bluuebunny/crossref_metadata_2025 huggingface dataset:
Paroxysmal Sympathetic Hyperactivity in Severe Anti-N-Methyl-d-Aspartate Receptor Encephalitis: A Single Center Retrospective Observational Study
Authors: Wang Dongmei , Su Shuang , Tan Miaoqin , Wu Yongming , Wang Shengnan
Published: April 2021

Background

Paroxysmal sympathetic hyperactivity (PSH) is a disorder with excessive sympathetic activity commonly recognized in patients with acquired brain injury. Autonomic instability is frequent in anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDARE). However, PSH in anti-NMDARE has gained little attention.

Methods

We retrospectively reviewed 24 patients diagnosed with severe anti-NMDARE in the neuro-intensive care unit (NICU) between 2014 and 2019. Patients were assessed with the PSH assessment measure (PSH-AM) scale, and categorized into “PSH+” group and “PSH-” group. The clinical characteristics, hospital mortality, and functional outcome by modified Rankin Scale (mRS) score at six months after discharge were compared between the two groups. Among patients with PSH+, the clinical features and pharmacotherapy of PSH were summarized and compared.

Results

Twenty-four patients were included in the study. Twelve of them (50%) were categorized as PSH+ based on PSH-AM scores. There were no significant differences in the demographic characteristic, GCS scores upon admission, incidence of status epilepticus, teratoma occurrence, hospital mortality, and 6-month mRS between PSH+ and PSH- groups. Patients with PSH+ had increased length of NICU stay, hospital stay and duration of mechanical ventilation. The most prominent clinical features of PSH in severe anti-NMDARE were tachycardia and hyperthermia, while posturing was the relatively mildest clinical feature. Propranolol and clonazepam were more commonly used than gabapentin in pharmacotherapy of PSH in severe anti-NMDARE.

Conclusions

The incidence of PSH in severe anti-NMDARE patients was as high as 50%. Patients with PSH demonstrated prolonged NICU stay, hospital stay and increased duration of mechanical ventilation, while no effect on hospital mortality and functional outcome. Clinicians should be aware of the distinctive characteristics and treatment options of PSH in severe anti-NMDARE.
Targeting the Notch Signaling Pathway in Chronic Inflammatory Diseases
Authors: Christopoulos Panagiotis F. , Gjølberg Torleif T. , Krüger Stig , Haraldsen Guttorm , Andersen Jan Terje , Sundlisæter Eirik
Published: April 2021

The Notch signaling pathway regulates developmental cell-fate decisions and has recently also been linked to inflammatory diseases. Although therapies targeting Notch signaling in inflammation in theory are attractive, their design and implementation have proven difficult, at least partly due to the broad involvement of Notch signaling in regenerative and homeostatic processes. In this review, we summarize the supporting role of Notch signaling in various inflammation-driven diseases, and highlight efforts to intervene with this pathway by targeting Notch ligands and/or receptors with distinct therapeutic strategies, including antibody designs. We discuss this in light of lessons learned from Notch targeting in cancer treatment. Finally, we elaborate on the impact of individual Notch members in inflammation, which may lay the foundation for development of therapeutic strategies in chronic inflammatory diseases.
Influence of the Prosumer Allocation and Heat Production on a District Heating Network
Authors: Ancona Maria Alessandra , Bianchi Michele , Branchini Lisa , De Pascale Andrea , Melino Francesco , Peretto Antonio , Rosati Jessica
Published: April 2021

To face the climate change and global warming issues, European countries have set new targets in order to reduce the CO2 emissions to 40% by 2030 and to 80% by 2050. The district heating networks, and in particular low-temperature networks, due to their efficient heat supply and distribution represent a key point for meeting these goals, as well as the renewable sources integration. Nowadays, in fact, about 40% of the energy consumed in Europe is for heating, most of which is provided by fossil fuels employment. This article concerns the smart district heating, namely, the possibility of a bidirectional energy exchange between the district heating network and the connected users. The main purpose of this study is to evaluate the possibility of including a prosumer—that is, a customer who can both consume and produce heat—in an existing small/medium district heating network. To this purpose, an in-house–developed software has been applied to analyze whether and which user of the district heating network is more suitable to be set as prosumer and the effect of the installed distributed generation system on the network. The results show how the choice of a prosumer over another and how the amount of exchanged thermal power affect the performance of the network, with a consequent need of a modification in its operation and management.
Standard Survey Data: Insights Into Private Sector Utilization
Authors: Montagu Dominic , Chakraborty Nirali
Published: April 2021

Universal Health Coverage in Low- and Middle-Income Countries is increasingly expanding through incorporation of private clinics, pharmacies, and hospitals into an overall health system funded in whole or part through government-managed health insurance. This underscores the importance of policies on health provision which apply across the whole delivery system regardless of ownership status. To advance understanding of private-sector policies, and to facilitate sharing of lessons across countries with similar public-private distributions, we have analyzed data on the source of inpatient and outpatient care from 65 countries. While past studies have conducted similar analysis, ours advances the field in two ways. First, we limit our analysis to data sets from 2010 through 2019, making our study more up-to-date than past studies, while changing health seeking patterns for maternal health since 2010 means that our data set is more representative of overall inpatient care. Second, while past multi-country analysis of public-private ownership have been based on the Demographic Health Surveys, we have added to this data from the Multiple Indicator Cluster Surveys, significantly increasing the countries in our analysis. We have aggregated our analysis by WHO's regions. Outside of the EURO region, where the private sector delivers just 4% of all healthcare services, the private sector remains significant, and in many countries represents more than half of all care. The private sector provides nearly 40% of all healthcare in PAHO, AFRO, and WPRO regions, 57% in SEARO, and 62% in EMRO. While specific countries with two recent surveys show variation in the scale of both inpatient and outpatient private provision, we did not find regional or global trends toward or away from private care within LMICs. Private inpatient care is most important for the wealthy in many countries; public vs. private care varies less, by wealth, for outpatient services.
Methodological Issue of Mitochondrial Isolation in Acute-Injury Rat Model: Asphyxia Cardiac Arrest and Resuscitation
Authors: Aoki Tomoaki , Okuma Yu , Becker Lance B. , Hayashida Kei , Shinozaki Koichiro
Published: April 2021

Background: Identification of the mechanisms underlying mitochondrial dysfunction is key to understanding the pathophysiology of acute injuries such as cardiac arrest (CA); however, effective methods for measurement of mitochondrial function associated with mitochondrial isolation have been debated for a long time. This study aimed to evaluate the dysregulation of mitochondrial respiratory function after CA while testing the sampling bias that might be induced by the mitochondrial isolation method.

Materials and Methods: Adult rats were subjected to 10-min asphyxia-induced CA. 30 min after resuscitation, the brain and kidney mitochondria from animals in sham and CA groups were isolated (n = 8, each). The mitochondrial quantity, expressed as protein concentration (isolation yields), was determined, and the oxygen consumption rates were measured. ADP-dependent (state-3) and ADP-limited (state-4) respiration activities were compared between the groups. Mitochondrial quantity was evaluated based on citrate synthase (CS) activity and cytochrome c concentration, measured independent of the isolation yields.

Results: The state-3 respiration activity and isolation yield in the CA group were significantly lower than those in the sham group (brain, p < 0.01; kidney, p < 0.001). The CS activity was significantly lower in the CA group as compared to that in the sham group (brain, p < 0.01; kidney, p < 0.01). Cytochrome c levels in the CA group showed a similar trend (brain, p = 0.08; kidney, p = 0.25).

Conclusions: CA decreased mitochondrial respiration activity and the quantity of mitochondria isolated from the tissues. Owing to the nature of fragmented or damaged mitochondrial membranes caused by acute injury, there is a potential loss of disrupted mitochondria. Thus, it is plausible that the mitochondrial function in the acute-injury model may be underestimated as this loss is not considered.
A Clinical Perspective on the Role of Electronic Devices in Monitoring and Promoting Adherence in Airways Disease
Authors: Brennan Vincent , Mulvey Christopher , Greene Garrett , Hale Elaine Mac , Costello Richard W.
Published: April 2021

Poor adherence to treatment is a common reason why patients with chronic disease have worse outcomes than might be expected. Poor treatment adherence is of particular concern among people with airways disease because, apart from not taking treatment as prescribed, inhaled medication can also be administered incorrectly. Recently, a number of technological advances that accurately document when an inhaled treatment has been used and, in certain instances, how it was used have been developed. There is good evidence from a number of research groups that these devices, either by patient reminders or physician feedback, promote adherence to inhaled treatments. What is less certain is how, in a real-world setting, these devices change outcomes. In this perspective article, the role of electronic devices in quantifying treatment use and addressing poor treatment adherence and their potential role in clinical practice outside of clinical validation trials are described.
Role of Probiotic Bacilli in Developing Synbiotic Food: Challenges and Opportunities
Authors: Szlufman Carolina , Shemesh Moshe
Published: April 2021

The human body is inhabited by a vast diversity of probiotic microorganisms that could positively affect human physiology. Besides, prebiotic food substances may induce symbiotic relationship among probiotic species through the successful establishment of commensal microbiota, whose connections with the host are multifaceted and multidirectional. As deliberated throughout this review, prebiotic and synbiotic foods contain the capability to stimulate numerous health characteristics in host organisms through various means. Predominantly, the normal microbiota fosters the digestion of food and may boost the innate and adaptive immune system’s functionalities. Therefore, live probiotic bacteria, for instance, probiotic Bacilli obtained together with prebiotic food, can help stimulate healthiness in humans. Thus, we discuss how certain dietary fibers may preserve the probiotic efficacy by serving as the scaffold for probiotic Bacilli to colonize them through forming symbiotic interactions. The fibers can essentially promote protection by encapsulating probiotic Bacilli against various environmental and physical stresses that might kill the free-living bacterial cells. Besides, these fibers would serve as prebiotic substances that would eventually be utilized for the proliferation of probiotic cells. It is believed that applying this conceptual idea will provide a novel platform toward developing probiotic and synbiotic foods, as discussed in this review.
Characterization of Weak Protein Domain Structure by Spin-Label Distance Distributions
Authors: Ritsch Irina , Esteban-Hofer Laura , Lehmann Elisabeth , Emmanouilidis Leonidas , Yulikov Maxim , Allain Frédéric H.-T. , Jeschke Gunnar
Published: April 2021

Function of intrinsically disordered proteins may depend on deviation of their conformational ensemble from that of a random coil. Such deviation may be hard to characterize and quantify, if it is weak. We explored the potential of distance distributions between spin labels, as they can be measured by electron paramagnetic resonance techniques, for aiding such characterization. On the example of the intrinsically disordered N-terminal domain 1–267 of fused in sarcoma (FUS) we examined what such distance distributions can and cannot reveal on the random-coil reference state. On the example of the glycine-rich domain 188–320 of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) we studied whether deviation from a random-coil ensemble can be robustly detected with 19 distance distribution restraints. We discuss limitations imposed by ill-posedness of the conversion of primary data to distance distributions and propose overlap of distance distributions as a fit criterion that can tackle this problem. For testing consistency and size sufficiency of the restraint set, we propose jack-knife resampling. At current desktop computers, our approach is expected to be viable for domains up to 150 residues and for between 10 and 50 distance distribution restraints.
Social Disconnectedness, Loneliness, and Mental Health Among Adolescents in Danish High Schools: A Nationwide Cross-Sectional Study
Authors: Santini Ziggi Ivan , Pisinger Veronica S. C. , Nielsen Line , Madsen Katrine Rich , Nelausen Malene Kubstrup , Koyanagi Ai , Koushede Vibeke , Roffey Sue , Thygesen Lau C. , Meilstrup Charlotte
Published: April 2021

Background:Previous research has suggested that social disconnectedness experienced at school is linked to mental health problems, however, more research is needed to investigate (1) whether the accumulation of various types of social disconnectedness is associated with risk for mental health problems, and (2) whether loneliness is a mechanism that explains these associations.

Methods:Using data from the Danish National Youth Study 2019 (UNG19), nation-wide cross-sectional data from 29,086 high school students in Denmark were analyzed to assess associations between social disconnectedness experienced at school (lack of classmate support, lack of teacher support, lack of class social cohesion, and not being part of the school community) and various mental health outcomes, as well as the mediating role of loneliness for each type of disconnectedness. Multilevel regression analyses were conducted to assess the associations.

Results:Descriptive analyses suggest that 27.5% of Danish high school students experience at least one type of social disconnectedness at school. Each type of social disconnectedness was positively associated with mental health problems (depression symptoms, anxiety symptoms, stress, sleep problems, suicidal ideation, non-suicidal self-injury, eating disorder, body dissatisfaction, and low self-esteem) and negatively associated with mental well-being. In all cases, loneliness significantly mediated the associations. We found a clear dose-response pattern, where each addition in types of social disconnectedness was associated with (1) stronger negative coefficients with mental well-being and (2) stronger positive coefficients with mental health problems.

Conclusion:Our results add to a large evidence-base suggesting that mental health problems among adolescents may be prevented by promoting social connectedness at school. More specifically, fostering social connectedness at school may prevent loneliness, which in turn may promote mental well-being and prevent mental health problems during the developmental stages of adolescence. It is important to note that focusing on single indicators of school social connectedness/disconnectedness would appear to be insufficient. Implications for practices within school settings to enhance social connectedness are discussed.
Nucleolin Rescues TDP-43 Toxicity in Yeast and Human Cell Models
Authors: Peggion Caterina , Massimino Maria Lina , Stella Roberto , Bortolotto Raissa , Agostini Jessica , Maldi Arianna , Sartori Geppo , Tonello Fiorella , Bertoli Alessandro , Lopreiato Raffaele
Published: April 2021

TDP-43 is a nuclear protein involved in pivotal processes, extensively studied for its implication in neurodegenerative disorders. TDP-43 cytosolic inclusions are a common neuropathologic hallmark in amyotrophic lateral sclerosis (ALS) and related diseases, and it is now established that TDP-43 misfolding and aggregation play a key role in their etiopathology. TDP-43 neurotoxic mechanisms are not yet clarified, but the identification of proteins able to modulate TDP-43-mediated damage may be promising therapeutic targets for TDP-43 proteinopathies. Here we show by the use of refined yeast models that the nucleolar protein nucleolin (NCL) acts as a potent suppressor of TDP-43 toxicity, restoring cell viability. We provide evidence that NCL co-expression is able to alleviate TDP-43-induced damage also in human cells, further supporting its beneficial effects in a more consistent pathophysiological context. Presented data suggest that NCL could promote TDP-43 nuclear retention, reducing the formation of toxic cytosolic TDP-43 inclusions.
Baseline Cerebral Ischemic Core Quantified by Different Automatic Software and Its Predictive Value for Clinical Outcome
Authors: Shi Zhang , Li Jing , Zhao Ming , Zhang Minmin , Wang Tiegong , Chen Luguang , Liu Qi , Wang He , Lu Jianping , Zhao Xihai
Published: April 2021

Purpose

This study aims to investigate the agreement of three software packages in measuring baseline ischemic core volume (ICV) and penumbra volume (PV), and determine their predictive values for unfavorable clinical outcome in patients with endovascular thrombectomy (EVT).

Methods

Patients with acute ischemic stroke who underwent computed tomographic perfusion (CTP) were recruited. Baseline CTP measurements including ICV and PV were calculated by three software packages of IntelliSpace Portal (ISP), Rapid Processing of Perfusion and Diffusion (RAPID), and fast-processing of ischemic stroke (F-STROKE). All patients received EVT, and the modified Rankin scale (mRS) at 90 days after EVT was assessed to determine the clinical outcomes (favorable: mRS = 0–2; unfavorable: mRS = 3–6). The agreement of CTP measurements among three software packages was determined using intraclass correlation coefficient (ICC). The associations between CTP measurements and unfavorable clinical outcome were analyzed using logistic regression. Receiver operating characteristic curves were conducted to calculate the area under the curve (AUC) of CTP measurements in predicting unfavorable clinical outcome.

Results

Of 223 recruited patients (68.2 ± 11.3 years old; 145 males), 17.0% had unfavorable clinical outcome after EVT. Excellent agreement between F-STROKE and RAPID was found in measuring ICV (ICC 0.965; 95% CI 0.956–0.973) and PV (ICC 0.966; 95% CI 0.956–0.973). ICVs measured by three software packages were significantly associated with unfavorable clinical outcome before (odds ratios 1.012–1.018, all P < 0.01) and after (odds ratios 1.003–1.014, all P < 0.05) adjusted for confounding factors (age, gender, TOAST classification, and NIHSS on admission). In predicting unfavorable clinical outcome, ICV measured by F-STROKE showed similar performance to that measured by RAPID (AUC 0.701 vs. 0.717) but higher performance than that measured by ISP (AUC 0.629).

Conclusions

The software of F-STROKE has excellent agreement with the widely used analysis tool of RAPID in measuring ICV and PV. The ischemic core volume measured by both F-STROKE and RAPID is a stronger predictor for unfavorable clinical outcome after EVT compared to ISP.
Identification of Two Novel Peptides That Inhibit α-Synuclein Toxicity and Aggregation
Authors: Popova Blagovesta , Wang Dan , Rajavel Abirami , Dhamotharan Karthikeyan , Lázaro Diana F. , Gerke Jennifer , Uhrig Joachim F. , Hoppert Michael , Outeiro Tiago F. , Braus Gerhard H.
Published: April 2021

Aggregation of α-synuclein (αSyn) into proteinaceous deposits is a pathological hallmark of a range of neurodegenerative diseases including Parkinson’s disease (PD). Numerous lines of evidence indicate that the accumulation of toxic oligomeric and prefibrillar αSyn species may underpin the cellular toxicity and spread of pathology between cells. Therefore, aggregation of αSyn is considered a priority target for drug development, as aggregation inhibitors are expected to reduce αSyn toxicity and serve as therapeutic agents. Here, we used the budding yeast S. cerevisiae as a platform for the identification of short peptides that inhibit αSyn aggregation and toxicity. A library consisting of approximately one million peptide variants was utilized in two high-throughput screening approaches for isolation of library representatives that reduce αSyn-associated toxicity and aggregation. Seven peptides were isolated that were able to suppress specifically αSyn toxicity and aggregation in living cells. Expression of the peptides in yeast reduced the accumulation of αSyn-induced reactive oxygen species and increased cell viability. Next, the peptides were chemically synthesized and probed for their ability to modulate αSyn aggregation in vitro. Two synthetic peptides, K84s and K102s, of 25 and 19 amino acids, respectively, significantly inhibited αSyn oligomerization and aggregation at sub-stoichiometric molar ratios. Importantly, K84s reduced αSyn aggregation in human cells. These peptides represent promising αSyn aggregation antagonists for the development of future therapeutic interventions.
Case Report: Next-Generation Sequencing Reveals Tumor Origin in a Female Patient With Brain Metastases
Authors: Li Qun , Zhang Xiaoyan , Feng Jiao , Cheng Dezhi , Cai Lin , Dai Zhang’an , Zhao Shuyu , Li Jianmin , Huang Jingjing , Fang Yu , Zhu Honglin , Wang Danhua , Wang Sizhen , Ma Tonghui , Lu Xianghe
Published: April 2021

Background

Brain metastasis mainly originates from lung cancer. Napsin A and TTF-1 factors have frequently been detected in lung adenocarcinoma cases. Brain metastasis tumors with napsin A and TTF-1 positive are easily classified as lung adenocarcinoma origin. However, some thyroid cancers also exhibit these clinical features. Besides, lung is the most common metastasis of undifferential thyroid cancer. Therefore, it requires development of novel diagnostic tools to aid in distinguishing between pulmonary and thyroid origin.

Patient Findings

We reported a case that was initially diagnosed as brain metastatic lung cancer based on immunohistochemistry results. Analysis of next-generation sequencing (NGS) data from the brain lesion revealed that the cancer may have originated from the thyroid. We detected combo mutations in TERT promoter mutation, RET fusion and TP53, which are common in undifferential thyroid cancer (UTC), but rare for lung cancer. These results, coupled with identification of PAX8, indicated that this patient had UTC. Additionally, her three sons, despite being asymptomatic, were all diagnosed with papillary thyroid carcinoma.

The patient received anlotinib treatment and showed good clinical outcomes. One month after anlotinib treatment, the pulmonary nodules were found to be controlled, and the thyroid tumor drastically reduced, and tracheal compression relieved. She continued anlotinib treatment for the following two months, but died one month later because the treatment stopped owing to financial reasons. All her sons underwent total thyroidectomy with lymph node dissection.

Conclusions

Although NGS has been reported to assist in diagnosis of the origin of some tumors, this is the first evidence of NGS for the determination of the origin of thyroid tumors. To our knowledge, this is the first time that a combination of multiple mutations has been used to help determine the origin of a tumor, compared with the previous single mutant gene. Moreover, this is the first evidence on the use of anlotinib for treatment of UTC with distant metastasis. Besides, all three sons of the patient had thyroid carcinoma in subsequent examinations, indicating high-risk for familial non-medullary thyroid cancer in UTC patients and necessity for performing thyroid ultrasound testing in other family members.
Hepatoid Adenocarcinoma of the Stomach: Current Perspectives and New Developments
Authors: Xia Ruolan , Zhou Yuwen , Wang Yuqing , Yuan Jiaming , Ma Xuelei
Published: April 2021

Hepatoid adenocarcinoma of the stomach (HAS) is a rare malignant tumor, accounting for only 0.17–15% of gastric cancers. Patients are often diagnosed at an advanced disease stage, and their symptoms are similar to conventional gastric cancer (CGC) without specific clinical manifestation. Morphologically, HAC has identical morphology and immunophenotype compared to hepatocellular carcinoma (HCC). This is considered to be an underestimation in diagnosis due to its rare incidence, and no consensus is reached regarding therapy. HAS generally presents with more aggressive behavior and worse prognosis than CGC. The present review summarizes the current literature and relevant knowledge to elaborate on the epidemic, potential mechanisms, clinical manifestations, diagnosis, management, and prognosis to help clinicians accurately diagnose and treat this malignant tumor.
Hydronephrosis Classifications: Has UTD Overtaken APD and SFU? A Worldwide Survey
Authors: Vallasciani Santiago , Bujons Tur Anna , Gatti John , Machado Marcos , Cooper Christopher S. , Farrugia Marie Klaire , Zhou Huixia , El Anbari Mohammed , Lopez Pedro-José
Published: April 2021

Objective: To collect baseline information on the ultrasonographic reporting preferences.

Method: A 13-multiple choice questionnaire was designed and distributed worldwide among pediatric urologists, pediatric surgeons, and urologists. The statistical analysis of the survey data consisted of 3 steps: a univariate analysis, a bivariate and a multivariate analysis.

Results: Three hundred eighty participants responded from all the continents. The bivariate analysis showed the significant differences in the geographical area, the years of experience and the volume of cases. Most of the physicians prefer the SFU and APD systems because of familiarity and simplicity (37 and 34%, respectively). Respondents noted that their imaging providers most often report findings utilizing the mild-moderate-severe system or the APD measurements (28 and 39%, respectively) except for North America (SFU in 50%). Multivariate analysis did not provide significant differences.

Conclusion: Our study evaluates the opinions regarding the various pediatric hydronephrosis classification systems from a large number of specialists and demonstrates that there is no single preferred grading system. The greatest reported shortcoming of all the systems was the lack of universal utilization. The observations taken from this study may serve as basis for the construction of a common worldwide system. As APD and SFU are the preferred systems and the UTD a newer combination of both, it is possible that with time, UTD may become the universal language for reporting hydronephrosis. This time, based on the result of this survey, seems not arrived yet.
The Cardioprotective Mechanism of Phenylaminoethyl Selenides (PAESe) Against Doxorubicin-Induced Cardiotoxicity Involves Frataxin
Authors: Fu Xiaoyu , Eggert Mathew , Yoo Sieun , Patel Nikhil , Zhong Juming , Steinke Ian , Govindarajulu Manoj , Turumtay Emine Akyuz , Mouli Shravanthi , Panizzi Peter , Beyers Ronald , Denney Thomas , Arnold Robert , Amin Rajesh H.
Published: April 2021

Doxorubicin (DOX) is an anthracycline cancer chemotherapeutic that exhibits cumulative dose-limiting cardiotoxicity and limits its clinical utility. DOX treatment results in the development of morbid cardiac hypertrophy that progresses to congestive heart failure and death. Recent evidence suggests that during the development of DOX mediated cardiac hypertrophy, mitochondrial energetics are severely compromised, thus priming the cardiomyocyte for failure. To mitigate cumulative dose (5 mg/kg, QIW x 4 weeks with 2 weeks recovery) dependent DOX, mediated cardiac hypertrophy, we applied an orally active selenium based compound termed phenylaminoethyl selenides (PAESe) (QIW 10 mg/kg x 5) to our animal model and observed that PAESe attenuates DOX-mediated cardiac hypertrophy in athymic mice, as observed by MRI analysis. Mechanistically, we demonstrated that DOX impedes the stability of the iron-sulfur cluster biogenesis protein Frataxin (FXN) (0.5 fold), resulting in enhanced mitochondrial free iron accumulation (2.5 fold) and reduced aconitase activity (0.4 fold). Our findings further indicate that PAESe prevented the reduction of FXN levels and the ensuing elevation of mitochondrial free iron levels. PAESe has been shown to have anti-oxidative properties in part, by regeneration of glutathione levels. Therefore, we observed that PAESe can mitigate DOX mediated cardiac hypertrophy by enhancing glutathione activity (0.4 fold) and inhibiting ROS formation (1.8 fold). Lastly, we observed that DOX significantly reduced cellular respiration (basal (5%) and uncoupled (10%)) in H9C2 cardiomyoblasts and that PAESe protects against the DOX-mediated attenuation of cellular respiration. In conclusion, the current study determined the protective mechanism of PAESe against DOX mediated myocardial damage and that FXN is implicitly involved in DOX-mediated cardiotoxicity.
Triptolide Modulates the Expression of Inflammation-Associated lncRNA-PACER and lincRNA-p21 in Mycobacterium tuberculosis–Infected Monocyte-Derived Macrophages
Authors: Tamgue Ousman , Chia Julius Ebua , Brombacher Frank
Published: April 2021

Triptolide is a diterpene triepoxide, which performs its biological activities via mechanisms including induction of apoptosis, targeting of pro-inflammatory cytokines, and reshaping of the epigenetic landscape of target cells. However, the targeting of long non-coding RNAs (lncRNAs) by triptolide has not yet been investigated, despite their emerging roles as key epigenetic regulators of inflammation and immune cell function during Mycobacterium tuberculosis (Mtb) infection. Hence, we investigated whether triptolide targets inflammation-associated lncRNA-PACER and lincRNA-p21 and how this targeting associates with Mtb killing within monocyte-derived macrophages (MDMs).Using RT-qPCR, we found that triptolide induced the expression of lincRNA-p21 but inhibited the expression of lncRNA-PACER in resting MDMs in a dose- and time-dependent manner. Moreover, Mtb infection induced the expression of lincRNA-p21 and lncRNA-PACER, and exposure to triptolide before or after Mtb infection led to further increase of Mtb-induced expression of these lncRNAs in MDMs. We further found that contrary to lncRNA-PACER, triptolide time- and dose-dependently upregulated Ptgs-2, which is a proximal gene regulated by lncRNA-PACER. Also, low-concentration triptolide inhibited the expression of cytokine IL-6, a known target of lincRNA-p21. Mtb infection induced the expression of IL-6 and Ptgs-2, and triptolide treatment further increased IL-6 but decreased Ptgs-2 expression in Mtb-infected MDMs. The inverse relation between the expression of these lncRNAs and their target genes is concordant with the conception that these lncRNAs mediate, at least partially, the cytotoxic and/or anti-inflammatory activities of triptolide in both resting and activated MDMs. Using the CFU count method, we found that triptolide decreased the intracellular growth of Mtb HN878. The alamarBlue assay showed that this decreased Mtb HN878 growth was not as a result of direct targeting of Mtb HN878 by triptolide, but rather evoking MDMs’ intracellular killing mechanisms which we speculate could include triptolide-induced enhancement of MDMs’ effector killing functions mediated by lncRNA-PACER and lincRNA-p21. Altogether, these results provide proof of the modulation of lncRNA-PACER and lincRNA-p21 expression by triptolide, and a possible link between these lncRNAs, the enhancement of MDMs’ effector killing functions and the intracellular Mtb-killing activities of triptolide. These findings prompt for further investigation of the precise contribution of these lncRNAs to triptolide-induced activities in MDMs.
Systems Pharmacology Study of the Anti-Liver Injury Mechanism of Citri Reticulatae Pericarpium
Authors: Wu Jianxiong , Ye Xietao , Yang Songhong , Yu Huan , Zhong Lingyun , Gong Qianfeng
Published: April 2021

Liver diseases are mostly triggered by oxidative stress and inflammation, leading to extracellular matrix overproduction and prone to develop into liver fibrosis, cirrhosis and hepatocellular carcinoma. Liver injury (LI) refers to various pathogenic factors leading to the destruction of stem cells that then affect the liver’s normal function, causing a series of symptoms and abnormal liver function indicators. Citri Reticulatae Pericarpium (CRP) is one of the most commonly used traditional Chinese medicines; it contains flavonoids including hesperidin, nobiletin, and tangeretin. CRP has antibacterial, antioxidant, and antitumor effects that reduce cholesterol, prevent atherosclerosis and decrease LI. Here we analyzed the components of CRP and their targets of action in LI treatment and assessed the relationships between them using a systems pharmacology approach. Twenty-five active ingredients against LI were selected based on ultra-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry results and databases. The drug targets and disease-related targets were predicted. The 117 common targets were used to construct a protein-protein interaction network. We identified 1719 gene ontology items in LI treatment, including 1,525 biological processes, 55 cellular components, and 139 molecular functions. These correlated with 49 Kyoto Encyclopedia of Genes and Genomes pathways. These findings suggest that CRP may counteract LI by affecting apoptotic, inflammatory, and energy metabolism modules. In vitro experiments suggested that the mechanism may involve hesperidin and naringenin acting on CASP3, BAX, and BCL2 to affect the apoptosis pathway, attenuating liver fibrosis. Naringenin significantly inhibited AKT1 phosphorylation, which in turn mediated activation of the phosphoinositide 3-kinase-Akt signaling pathways against LI. This study provides a reference for systematically exploring the mechanism of CRP’s anti-LI action and is also expands of the application of systems pharmacology in the study of traditional Chinese medicine.
A New Insight for the Identification of Oncogenic Variants in Breast and Prostate Cancers in Diverse Human Populations, With a Focus on Latinos
Authors: Varela Nelson M. , Guevara-Ramírez Patricia , Acevedo Cristian , Zambrano Tomás , Armendáriz-Castillo Isaac , Guerrero Santiago , Quiñones Luis A. , López-Cortés Andrés
Published: April 2021

Background: Breast cancer (BRCA) and prostate cancer (PRCA) are the most commonly diagnosed cancer types in Latin American women and men, respectively. Although in recent years large-scale efforts from international consortia have focused on improving precision oncology, a better understanding of genomic features of BRCA and PRCA in developing regions and racial/ethnic minority populations is still required.

Methods: To fill in this gap, we performed integrated in silico analyses to elucidate oncogenic variants from BRCA and PRCA driver genes; to calculate their deleteriousness scores and allele frequencies from seven human populations worldwide, including Latinos; and to propose the most effective therapeutic strategies based on precision oncology.

Results: We analyzed 339,100 variants belonging to 99 BRCA and 82 PRCA driver genes and identified 18,512 and 15,648 known/predicted oncogenic variants, respectively. Regarding known oncogenic variants, we prioritized the most frequent and deleterious variants of BRCA (n = 230) and PRCA (n = 167) from Latino, African, Ashkenazi Jewish, East Asian, South Asian, European Finnish, and European non-Finnish populations, to incorporate them into pharmacogenomics testing. Lastly, we identified which oncogenic variants may shape the response to anti-cancer therapies, detailing the current status of pharmacogenomics guidelines and clinical trials involved in BRCA and PRCA cancer driver proteins.

Conclusion: It is imperative to unify efforts where developing countries might invest in obtaining databases of genomic profiles of their populations, and developed countries might incorporate racial/ethnic minority populations in future clinical trials and cancer researches with the overall objective of fomenting pharmacogenomics in clinical practice and public health policies.
Pharmacokinetic and Pharmacodynamic Considerations in Relation to Calcineurin Usage in Elderly Kidney Transplant Recipients
Authors: Cossart Amelia R. , Isbel Nicole M. , Scuderi Carla , Campbell Scott B. , Staatz Christine E.
Published: April 2021

This review summarizes how possible age-related changes in tacrolimus and cyclosporine pharmacokinetics and pharmacodynamics may influence drug dosing and monitoring in the elderly, and highlights how micro-sampling may be useful in this cohort in the future. Advancing biological age leads to physiological changes that can affect drug absorption, distribution, metabolism and excretion, as well as immune system responsiveness. Some studies have shown that elderly recipients may have higher dose-adjusted exposure and/or lower clearance of the calcineurin inhibitors, suggesting that doses may need to be lowered in elderly recipients. Only one study has examined how aging effects drug target enzyme activity and demonstrated that age does not correlate with the calcineurin inhibitor half-maximal inhibitory concentration. Several studies have shown elderly kidney transplant recipients have increased risk of both morbidity and mortality, compared to younger adults due to increased susceptibility to immunosuppressant side effects, particularly cardiovascular disease, infection and malignancy. Current immunosuppressant dosing and monitoring protocols often make no adjustments for age. Lower maintenance immunosuppressant targets in elderly recipients may decrease patient susceptibility to drug side effects, however, further studies are required and appropriate targets need to be established. Blood draw by micro-sampling may be useful for drug monitoring in this cohort in the future, as blood collection is minimally invasive and less painful than venepuncture. Micro-sampling could also make further pharmacokinetic, pharmacodynamics and outcome studies in the elderly more feasible.
Identification of the Key Role of NF-κB Signaling Pathway in the Treatment of Osteoarthritis With Bushen Zhuangjin Decoction, a Verification Based on Network Pharmacology Approach
Authors: Xu Yunteng , Li Hui , He Xiaojuan , Huang Yanfeng , Wang Shengjie , Wang Lili , Fu Changlong , Ye Hongzhi , Li Xihai , Asakawa Tetsuya
Published: April 2021

This study aimed to identify whether the NF-κB signaling pathway plays a key role in the treatment of osteoarthritis (OA) with Bushen Zhuangjin Decoction (BZD) based on a typical network pharmacology approach (NPA). Four sequential experiments were performed: 1) conventional high-performance liquid chromatography (HPLC), 2) preliminary observation of the therapeutic effects of BZD, 3) NPA using three OA-related gene expression profiles, and 4) verification of the key pathway identified by NPA. Only one HPLC-verified compound (paeoniflorin) was identified from the candidate compounds discovered by NPA. The genes verified in the preliminary observation were also identified by NPA. NPA identified a key role for the NF-κB signaling pathway in the treatment of OA with BZD, which was confirmed by conventional western blot analysis. This study identified and verified NF-κB signaling pathway as the most important inflammatory signaling pathway involved in the mechanisms of BZD for treating OA by comparing the NPA results with conventional methods. Our findings also indicate that NPA is a powerful tool for exploring the molecular targets of complex herbal formulations, such as BZD.
P- Hydroxybenzyl Alcohol Alleviates Oxidative Stress in a Nonalcoholic Fatty Liver Disease Larval Zebrafish Model and a BRL-3A Hepatocyte Via the Nrf2 Pathway
Authors: An Jing , Cheng Lijun , Yang Liping , Song Nali , Zhang Ju , Ma Kejian , Ma Ji
Published: April 2021

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and it has gradually become the main disease burden in the world. However, the pathogenesis of NAFLD is complex, involving such things as dyslipidemia, oxidative stress, inflammation, etc. This brings to the table a significant challenge for drug development, and there is still no drug approved by the FDA on the market to treat the disease. GAS and HBA are active ingredients of the orchidaceae plant gastrodia elata and have exhibit effects in ameliorating nervous system diseases caused by oxidative stress. HBA is a metabolite of GAS that could perform lipid regulation and improve oxidative stress on HCD-induced NAFLD larval zebrafish, as reported by previous studies; we therefore explored the role of HBA in lipid regulation and oxidative stress on HCD-induced NAFLD larval zebrafish in vivo and FFA-induced BRL-3A hepatocyte in vitro. The gene expression of lipogenesis, inflammation, and oxidative stress were measured to investigate the underlying mechanism of HBA, and the potential protein target of HBA was explored by immunofluorescence. Altogether, our data highlight the role of HBA in improving NAFLD by use of its lipid-lowering and anti-oxidative properties via the Nrf2/HO-1 signaling pathway, providing a potential therapeutic compound for NAFLD treatment.
Eunuchs or Females? Causes and Consequences of Gynodioecy on Morphology, Ploidy, and Ecology of Stellaria graminea L. (Caryophyllaceae)
Authors: Kučera Jaromír , Svitok Marek , Gbúrová Štubňová Eliška , Mártonfiová Lenka , Lafon Placette Clément , Slovák Marek
Published: April 2021

Plant speciation results from intricate processes such as polyploidization, reproductive strategy shifts and adaptation. These evolutionary processes often co-occur, blurring their respective contributions and interactions in the speciation continuum. Here, relying on a large-scale study, we tested whether gynodioecy triggers the divergent evolution of flower morphology and genome between sexes, and contributes to the establishment of polyploids and colonization of ecological niches in Stellaria graminea. We found that gynodioecy in S. graminea leads to flower morphology divergence between females and hermaphrodites, likely due to sexual selection. Contrary to our expectations, gynodioecy occurs evenly in diploids and tetraploids, suggesting that this reproductive strategy was not involved in the establishment of polyploids. Both diploid and tetraploid females have a larger genome size than hermaphrodites, suggesting the presence of sex chromosomes. Finally, ecology differs between cytotypes and to a lesser extent between sexes, suggesting that the link between environment and presence of females is indirect and likely explained by other aspects of the species’ life history. Our study shows that gynodioecy leads to the consistent evolution of sexual traits across a wide range of populations, cytotypes and environments within a given species, and this likely contributes to the phenotypic and genetic distinctiveness of the species from its sister clades.
The Role of Light and Circadian Clock in Regulation of Leaf Senescence
Authors: Lee Juhyeon , Kang Myeong Hoon , Kim Jung Yeon , Lim Pyung Ok
Published: April 2021

Leaf senescence is an integrated response of the cells to develop age information and various environmental signals. Thus, some of the genes involved in the response to environmental changes are expected to regulate leaf senescence. Light acts not only as the primary source of energy for photosynthesis but also as an essential environmental cue that directly control plant growth and development including leaf senescence. The molecular mechanisms linking light signaling to leaf senescence have recently emerged, exploring the role of Phytochrome-Interacting Factors (PIFs) as a central player leading to diverse senescence responses, senescence-promoting gene regulatory networks (GRNs) involving PIFs, and structural features of transcription modules in GRNs. The circadian clock is an endogenous time-keeping system for the adaptation of organisms to changing environmental signals and coordinates developmental events throughout the life of the plant. Circadian rhythms can be reset by environmental signals, such as light-dark or temperature cycles, to match the environmental cycle. Research advances have led to the discovery of the role of core clock components as senescence regulators and their underlying signaling pathways, as well as the age-dependent shortening of the circadian clock period. These discoveries highlight the close relationship between the circadian system and leaf senescence. Key issues remain to be elucidated, including the effect of light on leaf senescence in relation to the circadian clock, and the identification of key molecules linking aging, light, and the circadian clock, and integration mechanisms of various senescence-affecting signals at the multi-regulation levels in dynamics point of view.
Considering Situational Variety in Contextualized Aging Research – Opinion About Methodological Perspectives
Authors: Wolf Friedrich , Seifert Alexander , Martin Mike , Oswald Frank
Published: April 2021

Due to the increasingly heterogeneous trajectories of aging, gerontology requires theoretical models and empirical methods that can meaningfully, reliably, and precisely describe, explain, and predict causes and effects within the aging process, considering particular contexts and situations. Human behavior occurs in contexts; nevertheless, situational changes are often neglected in context-based behavior research. This article follows the tradition of environmental gerontology research based on Lawton’s Person-Environment-Interaction model (P-E model) and the theoretical developments of recent years. The authors discuss that, despite an explicit time component, current P-E models could be strengthened by focusing on detecting P-E interactions in various everyday situations. Enhancing Lawton’s original formula via a situationally based component not only changes the theoretical perspectives on the interplay between person and environment but also demands new data collection approaches in empirical environmental research. Those approaches are discussed through the example of collecting mobile data with smartphones. Future research should include the situational dimension to investigate the complex nature of person environment interactions.