bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunotherapy in Acute Myeloid Leukemia: Where We Stand
Authors: Isidori Alessandro , Cerchione Claudio , Daver Naval , DiNardo Courtney , Garcia-Manero Guillermo , Konopleva Marina , Jabbour Elias , Ravandi Farhad , Kadia Tapan , Burguera Adolfo de la Fuente , Romano Alessandra , Loscocco Federica , Visani Giuseppe , Martinelli Giovanni , Kantarjian Hagop , Curti Antonio
Published: May 2021

In the past few years, our improved knowledge of acute myeloid leukemia (AML) pathogenesis has led to the accelerated discovery of new drugs and the development of innovative therapeutic approaches. The role of the immune system in AML development, growth and recurrence has gained increasing interest. A better understanding of immunological escape and systemic tolerance induced by AML blasts has been achieved. The extraordinary successes of immune therapies that harness the power of T cells in solid tumors and certain hematological malignancies have provided new stimuli in this area of research. Accordingly, major efforts have been made to develop immune therapies for the treatment of AML patients. The persistence of leukemia stem cells, representing the most relevant cause of relapse, even after allogeneic stem cell transplant (allo-SCT), remains a major hurdle in the path to cure for AML patients. Several clinical trials with immune-based therapies are currently ongoing in the frontline, relapsed/refractory, post-allo-SCT and minimal residual disease/maintenance setting, with the aim to improve survival of AML patients. This review summarizes the available data with immune-based therapeutic modalities such as monoclonal antibodies (naked and conjugated), T cell engagers, adoptive T-cell therapy, adoptive-NK therapy, checkpoint blockade via PD-1/PD-L1, CTLA4, TIM3 and macrophage checkpoint blockade via the CD47/SIRPa axis, and leukemia vaccines. Combining clinical results with biological immunological findings, possibly coupled with the discovery of biomarkers predictive for response, will hopefully allow us to determine the best approaches to immunotherapy in AML.
A Nomogram for Predicting Lymphovascular Invasion in Superficial Esophageal Squamous Cell Carcinoma
Authors: Ruan Rongwei , Chen Shengsen , Tao Yali , Yu Jiangping , Zhou Danping , Cui Zhao , Shen Qiwen , Wang Shi
Published: May 2021

The lymphovascular invasion (LVI) status facilitates the determination of the optimal therapeutic strategy for superficial esophageal squamous cell carcinoma (SESCC), but in clinical practice, LVI must be confirmed by postoperative pathology. However, studies of the risk factors for LVI in SESCC are limited. Consequently, this study aimed to identify the risk factors for LVI and use these factors to establish a prediction model. The data of 516 patients who underwent radical esophagectomy between January 2007 and September 2019 were retrospectively collected (training set, n=361, January 2007 to May 2015; validation set, n=155, June 2015 to September 2019). In the training set, least absolute shrinkage and selection operator (LASSO) regression and multivariate analyses were utilized to identify predictive factors for LVI in patients with SESCC. A nomogram was then developed using these predictors. The area under the curve (AUC), calibration curve, and decision curve were used to evaluate the efficiency, accuracy, and clinical utility of the model. LASSO regression indicated that the tumor size, depth of invasion, tumor differentiation, lymph node metastasis (LNM), sex, circumferential extension, the presence of multiple lesions, and the resection margin were correlated with LVI. However, multivariate analysis revealed that only the tumor size, depth of invasion, tumor differentiation, and LNM were independent risk factors for LVI. Incorporating these four variables, model 1 achieved an AUC of 0.817 in predicting LVI. Adding circumferential extension to model 1 did not appreciably change the AUC and integrated discrimination improvement, but led to a significant increase in the net reclassification improvement (p=0.011). A final nomogram was constructed by incorporating tumor size, depth of invasion, tumor differentiation, LNM, and circumferential extension and showed good discrimination (training set, AUC=0.833; validation set, AUC=0.819) and good calibration in the training and validation sets. Decision curve analysis demonstrated that the nomogram was clinically useful in both sets. Thus, it is possible to predict the status of LVI using this nomogram scoring system, which can aid the selection of an appropriate treatment plan.
CDK9: A Comprehensive Review of Its Biology, and Its Role as a Potential Target for Anti-Cancer Agents
Authors: Anshabo Abel Tesfaye , Milne Robert , Wang Shudong , Albrecht Hugo
Published: May 2021

Cyclin-dependent kinases (CDKs) are proteins pivotal to a wide range of cellular functions, most importantly cell division and transcription, and their dysregulations have been implicated as prominent drivers of tumorigenesis. Besides the well-established role of cell cycle CDKs in cancer, the involvement of transcriptional CDKs has been confirmed more recently. Most cancers overtly employ CDKs that serve as key regulators of transcription (e.g., CDK9) for a continuous production of short-lived gene products that maintain their survival. As such, dysregulation of the CDK9 pathway has been observed in various hematological and solid malignancies, making it a valuable anticancer target. This therapeutic potential has been utilized for the discovery of CDK9 inhibitors, some of which have entered human clinical trials. This review provides a comprehensive discussion on the structure and biology of CDK9, its role in solid and hematological cancers, and an updated review of the available inhibitors currently being investigated in preclinical and clinical settings.
The Genotype and Phenotype of Proline-Rich Transmembrane Protein 2 Associated Disorders in Chinese Children
Authors: Luo Han-yu , Xie Ling-ling , Hong Si-qi , Li Xiu-juan , Li Mei , Hu Yue , Ma Jian-nan , Wu Peng , Zhong Min , Cheng Min , Li Ting-song , Jiang Li
Published: May 2021

Objectives: To study the genetic and clinical characteristics of Chinese children with pathogenic proline-rich transmembrane protein 2 (PRRT2) gene-associated disorders.

Methods: Targeted next generation sequencing (NGS) was used to identify pathogenic PRRT2 variations in Chinese children with epilepsy and/or kinesigenic dyskinesia. Patients with confirmed PRRT2-associated disorders were monitored and their clinical data were analyzed.

Results: Forty-four patients with pathogenic PRRT2 variants were recruited. Thirty-five of them (79.5%) had heterozygous mutations, including 30 frameshifts, three missenses, one nonsense, and one splice site variant. The c.649dupC was the most common variant (56.8%). Eight patients (18.2%) showed whole gene deletions, and one patient (2.3%) had 16p11.2 microdeletion. Thirty-four cases (97.1%) were inherited and one case (2.9%) was de novo. Forty patients were diagnosed with benign familial infantile epilepsy (BFIE), two patients had paroxysmal kinesigenic dyskinesia (PKD) and two had infantile convulsions and choreoathetosis (ICCA). Patients with whole gene deletions had a later remission than patients with heterozygous mutations (13.9 vs. 7.1 months, P = 0.001). Forty-two patients were treated with antiseizure medications (ASMs). At last follow-up, 35 patients, including one who did not receive therapy, were asymptomatic, and one patient without ASMs died of status epilepticus at 12 months of age. One patient developed autism, and one patient showed mild developmental delay/intellectual disability.

Conclusion: Our data suggested that patients with whole gene deletions could have more severe manifestations in PRRT2-associated disorders. Conventional ASMs, especially Oxcarbazepine, showed a good treatment response.
In-Vitro α-amylase, α-glucosidase Inhibitory Activities and In-Vivo Anti-Hyperglycemic Potential of Different Dosage Forms of Guduchi (Tinospora Cordifolia [Willd.] Miers) Prepared With Ayurvedic Bhavana Process
Authors: Sharma Rohit , Bolleddu Rajesh , Maji Jayanta K. , Ruknuddin Galib , Prajapati Pradeep K.
Published: May 2021

Guduchi(Tinospora cordifolia[Willd.] Miers) is a flagship rejuvenating herb of Ayurveda with reported anti-diabetic potential. In the present study, different dosage forms ofGuduchistem (growing on neem tree) were developed by adopting Ayurvedic pharmaceutical process ofBhavana(levigation).Guduchi Churna(GC) was subjected to 07 timesBhavanaseparately with its own extracted juice, decoction and potable water, and dosage forms namelySvarasa Bhavita Guduchi Churna(SBGC),Kwatha Bhavita Guduchi Churna(KBGC), andJala Bhavita Guduchi Churna(JBGC) were prepared. The present study was aimed to evaluate the role ofBhavanaon the potentiation of therapeutic properties ofGuduchi. Sequential solvent extracts (5, 10, 15 and 25%) of GC, SBGC, KBGC and JBGC were prepared in different solvents [phosphate buffer, hexane, dichloromethane (DCM), chloroform] and screened for theα-amylase andα-glucosidase inhibitory activity. The results revealed that phosphate buffer and DCM extracts of SBGC exhibited strongα-amylase inhibitory potential (>80% inhibition at 25% concentration) followed by KBGC, JBGC and GC with reference to the standard acarbose. Inα-glucosidase inhibitory activity, maximum inhibition was observed in DCM and chloroform extracts of SBGC (>85% inhibition at 25% concentration), followed by KBGC (>80% inhibition at 25% concentration), JBGC and GC.In vivoanti-hyperglycemic studies were carried out by oral glucose tolerance test in Swiss albino mice. Test drugs (JBGC, KBGC, SBGC) treated groups showed marginal decrease of blood glucose levels in normo glycemic mice. However, the blood glucose level in test drug JBGC, KBGC and SBGC treated groups was still within normal range in overnight fasted mice. In oral glucose tolerance test, among all dosage forms SBGC (51.08%) produced pronounced anti-hyperglycemic effect followed by KBGC (42.57%) at a dose of 520 mg/kg. The GC, JBGC, KBGC and SBGC samples were also standardized using berberine (a well established anti-diabetic compound) as a marker compound by HPTLC fingerprint analysis. Findings of the present study indicate that SBGC and KBGC can be used in the treatment of diabetes mellitus and gives supporting evidence to Ayurvedic claims that theBhavanaprocess has pharmaceutico-therapeutic significance in Ayurvedic drug development.
A Systematic Review on Comparative Analysis, Toxicology, and Pharmacology of Medicinal Plants Against Haemonchus contortus
Authors: Ali Rehman , Rooman Muhammad , Mussarat Sakina , Norin Sadia , Ali Shandana , Adnan Muhammad , Khan Shahid Niaz
Published: May 2021

Background:Haemonchus contortus is an important pathogenic nematode parasite and major economic constraint of small ruminants in tropics and subtropics regions. This review is an attempt to systematically address the; (a) efficacy of different plants against H. contortus by in vitro and in vivo proof; (b) toxicology, mechanism of action, and active phyto-compounds involve in anti-haemonchiasis activity; (c) and comparative analysis of plant species evaluated both in vitro and in vivo.

Methods: Online databases (Google Scholar, PubMed, Scopus, and ScienceDirect) were searched and published research articles (1980–2020) were gathered and reviewed.

Results: A total of 187 plant species were reported belonging to 59 families and 145 genera with Asteraceae and Fabaceae being frequently used. Out of the total plant species, 171 species were found to be evaluated in vitro and only 40 species in vivo. Twenty-four species were commonly evaluated for in vitro and in vivo anti-haemonchiasis activity. Among the reported assays, egg hatching test (EHT) and fecal egg count reduction (FECR) were the most widely used assays in vitro and in vivo, respectively. Moreover, sheep were the frequently used experimental model in vivo. After comparative analysis, Lachesiodendron viridiflorum, Corymbia citriodora, Calotropis procera, and Artemisia herba-alba were found highly effective both in vitro and in vivo. L. viridiflorum inhibited enzymatic activities and metabolic processes of the parasite and was found to be safe without toxic effects. C. citriodora was moderately toxic in vivo, however, the plant extract produced promising nematicidal effects by causing muscular disorganization and changes in the mitochondrial profile. Additionally, C. procera and A. herba-alba despite of their high anti-haemonchiasis activity were found to be highly toxic at the tested concentrations. C. procera caused perforation and tegumental disorganization along with adult worm paralysis. Nineteen compounds were reported, among which anethole and carvone completely inhibited egg hatching in vitro and significantly reduced fecal egg count, decreased male length, and reproductive capacity of female in vivo.

Conclusion: This review summarized different medicinal plants owing to nematicidal activities against H. contortus eggs, larvae, and adult worms. Plants like L. viridiflorum, C. citriodora, C. procera, and A. herba-alba, while compounds anethole and carvone having promising nematicidal activities and could be an alternative source for developing novel drugs after further investigation.
Comparative Efficacy of Oral Chinese Patent Medicine for Chronic Prostatitis/Chronic Pelvic Pain Syndrome With Sexual Dysfunction: A Bayesian Network Meta-Analysis of Randomized Controlled Trials
Authors: Zhang Yang , Ma Hongzhao , Nan Tao , Li Yongqiang , Zheng Wei , Zhou Zhihui , Gong Xiaoyong
Published: May 2021

Background: Oral Chinese patent medicine (OCPM) combined with western medicine (WM) are believed to be effective for the therapy of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) with sexual dysfunction (SD). These western medicines mainly involve antibiotics, phosphodiesterase type-5 inhibitor (PDE-5i), α-blockers. But there is no randomized controlled trial (RCT) that directly compares the efficacy of different OCPM. Hence, we operated a network meta-analysis (NMA) to contrast the efficacy of different OCPM for CP/CPPS with SD.

Methods: Relevant studies were searched in PubMed, Cochrane Library, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), and Wanfang database. All of the RCTs concentrated on the use of OCPM to cure CP/CPPS with SD from the inception of the databases to November 2020. We appraised the risk of bias under the Cochrane Handbook and CONSORT statement. The data were statistically analyzed via STATA 13.0 and WinBUGS 1.4.3 instrument.

Results: Altogether, 30 pieces of literature with 2,996 participants containing 11 oral Chinese patent medicine and 11 interventions were included in the NMA. In terms of The National Institutes of Health chronic prostatitis symptom index (NIH-CPSI), Qianlie Shutong Capsules (QLSTC) + WM had the most possible of being the optimal treatment. In the light of the International Index of Erectile Function (IIEF-5), Congrong Yishen Granules (CRYSG) + WM had the most possible of being the optimal treatment. Shugan Yiyang Capsules (SGYYC) + WM performed the highest likelihood efficacy under cluster rank graph combined NIH-CPSI and IIEF-5. Liuwei Dihuang Pills/Yougui capsules (LWDHP/YGC) + WM had highly possible to be the optimal treatment not only for the clinical effective rate of CP/CPPS but also for the clinical effective rate of SD. Considering four outcomes, QLSTC, CRYSG, SGYYC, LWDHP/YGC, Qianlie Beixi Capsules (QLBXC) plus WM were the best therapy approach for CP/CPPS with SD, especially LWDHP/YGC + WM and QLBXC + WM.

Conclusion: Based on the NMA, QLSTC, CRYSG, SGYYC, LWDHP/YGC, QLBXC plus WM demonstrated the maximum probability of being the optimal therapies. Owing to the limitations of this research, these results should be confirmed by elaborate RCTs.

Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42021224060].
Association of NQO2 With UDP-Glucuronosyltransferases Reduces Menadione Toxicity in Neuroblastoma Cells
Authors: Chhour Monivan , Perio Pierre , Gayon Regis , Ternet-Fontebasso Hélène , Ferry Gilles , Nepveu Françoise , Boutin Jean A. , Sudor Jan , Reybier Karine
Published: May 2021

The balance between detoxification and toxicity is linked to enzymes of the drug metabolism Phase I (cytochrome P450 or oxidoreductases) and phase II conjugating enzymes (such as the UGTs). After the reduction of quinones, the product of the reaction, the quinols—if not conjugated—re-oxidizes spontaneously to form the substrate quinone with the concomitant production of the toxic reactive oxygen species (ROS). Herein, we documented the modulation of the toxicity of the quinone menadione on a genetically modified neuroblastoma model cell line that expresses both the quinone oxidoreductase 2 (NQO2, E.C. 1.10.5.1) alone or together with the conjugation enzyme UDP-glucuronosyltransferase (UGT1A6, E.C. 2.4.1.17), one of the two UGT isoenzymes capable to conjugate menadione. As previously shown, NQO2 enzymatic activity is concomitant to massive ROS production, as previously shown. The quantification of ROS produced by the menadione metabolism was probed by electron-paramagnetic resonance (EPR) on cell homogenates, while the production of superoxide was measured by liquid chromatography coupled to mass spectrometry (LC-MS) on intact cells. In addition, the dysregulation of the redox homeostasis upon the cell exposure to menadione was studied by fluorescence measurements. Both EPR and LCMS studies confirmed a significant increase in the ROS production in the NQO2 overexpressing cells due to the fast reduction of quinone into quinol that can re-oxidize to form superoxide radicals. However, the effect of NQO2 inhibition was drastically different between cells overexpressing only NQO2 vs. both NQO2 and UGT. Whereas NQO2 inhibition decreases the amount of superoxide in the first case by decreasing the amount of quinol formed, it increased the toxicity of menadione in the cells co-expressing both enzymes. Moreover, for the cells co-expressing QR2 and UGT the homeostasis dysregulation was lower in presence of menadione than for the its counterpart expressing only QR2. Those results confirmed that the cooperation of the two enzymes plays a fundamental role during the cells’ detoxification process. The fluorescence measurements of the variation of redox homeostasis of each cell line and the detection of a glucuronide form of menadiol in the cells co-expressing NQO2 and UGT1A6 enzymes further confirmed our findings.
Polyphyllin Ⅲ-Induced Ferroptosis in MDA-MB-231 Triple-Negative Breast Cancer Cells can Be Protected Against by KLF4-Mediated Upregulation of xCT
Authors: Zhou Yulu , Yang Jingjing , Chen Cong , Li Zhaoqing , Chen Yongxia , Zhang Xun , Wang Linbo , Zhou Jichun
Published: May 2021

Ferroptosis, which is characterized by the accumulation of intracellular iron and subsequent lipid peroxidation, is a newly discovered form of regulated cell death and plays an important role in tumor suppression. Herein, we showed that Polyphyllin III, which is a major saponin extracted from Paris polyphylla rhizomes, exerted its proliferation-inhibitory effect on MDA-MB-231 triple-negative breast cancer cells mainly through ACSL4-mediated lipid peroxidation elevation and ferroptosis induction. ACSL4 deletion partly attenuated Polyphyllin III-induced ferroptosis. Polyphyllin III treatment also induced KLF4-mediated protective upregulation of xCT, which is the negative regulator of ferroptosis. Interestingly, combination with the xCT inhibitor sulfasalazine (SAS) or downregulation of KLF4 sensitized MDA-MB-231 cells to Polyphyllin III. Furthermore, in vivo xenograft models, SAS significantly sensitized MDA-MB-231 breast cancer cells to Polyphyllin III, likely by enhancing intracellular lipid peroxidation and ferroptosis. The results of this study collectively demonstrated that Polyphyllin III exerts its anticancer effect by inducing ferroptosis via ACSL4 in MDA-MB-231 breast cancer cells. More importantly, we observed for the first time that KLF4-mediated xCT upregulation serves as negative feedback during ferroptosis progression, which might contribute to drug resistance in cancer treatment.
Hitchhiking on Controlled-Release Drug Delivery Systems: Opportunities and Challenges for Cancer Vaccines
Authors: Han Lu , Peng Ke , Qiu Li-Ying , Li Meng , Ruan Jing-Hua , He Li-Li , Yuan Zhi-Xiang
Published: May 2021

Cancer vaccines represent among the most promising strategies in the battle against cancers. However, the clinical efficacy of current cancer vaccines is largely limited by the lack of optimized delivery systems to generate strong and persistent antitumor immune responses. Moreover, most cancer vaccines require multiple injections to boost the immune responses, leading to poor patient compliance. Controlled-release drug delivery systems are able to address these issues by presenting drugs in a controlled spatiotemporal manner, which allows co-delivery of multiple drugs, reduction of dosing frequency and avoidance of significant systemic toxicities. In this review, we outline the recent progress in cancer vaccines including subunit vaccines, genetic vaccines, dendritic cell-based vaccines, tumor cell-based vaccines and in situ vaccines. Furthermore, we highlight the efforts and challenges of controlled or sustained release drug delivery systems (e.g., microparticles, scaffolds, injectable gels, and microneedles) in ameliorating the safety, effectiveness and operability of cancer vaccines. Finally, we briefly discuss the correlations of vaccine release kinetics and the immune responses to enlighten the rational design of the next-generation platforms for cancer therapy.
Increasing Efficiency of Repetitive Electroacupuncture on Purine- and Acid-Induced Pain During a Three-Week Treatment Schedule
Authors: Li Jie , Zhang Ying , Illes Peter , Tang Yong , Rubini Patrizia
Published: May 2021

Acupuncture (AP) is an important constituent of the therapeutic repertoire of traditional Chinese medicine and has been widely used to alleviate chronic painful conditions all over the world. We studied in rats the efficiency of electroacupuncture (EAP) applied to the Zusanli acupoint (ST36) as an analgesic treatment over a 3-week period of time on purine (α,β-methylene ATP, dibenzoyl-ATP)- and acid (pH 6.0 medium)-induced pain in the rat paw. The two ATP derivatives stimulated P2X3 and P2X7 receptors, respectively, while the slightly acidic medium stimulated the “acid-sensitive ion channel 3” (ASIC3). It was found that the P2X7 receptor and ASIC-mediated pain was counteracted by EAP with greater efficiency at the end than at the beginning of the treatment schedule, while the P2X3 receptor–mediated pain was not. Our findings have important clinical and theoretical consequences, among others, because they are difficult to reconcile with the assumption that AP is primarily due to the release of peripheral and central opioid peptides causing the well-known tolerance to their effects. In consequence, AP is a convenient therapeutic instrument to treat subacute and chronic pain.
Does Transient Receptor Potential Vanilloid Type 1 Alleviate or Aggravate Pathological Myocardial Hypertrophy?
Authors: Yan Qiqi , Tang Jun , Zhang Xin , Wu Liuyang , Xu Yunyi , Wang Lihong
Published: May 2021

Transient receptor potential vanilloid type 1 (TRPV1) is a non-selective cation channel, which is involved in the endogenous stress adaptation mechanism for protection of the heart as well as the occurrence and development of some heart diseases. Although the effect of activation of the TRPV1 channel on different types of non-neural cells in the heart remains unclear, most data show that stimulation of sensory nerves expressing TRPV1 or stimulation/overexpression of the TRPV1 channel has a beneficial role in heart disease. Some studies have proven that TRPV1 has an important relationship with pathological myocardial hypertrophy, but the specific mechanism and effect are not clear. In order to help researchers better understand the relationship between TRPV1 and pathological myocardial hypertrophy, this paper aims to summarize the effect of TRPV1 and the related mechanism in the occurrence and development of pathological myocardial hypertrophy from the following three points of view: 1) role of TRPV1 in alleviation of pathological myocardial hypertrophy; 2) role of TRPV1 in aggravation of pathological myocardial hypertrophy; and 3) the point of view of our team of researchers. It is expected that new therapies can provide potential targets for pathological myocardial hypertrophy.
A Study on Augmented 3D Display Optimization Based on Holographic Optical Element for High Depth and Magnified Image
Authors: Ha Sungjae , Hwang Leehwan , Lee Jaehyun , Gentet Philippe , Kwon Soonchul , Lee Seunghyun
Published: May 2021

Modern Pepper's ghost—“floating hologram”—systems generally use transparent screens called half mirrors or foils. this system must have the same screen size as the image size in order to display a large-sized image. Further, depth of the image can only be obtained from the distance between the screen and the display panel. These limitations can be overcome using holographic optical elements (HOE). HOE is made by recording as a refractive force of the lens with holographic material. In this study, the numerical values of the reconstructed images were theoretically analyzed through optical ray tracing, and the theoretical design of the reconstructed image size and depth plane was numerically measured and experimentally verified.
A Subpopulation of Schwann Cell-Like Cells With Nerve Regeneration Signatures Is Identified Through Single-Cell RNA Sequencing
Authors: Wei Zairong , Shu Shenyou , Zhang Mingjun , Xie Sitian , Tang Shijie , Nie Kaiyu , Li Haihong
Published: May 2021

Schwann cell-like cells (SCLCs) derived from human amniotic mesenchymal stem cells (hAMSCs) have been shown to promote peripheral nerve regeneration, but the underlying molecular mechanism was still poorly understood. In order to investigate the heterogeneity and potential molecular mechanism of SCLCs in the treatment of peripheral nerve regeneration at a single cell level, single-cell RNA sequencing was applied to profile single cell populations of hAMSCs and SCLCs. We profiled 6,008 and 5,140 single cells from hAMSCs and SCLCs, respectively. Based on bioinformatics analysis, pathways associated with proliferation, ECM organization, and tissue repair were enriched within both populations. Cell cycle analysis indicated that single cells within these two populations remained mostly in the G0/G1 phase. The transformation of single cells from hAMSCs to SCLCs was characterized by pseudotime analysis. Furthermore, we identified a subpopulation of SCLCs that highly expressed genes associated with Schwann cell proliferation, migration, and survival, such as JUN, JUND, and NRG1., Genes such as PTGS2, PITX1, VEGFA, and FGF2 that promote nerve regeneration were also highly expressed in single cells within this subpopulation, and terms associated with inflammatory and tissue repair were enriched in this subpopulation by pathway enrichment analysis. Our results indicate that a subpopulation of SCLCs with nerve regeneration signatures may be the key populations that promote nerve regeneration.
Interaction Between Macro‐ and Micro-Nutrients in Plants
Authors: Kumar Suresh , Kumar Santosh , Mohapatra Trilochan
Published: May 2021

Nitrogen (N), phosphorus (P), sulfur (S), zinc (Zn), and iron (Fe) are some of the vital nutrients required for optimum growth, development, and productivity of plants. The deficiency of any of these nutrients may lead to defects in plant growth and decreased productivity. Plant responses to the deficiency of N, P, S, Fe, or Zn have been studied mainly as a separate event, and only a few reports discuss the molecular basis of biological interaction among the nutrients. Macro-nutrients like N, P, and/or S not only show the interacting pathways for each other but also affect micro-nutrient pathways. Limited reports are available on the investigation of two-by-two or multi-level nutrient interactions in plants. Such studies on the nutrient interaction pathways suggest that an MYB-like transcription factor, phosphate starvation response 1 (PHR1), acts as a master regulator of N, P, S, Fe, and Zn homeostasis. Similarly, light-responsive transcription factors were identified to be involved in modulating nutrient responses in Arabidopsis. This review focuses on the recent advances in our understanding of how plants coordinate the acquisition, transport, signaling, and interacting pathways for N, P, S, Fe, and Zn nutrition at the molecular level. Identification of the important candidate genes for interactions between N, P, S, Fe, and/or Zn metabolic pathways might be useful for the breeders to improve nutrient use efficiency and yield/quality of crop plants. Integrated studies on pathways interactions/cross-talks between macro‐ and micro-nutrients in the agronomically important crop plants would be essential for sustainable agriculture around the globe, particularly under the changing climatic conditions.
National Inspired or Locally Earned? The Locus of Local Political Support in a Multilevel Context
Authors: Steenvoorden Eefje H. , van der Meer Tom W. G.
Published: May 2021

Despite greater responsibility being passed to local and regional tiers of government in many European countries, we still have limited understanding about what shapes citizens' support for such tiers of government. On the one hand we expect citizens to evaluate local government on its own merits, depending on the performance of local units. Yet in the context of multi-layered governance, we argue that local political support is likely to be at least partly a derivative of attitudes to the national level. The Dutch Local Election Study 2016 offers us the possibility to test these expectations. We show that local political support is mainly (in the case of local democratic satisfaction) or substantially (in the case of local political trust) related to national political support. To the extent that local support is shaped by local evaluations, appraisals of output performance are more important than appraisals of input or throughput performance. There is some evidence that these relations are conditional. Political sophistication increases citizens' sensitivity to local performance. Yet, local embeddedness only modestly reduces citizens' reliance on national-level evaluations.
Fostering Cultures of Sustainability in a Multi-Unit Office Building: A Theory of Change
Authors: Dreyer Bianca Christel , Riemer Manuel , Spadafore Brittany , Marcus Joel , Fernandes Devon , Taylor Allan , Whitney Stephanie , Geobey Sean , Dennett Aisling
Published: May 2021

Psychological approaches to fostering sustainability are heavily focused on individual behaviors and often insufficiently address the physical and social contexts individuals are embedded in. This limits the ability to create meaningful, long-lasting change, as many of day-to-day behaviors are social practices embedded in broader cultural norms and systems. This is particularly true in the work context, where organizational cultures heavily condition both the actions of individual employees and the collective actions of organizations. Thus, we argue cultures, not behaviors, must become the focus of sustainability change efforts. In this paper, we present a theory of change aimed at fostering strong organizational cultures of sustainability (COS) within a high-performance multi-tenant office building. Our theory takes a systems perspective that incorporates the social and physical aspects of the work environment, and views culture change as a co-creative exercise involving engagement of multiple stakeholders. The paper concludes with implications for practice and research.
Of Time Gals and Mega Men: Empirical Findings on Gender Differences in Digital Game Genre Preferences and the Accuracy of Respective Gender Stereotypes
Authors: Lange Benjamin P. , Wühr Peter , Schwarz Sascha
Published: May 2021

We investigated the accuracy of gender stereotypes regarding digital game genre preferences. In Study 1, 484 female and male participants rated their preference for 17 game genres (gender differences). In Study 2, another sample of 226 participants rated the extent to which the same genres were presumably preferred by women or men (gender stereotypes). We then compared the results of both studies in order to determine the accuracy of the gender stereotypes. Study 1 revealed actual gender differences for most genres—mostly of moderate size. Study 2 revealed substantial gender stereotypes about genre preferences. When comparing the results from both studies, we found that gender stereotypes were accurate in direction for most genres. However, they were, to some degree, inaccurate in size: For most genres, gender stereotypes overestimated the actual gender difference with a moderate mean effect size.
A Systematic Review of Non-pharmacological Strategies to Reduce the Risk of Violence in Patients With Schizophrenia Spectrum Disorders in Forensic Settings
Authors: Slamanig Rudolf , Reisegger Andreas , Winkler Hildegard , de Girolamo Giovanni , Carrà Giuseppe , Crocamo Cristina , Fangerau Heiner , Markiewicz Inga , Heitzman Janusz , Salize Hans Joachim , Picchioni Marco , Wancata Johannes
Published: May 2021

Background: The purpose of this systematic review is to systematically investigate which non-pharmacological interventions are effective in reducing violence risk among patients with schizophrenia spectrum disorders (SSD) in forensic settings.

Methods: Six electronic data bases were searched. Two researchers independently screened 6,003 abstracts resulting in 143 potential papers. These were analyzed in detail by two independent researchers yielding 10 articles that could be used.

Results: Of the 10 articles, four were non-randomized controlled trials, three were pre-post studies without controls, and one was observational. Only two studies applied a randomized controlled trial design. Cognitive behavioral treatment programs were investigated in three studies. A broad range of other interventions were studied. Often outcome measures were specific to each study and sample sizes were small. Frequently, important methodological information was missing from the papers. It was not possible to carry out a meta-analysis due to the heterogeneity of the study designs and outcome measures.

Conclusion: Because of methodological limitations it is difficult to draw firm conclusions about the effectiveness of non-pharmacological interventions to reduce the risk of violence in patents with SSD in forensic psychiatry settings. Studies applying better methods in terms of study design, sample sizes and outcome measures are urgently needed.
Optimising a Simple Fully Convolutional Network for Accurate Brain Age Prediction in the PAC 2019 Challenge
Authors: Gong Weikang , Beckmann Christian F. , Vedaldi Andrea , Smith Stephen M. , Peng Han
Published: May 2021

Brain age prediction from brain MRI scans not only helps improve brain ageing modelling generally, but also provides benchmarks for predictive analysis methods. Brain-age delta, which is the difference between a subject's predicted age and true age, has become a meaningful biomarker for the health of the brain. Here, we report the details of our brain age prediction models and results in the Predictive Analysis Challenge 2019. The aim of the challenge was to use T1-weighted brain MRIs to predict a subject's age in multicentre datasets. We apply a lightweight deep convolutional neural network architecture, Simple Fully Convolutional Neural Network (SFCN), and combined several techniques including data augmentation, transfer learning, model ensemble, and bias correction for brain age prediction. The model achieved first place in both of the two objectives in the PAC 2019 brain age prediction challenge: Mean absolute error (MAE) = 2.90 years without bias removal (Second Place = 3.09 yrs; Third Place = 3.33 yrs), and MAE = 2.95 years with bias removal, leading by a large margin (Second Place = 3.80 yrs; Third Place = 3.92 yrs).
Couple Relationships Are Associated With Increased REM Sleep—A Proof-of-Concept Analysis of a Large Dataset Using Ambulatory Polysomnography
Authors: Drews Henning Johannes , Drews Annika
Published: May 2021

Background/Objectives:Rapid Eye Movement (REM) sleep is associated with memory consolidation and several health effects including stress response, mental health, and longevity. Recently, it has been shown that regularly co-sleeping couples have increased and stabilized REM sleep when co-sleeping as compared to sleeping individually. However, it remained unclear whether this is due to a specific effect of altering the usual sleeping environment by partner deprivation or due to a generalizable REM-sleep promoting effect of couple relationships. The present study aims to clarify this ambiguity.

Methods:Married or never married individuals were taken from the Sleep Heart Health Study (n= 5,804) and matched regarding sociodemographic and health parameters. Matching was done using propensity score matching (1:1, nearest neighbor) and resulted in two groups ofn= 69 each (married vs. never married). After confirmation of successful matching, samples were compared regarding REM sleep and other polysomnographic parameters (paired Studentst-tests or Wilcoxon signed-rank tests).

Results:Married individuals showed significantly higher levels of total and relative REM sleep as compared to never married individuals (allp's ≤ 0.003). Neither other sleep stages nor REM-sleep fragmentation differed between groups (allp's ≥ 0.29). Results regarding number of sleep cycles were ambiguous.

Conclusion:This is the first between-subjects study to show that couple relationships are associated with increased REM sleep. This finding represents a necessary (but not sufficient) condition for the previously hypothesized self-enhancing feedback loop of REM sleep and sociality as well as for REM-sleep promotion as a mechanism through which couple relationships prevent mental illness.
The Sensory and Perceptual Scaffolding of Absorption, Inner Speech, and Self in Psychosis
Authors: Rosen Cherise , Tufano Michele , Humpston Clara S. , Chase Kayla A. , Jones Nev , Abramowitz Amy C. , Franco Chakkalakal Ann , Sharma Rajiv P.
Published: May 2021

This study examines the interconnectedness between absorption, inner speech, self, and psychopathology. Absorption involves an intense focus and immersion in mental imagery, sensory/perceptual stimuli, or vivid imagination that involves decreased self-awareness and alterations in consciousness. In psychosis, the dissolution and permeability in the demarcation between self and one's sensory experiences and perceptions, and also between self-other and/or inter-object boundaries alter one's sense of self. Thus, as the individual integrates these changes new “meaning making” or understanding evolves as part of an ongoing inner dialogue and dialogue with others. This study consisted of 117 participants: 81 participants with psychosis and 36 controls. We first conducted a bivariate correlation to elucidate the relationship between absorption and inner speech. We next conducted hierarchical multiple regressions to examine the effect of absorption and inner speech to predict psychopathology. Lastly, we conducted a network analysis and applied extended Bayesian Information Criterion to select the best model. We showed that in both the control and psychosis group dialogic and emotional/motivational types of inner speech were strongly associated with absorption subscales, apart from the aesthetic subscale in the control group which was not significant, while in psychosis, condensed inner speech was uniquely associated with increased imaginative involvement. In psychosis, we also demonstrated that altered consciousness, dialogic, and emotional/motivational inner speech all predicted positive symptoms. In terms of network associations, imaginative involvement was the most central, influential, and most highly predictive node in the model from which all other nodes related to inner speech and psychopathology are connected. This study shows a strong interrelatedness between absorption, inner speech and psychosis thus identifying potentially fertile ground for future research and directions, particularly in the exploration into the underlying construct of imaginative involvement in psychotic symptoms.
ICD-11 Personality Disorders: Utility and Implications of the New Model
Authors: Mulder Roger T.
Published: May 2021

The ICD-11 classification of personality disorders represents a paradigm shift in diagnosis. This was felt necessary because previous personality disorder classifications had major problems. These included unnecessary complexity, inconsistency with data on normal personality traits, and minimal consideration of severity despite this being shown to be the major predictor of outcome. The ICD-11 classification abolishes all categories of personality disorder except for a general description of personality disorder. This diagnosis can be further specified as “mild,” “moderate,” or “severe.” Patient behavior can be described using one or more of five personality trait domains; negative affectivity, dissociality, anankastia, detachment, and disinhibition. Clinicians may also specify a borderline pattern qualifier. The ICD-11 shows considerable alignment with the DSM-5 Alternative Model for Personality Disorders. Early evidence around the reliability and validity of the new model appear promising, although at present there is still limited specific evidence due to the model being so recently finalized. However, for the model to be successful, it needs to be embraced by clinicians and used widely in normal clinical practice.
Cannabis Use in People With Obsessive-Compulsive Symptomatology: Results From a Mexican Epidemiological Sample
Authors: Nicolini Humberto , Martínez-Magaña José Jaime , Genis-Mendoza Alma Delia , Villatoro Velázquez Jorge Ameth , Camarena Beatriz , Fleiz Bautista Clara , Bustos-Gamiño Marycarmen , Aguilar García Alejandro , Lanzagorta Nuria , Medina-Mora María Elena
Published: May 2021

Recent studies suggest that the endocannabinoid system could play an important role in the physiopathology of obsessive-compulsive disorder (OCD). There are reports of effective treatment with derivatives of tetrahydrocannabinol (THC). The study of the genetic factor associated with psychiatric disorders has made possible an exploration of its contribution to the pharmacological response. However, very little is known about the genetic factor or the prevalence of cannabis use in the Mexican population with OCD. The objective of this study is to compare the prevalence of use and dependence on cannabis in individuals with obsessive-compulsive symptomatology (OCS) with that of individuals with other psychiatric symptoms (psychosis, depression, and anxiety), and to explore the association between genetic risk and use. The study includes a total of 13,130 individuals evaluated in the second stage of the 2016 National Survey of Drug, Alcohol, and Tobacco Use (Encodat 2016), with genetic analysis (polygenic risk scoring) of a subsample of 3,521 individuals. Obsessive symptomatology had a prevalence of 7.2% and compulsive symptomatology a prevalence of 8.6%. The proportion of individuals with OCS who had ever used cannabis was 23.4%, and of those with cannabis dependency was 2.7%, the latter figure higher than that in individuals with other psychiatric symptoms (hypomania, 2.6%; anxiety, 2.8%; depression, 2.3%), except psychosis (5.9%). Individuals with OCS who reported using cannabis had an increased genetic risk for cannabis dependence but not for OCD. We thus cannot know how the increased genetic risk of cannabis dependence in people with OCD is influenced by their pharmacological response to derivatives of THC. The results, however, suggest paths for future studies.
Prehabilitation for Frail Patients Undergoing Colorectal Surgery: Lessons Learnt From a Randomised Feasibility Study
Authors: Furyk Claire , Senthuran Siva , Nye Dia , Ho Yik H. , Leicht Anthony S.
Published: May 2021

There is substantial interest by clinicians to improve the health outcomes of older and frail patients following major surgery, with prehabilitation a potential and important component of future standard patient care. We studied the feasibility of a randomised controlled trial of pre-operative prehabilitation in frail patients scheduled for colorectal surgery in regional Australia. We conducted a single blind, parallel arm, randomised controlled trial in a regional referral centre where colorectal surgical patients aged over 50 were invited to participate and screened for frailty. Frail patients were randomised to undertake either a 4-week supervised exercise program with dietary advice, or usual care. The primary outcome was 6-min-walk-distance at baseline, pre-surgery (4 weeks later) and at follow-up (4–6 weeks post-operation). Secondary outcomes included physical activity level, health-related quality of life, and post-surgical complications. Feasibility outcomes were numbers of patients reaching each stage and barriers or reasons for withdrawal. Of 106 patients eligible for screening during the 2-year study period, only five were able to be randomised, of which one alone completed the entire study to follow-up. Fewer patients than expected met the frailty criteria (23.6%), and many (22.6%) were offered surgery in a shorter timeframe than the required 4 weeks. Physical and psychological aspects of frailty and logistical issues were key for patients declining study participation and/or not complying with the intervention and/or all outcome assessments. Feasibility for a large randomised controlled trial of prehabilitation for frail colorectal patients was poor (~5%) for our regional location. Addressing barriers, examination of a large, dense population base, and utilisation of a frailty-screening tool validated in surgical patients are necessary for future studies to identify the impact of prehabilitation for frail patients.