bluuebunny/crossref_metadata_2025 huggingface dataset:
Focal Adhesion Kinase (FAK)-Hippo/YAP transduction signaling mediates the stimulatory effects exerted by S100A8/A9-RAGE system in triple-negative breast cancer (TNBC)
Authors: Rigiracciolo Damiano Cosimo , Nohata Nijiro , Lappano Rosamaria , Cirillo Francesca , Talia Marianna , Adame-Garcia Sendi Rafael , Arang Nadia , Lubrano Simone , De Francesco Ernestina Marianna , Belfiore Antonino , Gutkind J. Silvio , Maggiolini Marcello
Published: June 2022

Background

Understanding the intricate signaling network involved in triple-negative breast cancer (TNBC) represents a challenge for developing novel therapeutic approaches. Here, we aim to provide novel mechanistic insights on the function of the S100A8/A9-RAGE system in TNBC.

Methods

TNM plot analyzer, Kaplan-Meier plotter, Meta-analysis, GEPIA2 and GOBO publicly available datasets were used to evaluate the clinical significance of S100A8/A9 and expression levels of S100A8/A9, RAGE and Filamin family members in breast cancer (BC) subtypes. METABRIC database and Cox proportional hazard model defined the clinical impact of high RAGE expression in BC patients. Multiple bioinformatics programs identified the main enriched pathways within high RAGE expression BC cohorts. By lentiviral system, TNBC cells were engineered to overexpress RAGE. Western blotting, immunofluorescence, nucleus/cytoplasm fractionation, qRT-PCR, gene silencing and luciferase experiments were performed to identify signal transduction mediators engaged by RAGE upon stimulation with S100A8/A9 in TNBC cells. Proliferation, colony formation and transwell migration assays were carried out to evaluate the growth and migratory capacity of TNBC cells. Statistical analysis was performed by ANOVA and independent t-tests.

Results

We found a remarkable high expression of S100A8 and S100A9 in BC, particularly in HER2-positive and TNBC, with the latter associated to worst clinical outcomes. In addition, high RAGE expression correlated with a poor overall survival in BC. Next, we determined that the S100A8/A9-RAGE system triggers FAK activation by engaging a cytoskeleton mechanosensing complex in TNBC cells. Through bioinformatics analysis, we identified the Hippo pathway as the most enriched in BC patients expressing high RAGE levels. In accordance with these data, we demonstrated the involvement of S100A8/A9-RAGE-FAK signaling in the control of Hippo/YAP activities, and we established the crucial contribution of RAGE-FAK-YAP circuitry in the growth and migratory effects initiated by S100A8/A9 in TNBC cells.

Conclusions

The present study provides novel mechanistic insights on RAGE actions in TNBC. Moreover, our findings suggest that RAGE-FAK-YAP transduction pathway could be exploited as a druggable system halting the aggressive TNBC subtype.
The influence of perceived stress on the human microbiome
Authors: Almand Austin T. , Anderson Allison P. , Hitt Brianna D. , Sitko John C. , Joy Rebekah M. , Easter Benjamin D. , Almand Erin A.
Published: June 2022

Objective

Microbial dysbiosis, a shift from commensal to pathogenic microbiota, is often associated with mental health and the gut–brain axis, where dysbiosis in the gut may be linked to dysfunction in the brain. Many studies focus on dysbiosis induced by clinical events or traumatic incidents; however, many professions in austere or demanding environments may encounter continuously compounded stressors. This study seeks to explore the relationship between microbial populations and stress, both perceived and biochemical.

Results

Eight individuals enrolled in the study to provide a longitudinal assessment of the impact of stress on gut health, with four individuals providing enough samples for analysis. Eleven core microbial genera were identified, although the relative abundance of these genera and other members of the microbial population shifted over time. Although our results indicate a potential relationship between perceived stress and microbial composition of the gut, no association with biochemical stress was observed. Increases in perceived stress seem to elucidate a change in potentially beneficial Bacteroides, with a loss in Firmicutes phyla. This shift occurred in multiple individuals, whereas using cortisol as a stress biomarker showed contradictory responses. These preliminary data provide a potential mechanism for gut monitoring, while identifying targets for downstream modulation.
Tomoelastography based on multifrequency MR elastography predicts liver function reserve in patients with hepatocellular carcinoma: a prospective study
Authors: Lin Huimin , Wang Yihuan , Zhou Jiahao , Yang Yuchen , Xu Xinxin , Ma Di , Chen Yongjun , Yang Chunxue , Sack Ingolf , Guo Jing , Li Ruokun , Yan Fuhua
Published: June 2022

Background

Estimating liver function reserve is essential for preoperative surgical planning and predicting post-hepatectomy complications in patients with hepatocellular carcinoma (HCC). We investigated hepatic viscoelasticity quantified by tomoelastography, a multifrequency magnetic resonance elastography technique, to predict liver function reserve.

Methods

One hundred fifty-six patients with suspected HCC (mean age, 60 ± 1 years; 131 men) underwent preoperative tomoelastography examination between July 2020 and August 2021. Sixty-nine were included in the final analysis, and their 15-min indocyanine green retention rates (ICG-R15s) were obtained to determine liver function reserve. Tomoelastography quantified the shear wave speed (c, m/s), which represents stiffness, and loss angle (φ, rad), which represents fluidity. Both were correlated with the ICG-R15. A prediction model based on logistic regression for major hepatectomy tolerance (ICG-R15 ≥ 14%) was established.

Results

Patients were assigned to either the ICG-R15 < 14% (n = 50) or ICG-R15 ≥ 14% (n = 19) group. Liverc(r = 0.617) andφ(r = 0.517) were positively correlated with the ICG-R15 (bothp < 0.001). At fibrosis stages F1–2,φwas positively correlated with the ICG-R15 (r = 0.528;p = 0.017), butcwas not (p = 0.104). At stages F3–4,c(r = 0.642;p < 0.001) andφ(r = 0.377;p = 0.008) were both positively correlated with the ICG-R15. The optimal cutoffs ofcandφfor predicting ICG-R15 ≥ 14% were 2.04 m/s and 0.79 rad, respectively. The area under the receiver operating characteristic curve was higher forc(0.892) than forφ(0.779;p = 0.045).

Conclusions

Liver stiffness and fluidity, quantified by tomoelastography, were correlated with liver function and may be used clinically to noninvasively assess liver function reserve and stratify treatments.
Research status and future prospects of extracellular vesicles in primary Sjögren’s syndrome
Authors: Zhao Jingwen , An Qi , Zhu Xueqing , Yang Baoqi , Gao Xinnan , Niu Yuhu , Zhang Liyun , Xu Ke , Ma Dan
Published: June 2022

Primary Sjögren’s syndrome (pSS) is a diffuse connective tissue disease characterized by the invasion of exocrine glands such as lacrimal and salivary glands, abnormal proliferation of T and B lymphocytes, and infiltration of tissue lymphocytes. With the development of modern medicine, although research on the pathogenesis, diagnosis, and treatment of pSS has made significant progress, its pathogenesis has not been fully understood. Meanwhile, in the era of individualized treatment, it remains essential to further explore early diagnosis and treatment methods. Exosomes, small vesicles containing proteins and nucleic acids, are a subtype of extracellular vesicles secreted by various cells and present in various body fluids. Exosomes contribute to a variety of biological functions, including intercellular signal transduction and pathophysiological processes, and may play a role in immune tolerance. Therefore, exosomes are key to understanding the pathogenesis of diseases. Exosomes can also be used as a therapeutic tool for pSS because of their biodegradability, low immunogenicity and toxicity, and the ability to bypass the blood–brain barrier, implying the prospect of a broad application in the context of pSS. Here, we systematically review the isolation, identification, tracing, and mode of action of extracellular vesicles, especially exosomes, as well as the research progress in the pathogenesis, diagnosis, and treatment of pSS.
Improving galegine production in transformed hairy roots of Galega officinalis L. via elicitation
Authors: Khezri Maryam , Asghari Zakaria Rasool , Zare Nasser , Johari-Ahar Mohammad
Published: June 2022

Galega officinalis L. is an herbaceous legume used to treat symptoms associated with hyperglycemia or diabetes mellitus because of its dominant alkaloid, galegine. In this study, we induced hairy roots in this plant using Rhizobium rhizogenes strain A4, and investigated the effect of type, concentration, and duration of elicitor application on galegine content and some phytochemical characteristics in the hairy roots. Hence, the best growing hairy root line in terms of growth rate was selected and subcultured for treatment with elicitors. Then, at the end of the log phase of growth, chitosan (100, 200, and 400 mg/L), salicylic acid (100, 200, and 300 mM), and ultrasound (1, 2, and 4 min) were applied to hairy roots culture medium. High-performance liquid chromatography (HPLC) showed that the content of galegine was significantly increased after elicitation compared with the control. Thus, the highest content of galegine (14.55 mg/g FW) was obtained 2 days after elicitation when ultrasonic waves were applied to the hairy root culture medium for 4 min. Also, elicitation resulted in a significant increase in the content of total phenol, flavonoid, H2O2 and MDA compared with the control. So that the highest total flavonoid content was obtained in hairy roots that were treated with ultrasonic waves for 4 min and harvested 2 days after elicitation; while, application of 400 mg/L chitosan for 4 days resulted in the highest total phenol (16.84 mg/g FW).

Graphical Abstract
Histone deacetylase 3 facilitates TNFα-mediated NF-κB activation through suppressing CTSB induced RIP1 degradation and is required for host defense against bacterial infection
Authors: Yang Liping , Chen Shengchuan , Xia Jingyan , Zhou Ying , Peng Linan , Fan Huimin , Han Yu , Duan Lihua , Cheng Genhong , Yang Heng , Xu Feng
Published: June 2022

Background

As important enzymes regulating acetylation, histone deacetylases (HDACs) participate in a series of cell physiological process. However, the mechanisms responsible for individual HDAC family members in regulating innate immunity remained to be elucidated. Here we sought to reveal the mechanism of HDAC3 in regulating the inflammatory response of macrophages.

Methods

RNAseq was done to detect the transcriptional influence of HDAC3 on macrophages. Kyoto Encyclopedia of Genes and Genomes was used to reveal the change of signaling pathways after HDAC3 knockout. CHIPseq was done to detect the deacetylation modification of HDAC3 on chromosome. Western blot, immunofluorescence, and real-time quantitative PCR were used to measure the change of genes and proteins’ levels. Mice were intratracheal instillation with lipopolysaccharide or Pseudomonas aeruginosa to determine the influence of HDAC3 on inflammatory response in vivo.

Results

HDAC3-deficient macrophages had increased expression of cathepsins resulting from elevated histone acetylation. Over-expressed cathepsins such as cathepsin B (CTSB) caused remarkable degradation of receptor (TNFRSF)-interacting serine-threonine kinase 1 (RIP1), which reduced TNFα mediated NF-κB activation and inflammatory response. Consistently, mice with macrophage specific knockout of HDAC3 were impaired in inflammatory response and thereby susceptible to Pseudomonas aeruginosa infection.

Conclusion

HDAC3 was required for protecting RIP1 from degrading by CTSB in macrophages. Decreased RIP1 in HDAC3 knockout macrophages impaired TNFα mediated NF-κB activation. Our studies uncovered important roles of HDAC3 in the regulation of cathepsin-mediated lysosomal degradation and RIP1-mediated inflammatory response in macrophages as well as in host defense against bacterial infection.
The phosphorylation to acetylation/methylation cascade in transcriptional regulation: how kinases regulate transcriptional activities of DNA/histone-modifying enzymes
Authors: Zhao Pin , Malik Samiullah
Published: June 2022

Transcription factors directly regulate gene expression by recognizing and binding to specific DNA sequences, involving the dynamic alterations of chromatin structure and the formation of a complex with different kinds of cofactors, like DNA/histone modifying-enzymes, chromatin remodeling factors, and cell cycle factors. Despite the significance of transcription factors, it remains unclear to determine how these cofactors are regulated to cooperate with transcription factors, especially DNA/histone modifying-enzymes. It has been known that DNA/histone modifying-enzymes are regulated by post-translational modifications. And the most common and important modification is phosphorylation. Even though various DNA/histone modifying-enzymes have been classified and partly explained how phosphorylated sites of these enzymes function characteristically in recent studies. It still needs to find out the relationship between phosphorylation of these enzymes and the diseases-associated transcriptional regulation. Here this review describes how phosphorylation affects the transcription activity of these enzymes and other functions, including protein stability, subcellular localization, binding to chromatin, and interaction with other proteins.
Party keepers: a significant community-based intervention for harm reduction
Authors: Zucker Roy , Mor Zohar , Abudin Anuar , Davis Glen , Arroyo Hansel , Wagner Kolasko Gal , Arad Dan , Shilo Guy
Published: June 2022

Background

Gay men use recreational drugs more often than heterosexuals—especially at social events. While partying at a venue, partygoers are at risk of drug overdosing, without access to an emergency help. This study evaluates a unique and novel intervention aimed at training men who have sex with men (MSM) and transgender individuals who frequent parties, to provide immediate assistance on-site to partygoers who have overdosed.

Methods

The Party Keepers (PK) course is a unique 4-h training course that provides the participants with tools to identify, prevent, and treat common medical syndromes that are associated with excessive substance use. Participants were asked to complete a questionnaire on their sociodemographic attributes; their sexual risk behaviour; pre-exposure prophylaxis (PrEP) use and drug-use behaviour before and after the course; and the emergency situations they encountered in party venues after the course.

Results

Of the 85 participants who completed the training and left valid contact information, 52 (62%) completed the questionnaires. Their average age was 37.0 years, most lived in Tel-Aviv, and were single. Participants reported that, after the course, they reduced their own use of recreational drugs (cocaine, amyl nitrates, alcohol), reduced their sexual risk behaviours, and significantly increased their use of PrEP. Of all the PKs, 63% (N = 32) indicated that they now provided first-aid and other assistance to partygoers at public venues, which enhanced their sense of community responsibility. In the multivariate analysis, a high level of confidence as a PK, and the knowledge gained in the course, predicted the incidence of subsequent assistance to partygoers in emergency situations.

Conclusions

The PK initiative—a harm-reduction intervention led by peers, aimed at fighting drug overdosing at gay venues—was useful in reducing drug use and sexual risk behaviours among the course participants. Most course participants also responded to drug-related emergency situations at gay parties, as a result. This evaluation of community health intervention within a sexual minority community can help health policy makers design more community based interventions and allocate resources to include community participants in harm-reduction policies.
Defective mitophagy and the etiopathogenesis of Alzheimer’s disease
Authors: Zeng Kuan , Yu Xuan , Mahaman Yacoubou Abdoul Razak , Wang Jian-Zhi , Liu Rong , Li Yi , Wang Xiaochuan
Published: June 2022

Accumulation of impaired mitochondria and energy metabolism disorders are non-negligible features of both aging and age-related neurodegeneration, including Alzheimer’s disease (AD). A growing number of studies suggest that mitophagy disorders play an important role in AD occurrence and development. The interaction between mitophagy deficits and Aβ or Tau pathology may form a vicious cycle and cause neuronal damage and death. Elucidating the molecular mechanism of mitophagy and its role in AD may provide insights into the etiology and mechanisms of AD. Defective mitophagy is a potential target for AD prevention and treatment.
RETRACTED ARTICLE: Inheritance and promotion of chinese traditional music culture in college piano education
Authors: Lu Dong
Published: June 2022

The purpose of the present research is to study the issues of inheritance and promotion of Chinese traditional music culture in college piano education. The research methodology builds on an empirical approach through a survey using a questionnaire for data collection. The present study involved 174 students from six Chinese colleges. Accordingly, students were divided into two groups based on the training approach. The experimental group included 87 students who received education under the previously elaborated program aimed at promoting Chinese traditional music culture; and the control group consisted of 87 students who received piano training under the conventional program. The results showed that for only 8% of the respondents the use of traditional Chinese music is the basis of learning, for 61% this type of music is practically not used. 88% of teachers concluded that there is a need to use Chinese traditional music in education because it displays elements that convey the symbolism of the Chinese people. The teaching criteria were to inform students about the need to apply Chinese national music while playing the piano; to introduce folk compositions for practicing technical elements into instruction; to update the repertoire and build students’ interest. Training based on the aforementioned criteria demonstrated that traditional music has become more popular. In particular, many students in the experimental group began to use this type of music while creating videos and shows (29%), participating in competitions and concerts (25%), and arranging musical compositions (21%). In the control group, students used folk music only while listening to musical compositions in their free time (57%) and teaching private piano lessons (11%). The present study has scientific and practical value as it demonstrates the effectiveness of promoting national music in educational institutions.
Patient experiences with patient-reported outcome measures in metastatic breast cancer trials: qualitative interviews
Authors: Romano Carla , Harris Nimanee , Gnanasakthy Ari , D’Alessio Denise , Chandiwana David
Published: June 2022

Background

Patient-reported outcome (PRO) measures are critical for assessing treatment benefit of anticancer treatments. Although PRO measures have been developed with the intention of capturing patient-centric concepts, a gap exists in understanding the patient experience with these tools. We characterized the experience of patients with metastatic breast cancer (mBC) with PRO measures in an oncology clinical trial setting to determine the importance, relevance, barriers, and facilitators for PRO completion.

Methods

The multicenter, qualitative design included semistructured interviews with 18 women with mBC who completed PRO measures in a clinical trial setting within 1 year of screening. Interviews began with concept elicitation to understand symptom characterization, decision to participate in a clinical trial, pre-trial expectations, and thoughts on study-related questionnaires. Cognitive debriefing was conducted to determine if items in a commonly used PRO instrument were relevant to the patient experience. Qualitative data were analyzed using a constant comparative approach.

Results

Participants described the need for detailed explanation of PRO measures at study start, including information about how the PRO data will likely be used to support drug development. Respondents who felt connected to clinical trial research were more likely to feel as if the measures adequately captured their experiences. Items that were deemed irrelevant or out of date to the patient experience may cause a respondent to feel marginalized and adds to the overall burden of PRO measure completion. Mode of PRO measure administration (electronic/paper) was important to some, but placement of the instrument completion within a study visit appeared to influence respondent willingness to fully engage with the measures. A lack of any type of feedback loop to allow respondents to learn from the captured PRO data was noted as important but missing from the patient experience.

Conclusions

PRO measures need to include content that is relevant to the patient experience over the course of the clinical trial period to be considered meaningful to respondents, and administration techniques also impact engagement. Robust communication strategies that socialize the intent, use, and results of PRO data may enrich the patient experience and support greater adherence to PRO completion in future studies.
Expected a posteriori scoring in PROMIS®
Authors: Chapman Robert
Published: June 2022

Background

The Patient-Reported Outcome Measurement Information System®(PROMIS®) was developed to reliably measure health-related quality of life using the patient’s voice. To achieve these aims, PROMIS utilized Item Response Theory methods in its development, validation and implementation. PROMIS measures are typically scored using a specific method to calculate scores, called Expected A Posteriori estimation.

Body

Expected A Posteriori scoring methods are flexible, produce accurate scores and can be efficiently calculated by statistical software. This work seeks to make Expected A Posteriori scoring methods transparent and accessible to a larger audience through description, graphical demonstration and examples. Further applications and practical considerations of Expected A Posteriori scoring are presented and discussed. All materials used in this paper are made available through the R Markdown reproducibility framework and are intended to be reviewed and reused. Commented statistical code for the calculation of Expected A Posteriori scores is included.

Conclusion

This work seeks to provide the reader with a summary and visualization of the operation of Expected A Posteriori scoring, as implemented in PROMIS. As PROMIS is increasingly adopted and implemented, this work will provide a basis for making psychometric methods more accessible to the PROMIS user base.
Design and evaluation of a multi-level reactive power market
Authors: Bozionek Jan , Wolgast Thomas , Nieße Astrid
Published: June 2022

The shift from conventional power plants on transmission level to distributed energy resources in the distribution grids requires procedures to enable efficient and economic reactive power exchange across different voltage levels. In this paper, we propose a multi-level reactive power market that enables reactive power provision from distributed energy resources to higher voltage levels. Each grid operator operates a local reactive power market and offers local reactive power potential, as an intermediary, to superordinate grid operators by passing on its aggregated cost curve and flexibility range. As a result, there is a low requirement of communication between the market participants and each grid operator is free to choose its local market rules as well as the optimization algorithm used. First results from a case study show that our decentralized market approach can realize an economically efficient multi-level reactive power provision that is close to a centrally computed optimal solution, without violating local grid constraints.
Does the implementation of clinical practice guidelines for low back and neck pain by physical therapists improve patient outcomes? A systematic review
Authors: Fillipo Rebecca , Pruka Katie , Carvalho Marissa , Horn Maggie E. , Moore Jordan , Ramger Benjamin , Clewley Derek
Published: June 2022

Background

Physical therapy for neck and low back pain is highly variable despite the availability of clinical practice guidelines (CPG). This review aimed to determine the impact of CPG implementation on patient-level outcomes for spinal pain. Implementation strategies were also examined to determine prevalence and potential impact.

Methods

Multiple databases were searched through April 2021 for studies assessing CPG implementation in physical therapy for neck and low back pain. Articles were screened for eligibility. The Modified Downs and Black checklist was utilized to determine study quality. Due to the heterogeneity between studies, a meta-analysis was not performed.

Results

Twenty-one studies were included in this review. Implementation strategies were significantly varied between studies. Outcomes pertaining to healthcare utilization, pain, and physical functioning were assessed in relation to the implementation of CPGs. Multiple implementation strategies were identified, with Managing Quality as the most frequently utilized key implementation process. Findings indicate CPG implementation decreased healthcare utilization, but inconsistent results were found with physical functioning and pain outcomes.

Conclusions

CPG implementation appears to have a beneficial effect on healthcare utilization outcomes, but may not impact pain and physical functioning outcomes. Effective CPG implementation strategies remain unknown, though utilizing implementation framework may improve outcomes. More research is needed to determine the most effective implementation strategies and effects on pain and physical function outcomes.
Strategies for implementing pet robots in care homes and nursing homes for residents with dementia: protocol for a modified Delphi study
Authors: Koh Wei Qi , Casey Dympna , Hoel Viktoria , Toomey Elaine
Published: June 2022

Background

Pet robots are a type of technology-based innovation that have shown positive psychosocial benefits for people with dementia in residential facilities, such as improving mood and social interaction and reducing agitation. Nevertheless, little is known about how pet robots can be implemented in care homes and nursing homes for dementia care in real-world practice. The objectives of this study are to (1) identify contextualised implementation strategies for implementing pet robots into care homes and nursing homes for dementia care and (2) achieve consensus on the most relevant strategies.

Method

This study is informed by a preceding scoping review and qualitative study, which used the Consolidated Framework of Implementation Research (CFIR) to identify multi-level determinants of implementation (i.e. barriers and facilitators). We will use the CFIR-ERIC matching tool to identify relevant implementation strategies from the Expert Recommendations for Implementing Change (ERIC) taxonomy to address these determinants. Data from the scoping review and qualitative study will be used to contextualise the generic ERIC strategies for our setting. After that, a group of key stakeholders will be consulted to further contextualise and refine these strategies. Next, a two-round modified Delphi process will be conducted. Fifty-four international expert participants including healthcare professionals and organisational leaders from care homes and nursing homes and academic researchers will be recruited through purposive sampling. During the first Delphi round, participants will be invited to rate the relevance of each implementation strategy on a 9-point Likert scale and provide comments or suggestions. Descriptive statistics will be used to identify whether consensus has been obtained. Inductive qualitative content analysis will be used to analyse and summarise textual responses for any new statements suggested by participants. Statements that do not reach consensus and new statements suggested in round 1 will be taken to the next round, which will follow the same rating process.

Discussion

This study will identify strategies for implementing pet robots in care homes and nursing homes for residents with dementia, which will have practical utility for clinicians, organisations and researchers. It will also demonstrate the practical application (and adaptation) of the CFIR-ERIC tool to identify and contextualise ERIC strategies.
2D QSAR, design, docking study and ADMET of some N-aryl derivatives concerning inhibitory activity against Alzheimer disease
Authors: Ajala Abduljelil , Uzairu Adamu , Shallangwa Gideon A. , Abechi Stephen E.
Published: June 2022

Background

Alzheimer disease (AD) is an ailment that disturbs mainly people of old age. The fundamental remedial way to deal with AD depends on the utilization of AChEI. The design of new intense and particular AChEI is critical in drug discovery. In silico technique will be used to solve the above problem. A new method was established to discover novel agents with better biological activity against Alzheimer disease.

Results

A validated model was established in this research to predict the biological activities of some anti-Alzheimer compounds and to design new hypothetical drugs influenced with molecular properties in the derived model; ATS4i, MATS2e, SpMax7_BhS, Energy(HOMO)and Molecular Weight and showed good correlationR2 = 0.936,R2adj = 0.907,Q2cv = 0.88, LOF = 0.0154 andR2ext = 0.881. All the descriptors in the model were in good agreement with the 15 test set predicted values. Five compounds were designed using D35rm as a template with improved activity. The compounds have higher and better binding scores (− 10.1, − 9.4, − 9.3, − 9.1 and − 8.1 all in kcal/mol) than the approved drugs (Donepezil =  − 7.4 kcal/mol).

Conclusion

As the outcome, every one of the selected and the designed compounds is created and improved as potential anti-Alzheimer agents. Despite this, the further test examines and in vivo investigations are recommended to assess the method of the activities and other pharmacological impacts on these compounds.
Transdiagnostic comparisons of intellectual abilities and work outcome in patients with mental disorders: multicentre study
Authors: Sumiyoshi Chika , Ohi Kazutaka , Fujino Haruo , Yamamori Hidenaga , Fujimoto Michiko , Yasuda Yuka , Uno Yota , Takahashi Junichi , Morita Kentaro , Katsuki Asuka , Yamamoto Maeri , Okahisa Yuko , Sata Ayumi , Katsumoto Eiichi , Koeda Michihiko , Hirano Yoji , Nakataki Masahito , Matsumoto Junya , Miura Kenichiro , Hashimoto Naoki , Makinodan Manabu , Takahashi Tsutomu , Nemoto Kiyotaka , Kishimoto Toshifumi , Suzuki Michio , Sumiyoshi Tomiki , Hashimoto Ryota
Published: June 2022

Background

Cognitive impairment is common in people with mental disorders, leading to transdiagnostic classification based on cognitive characteristics. However, few studies have used this approach for intellectual abilities and functional outcomes.

Aims

The present study aimed to classify people with mental disorders based on intellectual abilities and functional outcomes in a data-driven manner.

Method

Seven hundred and forty-nine patients diagnosed with schizophrenia, bipolar disorder, major depression disorder or autism spectrum disorder and 1030 healthy control subjects were recruited from facilities in various regions of Japan. Two independent k-means cluster analyses were performed. First, intelligence variables (current estimated IQ, premorbid IQ, and IQ discrepancy) were included. Second, number of work hours per week was included instead of premorbid IQ.

Results

Four clusters were identified in the two analyses. These clusters were specifically characterised in terms of IQ discrepancy in the first cluster analysis, whereas the work variable was the most salient feature in the second cluster analysis. Distributions of clinical diagnoses in the two cluster analyses showed that all diagnoses were unevenly represented across the clusters.

Conclusions

Intellectual abilities and work outcomes are effective classifiers in transdiagnostic approaches. The results of our study also suggest the importance of diagnosis-specific strategies to support functional recovery in people with mental disorders.
Investigating the relationship between euthanasia and/or assisted suicide and rates of non-assisted suicide: systematic review
Authors: Doherty Anne M. , Axe Caitlyn J. , Jones David A.
Published: June 2022

Background

Euthanasia and assisted suicide (EAS) are practices that aim to alleviate the suffering of people with life-limiting illnesses, but are controversial. One area of debate is the relationship between EAS and suicide rates in the population, where there have been claims that availability of EAS will reduce the number of self-initiated deaths (EAS and suicide combined). Others claim that legislation for EAS makes it acceptable to end one's own life, a message at variance with that of suicide prevention campaigns.

Aims

To examine the relationship between the introduction of EAS and rates of non-assisted suicide and self-initiated death.

Method

We conducted a systematic review to examine the association between EAS and rates of non-assisted suicide and of self-initiated death. We searched PubMed, Scopus, PsycINFO and Science Direct, until 20 December 2021. Studies that examined EAS and reported data on population-based suicide rates were included.

Results

Six studies met the inclusion criteria; four reported increases in overall rates of self-initiated death and, in some cases, increased non-assisted suicide. This increase in non-assisted suicide was mostly non-significant when sociodemographic factors were controlled for. Studies from Switzerland and Oregon reported elevated rates of self-initiated death among older women, consistent with higher rates of depressive illnesses in this population.

Conclusions

The findings of this review do not support the hypothesis that introducing EAS reduces rates of non-assisted suicide. The disproportionate impact on older women indicates unmet suicide prevention needs in this population.
Current State of Adjuvant Therapy for Melanoma: Less Is More, or More Is Better?
Authors: Lao Christopher D. , Khushalani Nikhil I. , Angeles Christina , Petrella Teresa M.
Published: June 2022

Advances in melanoma treatments over the past decade have changed the course of survival for patients. Several adjuvant therapies have been approved and are now considered standard of care for high-risk patients. These therapies have shown improvements for recurrence-free survival and distant metastases–free survival, but not overall survival, as the data are maturing. The 5-year recurrence-free survival in the COMBI-AD study, which compared dabrafenib and trametinib with placebo, was 65% and 58%, respectively. In the KEYNOTE-054 study, the recurrence-free survival at 3 years was 63.7% versus 41%. Despite these advances, approximately 50% of patients will succumb to their disease. Adjuvant therapy is considered potentially curative and avoids the morbidity of relapsed disease and the poor outcomes seen in metastatic disease. However, the lack of overall survival benefit in clinical trials of patients with high-risk stage II and stage III disease raises the question of whether it is more efficacious to treat when there is residual microscopic disease, or to wait until the disease recurs to avoid treating those who may have been cured by surgery alone. Immunotherapy also has the potential for substantial toxicity that may be lifelong; hence, discussion of risks and benefits of therapy is warranted because there should be less tolerance for substantial toxicity in the adjuvant setting. Adjuvant trials are needed that will integrate biomarkers to allow for better selection of patients who will truly benefit from adjuvant therapy.
COVID-19 and Cancer: Special Considerations for Patients Receiving Immunotherapy and Immunosuppressive Cancer Therapies
Authors: Goldman Jason D. , Gonzalez Michael A. , Rüthrich Maria Madeleine , Sharon Elad , von Lilienfeld-Toal Marie
Published: June 2022

Patients with cancer generally have a higher risk of adverse outcomes from COVID-19, with higher age, male sex, poor performance status, cancer type, and uncontrolled malignant disease as the main risk factors. However, the influence of specific cancer therapies varies and raises concerns during the pandemic. In patients undergoing cancer immunotherapy or other immunosuppressive cancer treatments, we summarize the evidence on outcomes from COVID-19; address the safety, immunogenicity, and efficacy of COVID-19 vaccination; and review COVID-19 antiviral therapeutics for the patient with cancer. Despite higher mortality for patients with cancer, treatment with immune checkpoint inhibitors does not seem to increase mortality risk based on observational evidence. Inhibitory therapies directed toward B-cell lineages, including monoclonal antibodies against CD20 and CAR T-cell therapies, are associated with poor outcomes in COVID-19; however, the data are sparse. Regarding vaccination in patients receiving immune checkpoint inhibitors, clinical efficacy comparable to that in the general population can be expected. In patients undergoing B-cell–depleting therapy, immunogenicity and clinical efficacy are curtailed, but vaccination is not futile, which is thought to be due to the cellular response. Vaccine reactogenicity and toxicity in all groups of patients with cancer are comparable to that of the general population. Preexposure prophylaxis with monoclonal antibodies directed against the viral spike may provide passive immunity for those not likely to mount an adequate vaccine response. If infected, prompt treatment with monoclonal antibodies or oral small molecule antivirals is beneficial, though with oral antiviral therapies, care must be taken to avoid drug interactions in patients with cancer.
Physical Activity Behaviors of a Middle-Age South African Cohort as Determined by Integrated Hip and Thigh Accelerometry
Authors: MICKLESFIELD LISA K. , WESTGATE KATE , SMITH ANTONIA , KUFE CLEMENT N. , MENDHAM AMY E. , LINDSAY TIM , WIJNDAELE KATRIEN , GOEDECKE JULIA H. , BRAGE SOREN
Published: June 2022

Purpose

Descriptive studies of objectively measured physical activity behaviors in African populations are rare. We developed a method of combining hip and thigh accelerometery signals to quantify and describe physical behaviors in middle-age South African men and women.

Methods

We integrated signals from two triaxial accelerometers worn simultaneously during free-living, in a subsample of the Middle-age Soweto Cohort (n = 794; mean (SD) age, 53.7 (6.3) yr). Acceleration time series from the accelerometers were combined and movement-related acceleration was derived using Euclidean Norm Minus One (in milligrams), to determine total movement volume (mean Euclidean Norm Minus One) and nonmovement time (<28 mg), light-intensity physical activity (LPA; 28–85 mg), and moderate- to vigorous-intensity physical activity (MVPA; >85 mg); thigh pitch angle and a sleep diary were used to divide nonmovement time (in minutes per day) into sleep, awake sitting/lying, and standing. Sociodemographic factors were self-reported, and weight and height were measured.

Results

Mean (SD) wear time was 128 (48) h. Movement volume was 15.0 (6.5) mg for men and 12.2 (3.4) mg for women. Men spent more time in MVPA and sitting/lying, whereas women spent more time standing. Age was inversely associated with movement volume, MVPA, and LPA. When compared with their normal-weight counterparts, men who were overweight or obese spent less time in MVPA, whereas women who were overweight or obese spent less time in LPA and more time sitting/lying. Socioeconomic status was inversely associated with total movement volume, MVPA, and time spent sleeping, and positively associated with time spent sitting/lying, in both men and women.

Conclusions

Integrating signals from hip and thigh accelerometers enables characterization of physical behaviors that can be applied in an African population.
Terahertz difference-frequency-generation quantum cascade lasers on silicon with wire grid current injectors
Authors: Kim Jae Hyun , Oberhausen Wolfhard , Jung Seungyong , Xu Jiaming , Mei Jialin , Kirch Jeremy D. , Mawst Luke J. , Botez Dan , Belkin Mikhail A.
Published: June 2022

We propose the concept and experimentally verify the operation of terahertz quantum cascade laser sources based on intra-cavity Cherenkov difference-frequency generation on a silicon substrate with the current injection layer configured as a metal wire grid. Such a current injector configuration enables high transmission of TM-polarized terahertz radiation into the silicon substrate while simultaneously providing a low-resistivity metal contact for current injection.
Tunable structural colors in all-dielectric photonic crystals using energetic ion beams
Authors: Li Junyang , Zhang Kaiyuan , Pang Chi , Zhao Yunpeng , Zhou Haiyang , Chen Hong , Lu Guang , Liu Fen , Wu Ailing , Du Guiqiang , Akhmadaliev Shavkat , Zhou Shengqiang , Chen Feng
Published: June 2022

The modulation of structural color through various methods has attracted considerable attention. Herein, a new modulation method for the structural colors in all-dielectric photonic crystals (PCs) using energetic ion beams is proposed. One type of periodic PC and two different defective PCs were experimentally investigated. Under carbon-ion irradiation, the color variation primarily originated from the blue shift of the optical spectra. The varying degrees of both the reflection and transmission structural colors mainly depended on the carbon-ion fluences. Such nanostructures are promising for tunable color filters and double-sided chromatic displays based on PCs.
Exact vectorial model for nonparaxial focusing of freeform wavefronts
Authors: González-Acuña Rafael G. , Thibault Simon
Published: June 2022

We present a new formalism, based on Richards–Wolf theory, to rigorously model nonparaxial focusing of radially polarized electromagnetic beams with freeform wavefront. The beams can be expressed in terms of Zernike polynomials. Our approach is validated by comparing known results obtained by Richards–Wolf theory. Our integral representation is compliant with diffraction theory, is thoroughly discussed and solved for various freeform wavefront that, so far, have not been treated analytically. The extension of the method to other polarization states is straightforward.
Tunable microwave frequency comb generation using a Si3N4-MDR based actively mode-locked OEO
Authors: Liu Pengcheng , Shi Shangqing , Lu Mengjia , Lin Dongdong , Cheng Wei , Lin Tong , Hu Guohua , Yun Binfeng , Cui Yiping
Published: June 2022

Microwave frequency combs (MFCs) have important applications in communication and sensing owing to their characteristics of large number of comb lines, wide frequency range, and high precision of comb spacing. In many applications, MFCs are required to emit signals with tunable center frequency and variable comb spacing to accommodate different operating frequency bands and accuracies. Here, we demonstrate a tunable MFC by injecting a low-frequency electrical signal into a tunable optoelectronic oscillator (OEO). Tuning of MFC’s center frequency and comb spacing are realized, allowing a frequency tuning range from 1 to 22 GHz and 50 comb lines within a 5 MHz bandwidth obtained in the MFC generator. In addition, the introduction of the silicon nitride micro-disk resonator (Si3N4-MDR) in the system paves the way for the integration of MFC generator.
Highly sensitive fiber optic biosensors with graphene-MoS2 heterostructure for hemoglobin detection
Authors: Xiao Gongli , Su Jiapeng , Yang Hongyan , Ou Zetao , Li Haiou , Liu Xingpeng , Wangyang Peihua , Luo Yunhan , Li Jianqing
Published: June 2022

Two-dimensional materials, which can be used to modify sensor surfaces to increase sensor sensitivity, have important research in the field of sensors. In this paper, we design a highly sensitive D-shaped photonic crystal fiber sensor with graphene-MoS2 heterostructure for hemoglobin detection. The research utilized the finite element method and involved addition of different layers of graphene and MoS2 to the optical fiber sensing area, and it was determined that the hybrid nano-heterostructures made of monolayer graphene and bilayer MoS2 provided the greatest improvement in sensor performance. The sensor shows excellent detection performance in 1.33∼1.38 refractive index units. Using incident light in the wavelength ranges of 650 nm and 850 nm, the proposed sensor has a maximum wavelength sensitivity of 4700 nm/RIU, a maximum amplitude sensitivity of 327.5 RIU-1, and a resolution of 2.17×10−5 RIU. The range of hemoglobin concentrations detected with this sensor was 0 g/L∼241 g/L, with an average sensitivity of 0.7 nm/(g/L). A fiber biosensor was enhanced with graphene-MoS2 hybrid nanostructures, which exhibit excellent photoelectric properties and detection performance, enabling highly sensitive, highly accurate, and real-time hemoglobin detection. The result shows the significant research value and application prospects in the field of biomedical detection.
Evaluation of strategies to modify Anti-SARS-CoV-2 monoclonal antibodies for optimal functionality as therapeutics
Authors: House Robert V. , Broge Thomas A. , Suscovich Todd J. , Snow Doris M. , Tomic Milan T. , Nonet Genevieve , Bajwa Kamaljit , Zhu Guangyu , Martinez Zachary , Hackett Kyal , Earnhart Christopher G. , Dorsey Nicole M. , Hopkins Svetlana A. , Natour Dalia S. , Davis Heather D. , Anderson Michael S. , Gainey Melicia R. , Cobb Ronald R.
Published: June 2022

The current global COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a public health crisis with more than 168 million cases reported globally and more than 4.5 million deaths at the time of writing. In addition to the direct impact of the disease, the economic impact has been significant as public health measures to contain or reduce the spread have led to country wide lockdowns resulting in near closure of many sectors of the economy. Antibodies are a principal determinant of the humoral immune response to COVID-19 infections and may have the potential to reduce disease and spread of the virus. The development of monoclonal antibodies (mAbs) represents a therapeutic option that can be produced at large quantity and high quality. In the present study, a mAb combination mixture therapy was investigated for its capability to specifically neutralize SARS-CoV-2. We demonstrate that each of the antibodies bind the spike protein and neutralize the virus, preventing it from infecting cells in anin vitrocell-based assay, including multiple viral variants that are currently circulating in the human population. In addition, we investigated the effects of two different mutations in the Fc portion (YTE and LALA) of the antibody on Fc effector function and the ability to alleviate potential antibody-dependent enhancement of disease. These data demonstrate the potential of a combination of two mAbs that target two different epitopes on the SARS-CoV2 spike protein to provide protection against SARS-CoV-2 infection in humans while extending serum half-life and preventing antibody-dependent enhancement of disease.