation levels non-invasively from the ECG alone. This may aid in patient selection and guiding mechanism-directed tailored treatment strategies.
Silencing Long Non-coding RNA Kcnq1ot1 Limits Acute Kidney Injury by Promoting miR-204-5p and Blocking the Activation of NLRP3 Inflammasome
Authors: Wang JunTao , Jiao Peng , Wei XiaoYing , Zhou Yun
Published: November 2021

Acute kidney injury (AKI) is a critical clinical disease characterized by an acute decrease in renal function. Long non-coding RNAs (LncRNAs) are important in AKI. This study aimed to explore the mechanism of lncRNA Kcnq1ot1 in AKI by sponging microRNA (miR)-204-5p as a competitive endogenous RNA (ceRNA). AKI mouse model and hypoxia/reoxygenation (H/R) model of human kidney (HK) cells were established. Kcnq1ot1 expression, cell proliferation, and apoptosis were measured. Binding relations among Kcnq1ot1, miR-204-5p, and NLRP3 were verified. Pathological changes and cell apoptosis were detected. The results showed that Kcnq1ot1 was highly expressed in the AKI model in vivo and in vitro. Kcnq1ot1 knockdown promoted cell proliferation and prevented apoptosis and inflammation. Furthermore, Kcnq1ot1 inhibited miR-204-5p expression by competitively binding to miR-204-5p in HK-2 cells. miR-204-5p targeted NLRP3 and NLRP3 overexpression averted the inhibiting effect of miR-204-5p on apoptosis and inflammation in HK-2 cells in vitro. Kcnq1ot1 knockdown in vivo promoted miR-204-5p expression, inhibited NLRP3 inflammasome activation, reduced levels of SCr, BUN, and KIM-1, and thus alleviated AKI and reduced apoptosis. In summary, silencing lncRNA Kcnq1ot1 inhibited AKI by promoting miR-204-5p and inhibiting NLRP3 inflammasome activation.
Gluteal Muscle Atrophy and Increased Intramuscular Lipid Concentration Are Not Mitigated by Daily Artificial Gravity Following 60-Day Head-Down Tilt Bed Rest
Authors: Tran Vienna , De Martino Enrico , Hides Julie , Cable Gordon , Elliott James M. , Hoggarth Mark , Zange Jochen , Lindsay Kirsty , Debuse Dorothée , Winnard Andrew , Beard David , Cook Jonathan A. , Salomoni Sauro E. , Weber Tobias , Scott Jonathan , Hodges Paul W. , Caplan Nick
Published: November 2021

Exposure to spaceflight and head-down tilt (HDT) bed rest leads to decreases in the mass of the gluteal muscle. Preliminary results have suggested that interventions, such as artificial gravity (AG), can partially mitigate some of the physiological adaptations induced by HDT bed rest. However, its effect on the gluteal muscles is currently unknown. This study investigated the effects of daily AG on the gluteal muscles during 60-day HDT bed rest. Twenty-four healthy individuals participated in the study: eight received 30 min of continuous AG; eight received 6 × 5 min of AG, interspersed with rest periods; eight belonged to a control group. T1-weighted Dixon magnetic resonance imaging of the hip region was conducted at baseline and day 59 of HDT bed rest to establish changes in volumes and intramuscular lipid concentration (ILC). Results showed that, across groups, muscle volumes decreased by 9.2% for gluteus maximus (GMAX), 8.0% for gluteus medius (GMED), and 10.5% for gluteus minimus after 59-day HDT bed rest (all p < 0.005). The ILC increased by 1.3% for GMAX and 0.5% for GMED (both p < 0.05). Neither of the AG protocols mitigated deconditioning of the gluteal muscles. Whereas all gluteal muscles atrophied, the ratio of lipids to intramuscular water increased only in GMAX and GMED muscles. These changes could impair the function of the hip joint and increased the risk of falls. The deconditioning of the gluteal muscles in space may negatively impact the hip joint stability of astronauts when reexpose to terrestrial gravity.
Time-Series Growth Prediction Model Based on U-Net and Machine Learning in Arabidopsis
Authors: Chang Sungyul , Lee Unseok , Hong Min Jeong , Jo Yeong Deuk , Kim Jin-Baek
Published: November 2021

Yield prediction for crops is essential information for food security. A high-throughput phenotyping platform (HTPP) generates the data of the complete life cycle of a plant. However, the data are rarely used for yield prediction because of the lack of quality image analysis methods, yield data associated with HTPP, and the time-series analysis method for yield prediction. To overcome limitations, this study employed multiple deep learning (DL) networks to extract high-quality HTTP data, establish an association between HTTP data and the yield performance of crops, and select essential time intervals using machine learning (ML). The images of Arabidopsis were taken 12 times under environmentally controlled HTPP over 23 days after sowing (DAS). First, the features from images were extracted using DL network U-Net with SE-ResXt101 encoder and divided into early (15–21 DAS) and late (∼21–23 DAS) pre-flowering developmental stages using the physiological characteristics of the Arabidopsis plant. Second, the late pre-flowering stage at 23 DAS can be predicted using the ML algorithm XGBoost, based only on a portion of the early pre-flowering stage (17–21 DAS). This was confirmed using an additional biological experiment (P < 0.01). Finally, the projected area (PA) was estimated into fresh weight (FW), and the correlation coefficient between FW and predicted FW was calculated as 0.85. This was the first study that analyzed time-series data to predict the FW of related but different developmental stages and predict the PA. The results of this study were informative and enabled the understanding of the FW of Arabidopsis or yield of leafy plants and total biomass consumed in vertical farming. Moreover, this study highlighted the reduction of time-series data for examining interesting traits and future application of time-series analysis in various HTPPs.
Herbivore-Mediated Selection on Floral Display Covaries Nonlinearly With Plant-Antagonistic Interaction Intensity Among Primrose Populations
Authors: Wu Yun , Barrett Spencer C. H. , Duan Xuyu , Zhang Jie , Cha Yongpeng , Tu Chengyi , Li Qingjun
Published: November 2021

Quantifying the relations between plant-antagonistic interactions and natural selection among populations is important for predicting how spatial variation in ecological interactions drive adaptive differentiation. Here, we investigate the relations between the opportunity for selection, herbivore-mediated selection, and the intensity of plant-herbivore interaction among 11 populations of the insect-pollinated plant Primula florindae over 2 years. We experimentally quantified herbivore-mediated directional selection on three floral traits (two display and one phenological) within populations and found evidence for herbivore-mediated selection for a later flowering start date and a greater number of flowers per plant. The opportunity for selection and strength of herbivore-mediated selection on number of flowers varied nonlinearly with the intensity of herbivory among populations. These parameters increased and then decreased with increasing intensity of plant-herbivore interactions, defined as an increase in the ratio of herbivore-damaged flowers per individual. Our results provide novel insights into how plant-antagonistic interactions can shape spatial variation in selection on floral traits and contribute toward understanding the mechanistic basis of geographic variation in angiosperm flowers.
Alcohol Acyltransferase Is Involved in the Biosynthesis of C6 Esters in Apricot (Prunus armeniaca L.) Fruit
Authors: Zhou Wanhai , Kong Wenbin , Yang Can , Feng Ruizhang , Xi Wanpeng
Published: November 2021

Short-chain esters derived from fatty acid contribute to the characteristic flavor of apricot fruit, and the biosynthesis of these compounds in fruit is catalyzed by alcohol acyltransferase (AAT). In this work, we investigated the AAT gene family via genome-wide scanning, and three AAT loci were identified in different linkage groups (LGs), with PaAAT1 (PARG22907m01) in LG7, PaAAT2 (PARG15279m01) in LG4, and PaAAT3 (PARG22697m01) in LG6. Phylogenetic analysis showed that PaAAT1 belongs to clade 3, while PaAAT2 and PaAAT3 belong to clade 1 and clade 2, respectively. In contrast, the three AAT genes present different expression patterns. Only PaAAT1 exhibited distinct patterns of fruit-specific expression, and the expression of PaAAT1 sharply increased during fruit ripening, which is consistent with the abundance of C4–C6 esters such as (E)-2-hexenyl acetate and (Z)-3-hexenyl acetate. The transient overexpression of PaAAT1 in Katy (KT) apricot fruit resulted in a remarkable decrease in hexenol, (E)-2-hexenol, and (Z)-3-hexenol levels while significantly increasing the corresponding acetate production (p < 0.01). A substrate assay revealed that the PaAAT1 protein enzyme can produce hexenyl acetate, (E)-2-hexenyl acetate, and (Z)-3-hexenyl acetate when C6 alcohols are used as substrates for the reaction. Taken together, these results indicate that PaAAT1 plays a crucial role in the production of C6 esters in apricot fruit during ripening.