bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimization Rubbing Fastness in Lyocell and Silk Fabric Dyeing with Tinospora cordifolia using Box-Behnken Design and Citrus limon Extract with Potassium Aluminium Sulfate Mordants
Authors:   School of Design, Mody University of Science and Technology, Lakshmangarh, Rajasthan, India, Guru Ramratan , Rani Jyoti ,   School of Design, Mody University of Science and Technology, Lakshmangarh, Rajasthan, India
Published: September 2023

The demand for environmentally friendly natural dyes has risen significantly. This study currently aims to assess the rub-fastness properties of silk and lyocell fabrics that have been dyed using Tinospora cordifolia stem extracts. This dyeing process involves the utilization of both Citrus limon and potassium aluminium sulfate as mordants. To achieve this objective, we have employed the Box-Behnken experimental research design for sample preparation. Our investigation delves into the influence of various processing factors, encompassing dye concentration, time duration, and temperature, on the rubbing fastness attributes of lyocell and silk fabrics treated with Citrus limon extract and alum mordant. The dye, sourced through an aqueous extraction method from Tinospora cordifolia stems, is subsequently employed in dyeing silk and lyocell fabrics, followed by mordanting using the meta-mordanting technique. The assessment of rubbing fastness quality is conducted using the standard test method AATCC 8 for both fabric types. Our experimental findings unveil a notable similarity in rubbing properties between lyocell and silk fabrics dyed with Citrus limon and those treated with potassium aluminium sulfate mordant. Intriguingly, fabric samples treated with Citrus limon mordants exhibit marginally enhanced rubbing (2 to 3 G to 5 G) results when juxtaposed with their counterparts treated with potassium aluminium sulfate mordant. Throughout the experimental course, it becomes evident that both temperature (35 °C, 50 °C, 65 °C) and time (40, 55 and 70 min) exert a significant influence on the wet and dry rubbing fastness characteristics of both silk and lyocell fabrics. Notably, as dyeing time and temperature increase, there is a corresponding rise in fabric dye uptake.
STUDY OF METHODS OF CREATING SERVICE-ORIENTED SOFTWARE SYSTEMS IN AZURE
Authors: Makieiev Oleksii , Kravets Natalia
Published: September 2023

The modern development of service-oriented software systems is accompanied by the wide use of cloud technologies, which affect the competitiveness of companies and their systems, which provide opportunities to expand the client base thanks to the coverage of several regions of the city or country.

The advantage of cloud services is availability in any part of the world where there is an Internet connection. Cloud providers provide a large volume of services for various needs: such as hosting, deployment of containers, file storage, databases, etc.

In particular, all the most popular cloud providers offer several options for creating service-oriented software systems, including both standard technologies and proprietary developments. This paper compares the methods of creating service-oriented software systems based on the Azure cloud platform: Azure Container Apps, Azure Kubernete Service, and Azure Red Hat OpenShift. The subject area of technologies for the implementation of service-oriented application architecture is considered, and criteria for the analysis of methods for implementing applications with such an architecture are proposed. A software solution for comparing methods of creating service-oriented applications based on the Azure cloud platform was designed and developed. The developed software system provides an opportunity to rent scooters, bicycles and cars.

The purpose of the study is a comparative analysis of the methods of creating service-oriented software systems based on Azure services, and the subject of the study is a software solution implemented using these methods.

The purpose of this work will be the development of a software system that will provide an opportunity to rent scooters, bicycles and cars. Using this system, we will investigate the deployment of this system on certain services from Azure.

The results of this research on Azure services: Azure Container Apps, Azure Kubernete Service and Azure Red Hat OpenShift can be used when creating a new software system, when expanding an existing software system, when transferring software system components from other platforms to the Azure platform using these services.
HARMONISASI NILAI TUKAR MENUKAR PUPUK KANDANG DENGAN ALAT PERTERNAKAN DI NAGARI KOTO BARU SUNGAI TARAB DALAM PERPEKTIF FIQH MUAMALAH
Authors: Wahyuni Sri , Yunarti Sri
Published: September 2023

The subject of the study is the Exchange Rate of Manure Exchange for Livestock Equipment in Nagari Koto Baru Sungai Tarab from the Fiqh Muamalah Perspective. The purpose of this study is to identify and analyze the motives for the exchange of manure and livestock equipment in Nagari Koto Baru Sungai Tarab, as well as to determine people's perceptions related to the status of manure, to determine the value of the benefits of exchanging manure with livestock equipment in Nagari Koto Baru Sungai Tarab in the perspective of fiqh muamalah. The research used was field research which was descriptive and qualitative in nature. Data collection techniques were observation, interviews, and documentation. Data validity assurance technique with source triangulation. This study found results, first in terms of the motive for the implementation of the exchange of manure with livestock equipment in Nagari Koto Baru Sungai Tarab triggered by the farmer's need for manure for agriculture to support crop yields, thus encouraging farmers to obtain manure from livestock by exchanging the manure. with livestock. This exchange activity does not have a clear contract and there is no agreement regarding the amount and object of goods exchanged. Second, from the public's perception of manure, manure is an important requirement that is beneficial for agricultural land. The community has never traded manure because it is considered unclean to be traded. Third, in terms of the value of the exchange benefits of exchanging manure for livestock equipment, this is in accordance with Allah's commands in surah Al-Maidah verse 2 and An-Nisa verse 29 and on the muamalah principle regarding muamalah transactions that must be based on willingness, helping each other, and not eating up wealth. each other in a bad way.
KONTROVERSI PERSYARATAN PENDIDIKAN CALON ANGGOTA LEGISLATIF PADA PASAL 240 UNDANG-UNDANG NOMOR 7 TAHUN 2017 PRESPEKTIF FIQIH SIYASAH DUSTURIYYAH
Authors: Astin Ulfa , Maghfira Saadatul , Zainuddin Zainuddin , Khairina Khairina
Published: September 2023

This study examines the Educational Requirements for Legislative Member Candidates in Law Number 7 of 2017 from Fiqh Siyasah Dusturiyah Perspective. From this problem, the question arises: How is the conversion that has occurred to the educational requirements for legislative candidates according to Law Number 7 of 2017, and whether legislative candidates with high school graduates said to be experts to become people's representatives? The type of research used is library research using qualitative research methods, with descriptive analysis. The requirements for high school graduate legislative candidates in article 240 letter (e) of Law Number 7 of 2017 concerning Elections, that from members of the public, political observers, to legislative members themselves, there are pros and cons with the education requirements of legislative candidates who only graduate from high school which can be said to be not yet an expert or knowledgeable with limited education and the age of 21 is classified as a very young age and minimal experience
PENERAPAN PENDEKATAN KEADILAN RESTORASI UNTUK MENCEGAH PERCERAIAN DI NAGARI SARUASO
Authors: Andryan Aldi , Khairina Khairina , Efendi Roni
Published: September 2023

The main problem of this research is the application of the restoration justice approach to prevent divorce in Nagari Saruaso. The data obtained shows that from 2020-2022 there were 162 divorce cases in Nagari Saruaso, this is a cause for concern. So it takes thought and solutions to anticipate it. So this study aims to provide an alternative to restoring household relations through a Restorative Justice approach to prevent divorce. This type of research is Juridical Sociology with Qualitative Typology, where data obtained from the field is narrated, interpreted to provide answers to the research object. Primary data sources are ninik mamak, religious scholars, cadiak pandai, bundo kanduang and the wali nagari government. Secondary data sources from books, journals, and laws and documents from Wali Nagari. The results of the study revealed, firstly, based on efforts to apply the restoration justice approach to prevent divorce in Nagari Saruaso, it was carried out by involving all components into one forum, namely the involvement of ninik mamak, religious scholars, cadiak pandai and bundo kanduang to provide advice so that divorce does not occur and spouses husband and wife back in harmony. That the concept of applying the Restorative Justice approach is carried out by all the above components through Gondang Sayak and Gondang Kuali to prevent Divorce in Nagari Saruaso. Gondang Sayak is a peace process that only involves the closest family, then Gondang Kuali is an effort to reconcile husband and wife by involving all components such as ninik mamak, pious scholars, cadak smart, bundo kanduang. Second, the obstacles in applying the restoration justice approach based on the research results are several factors, namely; economic factors, educational factors, modernization factors, Domestic Violence (KDRT) factors
TINJAUAN FATWA DSN-MUI TERHADAP PENYITAAN BARANG JAMINAN PADA KSPPS AL-ANSHARI KOTA BUKITTINGGI
Authors: Iqbal Muhammad , Iska Syukri , Zulkifli Zulkifli , Khairina Khairina
Published: September 2023

The purpose of this study was to find out or explore the procedures for confiscating collateral carried out at KSPPS Al-Anshari, Bukitinggi City and to analyze the juridical redemption of collateral confiscation carried out by KSPPS Al-Anshari, Bukitinggi City. The research method used by the author is qualitative research using field research with data collection techniques through interviews and documentation. Primary data sources consist of KSPPS Al-Anshari managers and employees. The data processing carried out here is qualitative. The results of the research that the author has done, First, the guarantee in the murabahah contract at KSPPS Al-Anshari is using property as collateral for debt, in practice the collateral in the financing is handed over to KSPPS Al-Anshari, but KSPPS Al-Anshari will give time leeway to customers to settle KSPPS Al-Anshari's debts, secondly regarding confiscated goods that are not in accordance with the fatwa because in the fatwa the confiscated goods should have been auctioned but the KSPPS Al-Anshari did not do so by making the confiscated goods an office operation. Islamic financing conditions in Indonesia in general are the Syafi'i (syafiiyyah) and Hambali (hanabillah) schools, that is, when the party responsible for the debt cannot pay it off, the debt is paid using assets or goods used as collateral or assets from the sale of assets used as collateral the. The benefits of collateral cannot be used as collateral (al-marhun), because the use of collateral is used up and damaged, therefore it cannot be used as collateral.
PERALIHAN HARTA PUSAKA TINGGI MENURUT HUKUM ADAT DAN HUKUM ISLAM (Studi Kasus di Jorong Nan IX Nagari Salimpaung)
Authors: Ridwan Arizon , Zulkifli Zulkifli , Effendi Amri
Published: September 2023

This study examines the transfer of high inheritance according to customary law and Islamic law in Jorong Nan IX Nagari Salimpaung. Using a qualitative approach, this study found that the factors that caused the transfer of high inheritance in Jorong Nan IX Nagari Salimpaung were members of the clan who wanted to build a house on high inheritance; there is one people whose descendants are almost extinct; clan members fight over high heirlooms; Members of the clan do not want to rotate the high inheritance until problems arise, even to the point of being physically involved in fighting over it. According to customary law, the transfer of high inheritance in Jorong Nan IX Nagari Salimpaung is considered wrong because it violates existing customary rules. Meanwhile, in terms of Islamic law, the transfer of high heirloom assets by dividing them into private property for members of the clan and being taken over into the private property of Tungganai which occurred in Jorong Nan IX Nagari Salimpaung is considered permissible. The actions of a Tungganai include Istihsan bi al-Maslahah, namely taking advantage and rejecting harm.
ARGUMENTASI YURIDIS PEMBERLAKUAN HUKUM KEPERDATAAN ISLAM DI INDONESIA
Authors: Natardi Natardi , Witro Doli
Published: September 2023

The configuration of law enforcement in the religious courts has simply been implemented. When he has to deal with the law as a product of politics and the law as a product of fiqih studies, the choice is quite delegative. On the one hand, it meets the demands of empirical reality from the institutionalized wheel of life, while on the other hand, it goes hand in hand with the signalization text of the muqasid sharia. Although the work of the scholars as stated in the Compilation of Islamic Law (KHI) can be said to be a monumental work, it is still an outline that is impossible to complete in deciding every case faced. Therefore, this article discusses the implementation of Islamic civil law in Indonesia which is considered very appropriate to be applied to Muslims, without disturbing the national legal system and disturbing other people. This article aims to highlight the importance of implementing Islamic civil law in Indonesia with juridical arguments. The results of the analysis show that juridically in the current reform era, the implementation of Islamic civil law in Indonesia has shown a bright spot where many products of legislation related to it have been produced and practiced by Muslims. Based on MPR RI Decree Number IV/MPR/1999 concerning GBHN 1999-2004, Chapter IV, letter A, point 2, the implementation of Islamic civil law in Indonesia is the state’s obligation to uphold the rule of law (law enforcement). In practicing Islamic civil law by Muslims in Indonesia, there are still many obstacles and obstacles. Even though the rule of law has become a state decree, some individuals are not happy with Islam using this issue as one of their political motives.
RELASI PRANATA LINGKUNGAN DENGAN LINGKUNGAN HIDUP PERSPEKTIF HUKUM ISLAM
Authors: Nurdiansyah Rifqi , Yulisa Ike , Witro Doli , Syamsarina Syamsarina , Lestari Zaenab Tri
Published: September 2023

Every human being is a caliph whose role is to provide prosperity for other humans and care for and maintain the environment they inhabit. Islamic teachings have regulated it; so that the principles of life as the main tasks and functions of humans must be following Islamic instructions. This article discusses the relationship between environmental institutions, the environment, and Islamic law and initiates an excellent social life in the view of Islam. This article aims to highlight the relationship between environmental institutions, the environment, and Islamic law. This article uses qualitative research methods that are literature review. The data in the articles are obtained from library materials such as books, articles, etc. related to environmental institutions, the environment, and Islamic law. The data analysis technique used in this article is the qualitative data analysis technique of Miles et al. namely data condensation, data presentation, and drawing conclusions. The results of the analysis show that environmental institutions are closely related to Islamic law, namely that Islam has given rules and assignments to humans to become caliphs on earth to manage nature as well as possible, in accordance with the rules that have been explained in the Koran and the rules regarding nature or the environment that made by humans themselves without violating what has been determined by God. Preserving the environment can be done by empowering as best as possible, the full environmental empowerment system in Islam that emphasizes the public benefit.
PERATURAN DAERAH NO 7 TAHUN 2018 TENTANG NAGARI PERIHAL KERAPATAN ADAT NAGARI PRESPEKTIF SIYASAH DUSTURIYAH
Authors: Jefry Jefry , Emrizal Emrizal , Putri Siska Elasta
Published: September 2023

This article discusses the background of the birth of Regional Regulation Number 7 of 2018 concerning Nagari regarding Kerapatan Adat Nagari (KAN), duties and functions of Kerapatan Adat Nagari (KAN), and Fiqh Review of Siyasah Duturiyah on Regional Regulation No 7 of 2018 concerning Nagari regarding KAN. This research is a library research method. This study uses a normative legal research typology, namely examining legislation/theories and literature review of secondary data relating to the background of the birth of Regional Regulation No. 7 of 2018 concerning Nagari regarding KAN and a review of Fiqh Siyasah Duturiyah on Regional Regulation No. 7 the Year 2018. The results of this study conclude that the birth of the Regional Regulation has been initiated in Regional Regulation No. 2 of 2007 but has not covered all those related to the parts of the KAN. The issuance of Regional Regulation No. 7 of 2018 reaffirms the parts of the KAN which include Niniak Mamak, Alim Ulama, Cadiak pandai, Bundo kanduang, and Parik paga Nagari. Thus, Regional Regulation No. 7 of 2018 concerning Nagari provides an opportunity for regions to form villages (government) based on customs according to the rights of origin of the local customary law community unit. The view of Siyasah Duturiyah fiqh where the duties and functions of the KAN do not deviate from the Fiqh rules that have been set by Regional Regulations.
TINJAUAN FIQH MUAMALAH TERHADAP PERJANJIAN CAGAK HUTANG
Authors: Riani Ativa , Renie Elsy
Published: September 2023

The purpose of the discussion of this article is to find out the use of cagak hutang and a review of fiqh muamalah in Nagari Simpang Sugiran, Guguak District, Lima Puluh Kota Regency. The type of research that the author uses is field research, namely field research that is qualitative in nature. Sampling technique the author uses a snowball sampling technique. The data collection technique that the author uses is interviews, documentation and observations related to the agreement on cagak hutang in Nagari Simpang Sugiran, Guguak District, Lima Puluh Kota Regency. From the research that the author has done, it shows that the debt reserve in Nagari Simpang Sugiran, Guguak District. People use cagak hutang in the form of living (moving) goods and inanimate (immovable) goods. Cagak hutang is used because they have no other choice, what is used as cagak hutang is the only thing that can be given by the debtor as collateral or foreclosure on his debt. In practice, most of the use of forked debt is in the control of the murtahin, he enjoys the results and uses the benefits of debt fork for his own benefit. The implementation of cagak hutang in Nagari Simpang Sugiran, Guguak District, Lima Puluh Kota Regency has become a habit and has raised social aspects in society that can overcome economic problems. This activity has become an alternative for the community to avoid hunger and poverty because it has helped the community's economy. In Islam, habits that have been carried out continuously and repeatedly in a society can be used as a source of law. However, in practice, the habit of using cagak hutang in Nagari Simpang Sugiran, Guguak District, Lima Puluh Kota Regency is included in a fasid habit or is contrary to the arguments of the Qur'an and Hadith.
TAUKIL WALI NIKAH KEPADA PENGHULU DI DESA PARIT KEBUMEN KECAMATAN RUPAT KABUPATEN BENGKALIS
Authors: Zakiyah Aida Ummi , Caniago Sulastri , Alfiander Dodon
Published: September 2023

Studi ini mengkaji tentang kontroversi taukil wali nikah kepada penghulu di Desa Parit Kebumen Kecamatan Rupat Kabupaten Bengkalis, permasalahan tersebut muncul pertanyaan: 1.Alasan masyarakat mentaukilkan wali nikah kepada penghulu, 2. Bagaimana analisis hukum keluarga Islam terhadap Fenomena taukil wali nikah di desa parit kebumen. Penelitian ini merupakan penelitian lapangan. data dan informasi yang diperoleh langsung dari responden dalam kasus taukil wali nikah di Desa Parit Kebumen, dengan metode pendekatan deduktif. Dan dianalisis dengan cara deduktif, penelitian ini menemukan hasil praktek taukil wali nikah di Desa Parit Kebumen bertentangan dengan konsep perwalian yang telah ditetapkan dalam hukum keluarga Islam.
Zero Trust Security Model for Enterprise Networks
Authors: M. Habash Rania , Khalel Mahmood
Published: September 2023

Zero Trust (ZT) is security model and follow the concept of ânever trust, always verifyâ. ZT require to strict identity verification for devise and clients trying to access recourses on private networks regardless of whether they are sitting within or outside the networks. As opposed to perimeter-based architecture, which makes the assumption that all internal network parties are trusted and all external network parties are untrusted. In enterprise network the internal network parties is automatically seen as trusted entities granting them access to network resources. The insider threat actor has been successful in exploiting their access. So that, enterprise networks become more exposed to inside and outside threads. As a result, we need to add the zero-trust principle to the enterprise network to protect it from the inside. In this paper, the ZT model, is assumed inside the militarized zone. There may be a threat to theÂ sensitive data. Any internal company network users cannot manipulation on his computer without permission from the administrator this is done by the groupÂ policies that have been implemented in ZT. This model has been shown to be quite effective in protecting the sensitive data against unauthorized access and also the manipulation by the insider user. Following that, an attack originating from inside ofÂ the network was launched against the enterprise and zero trust network. In the enterprise network, the network was effectively attacked, and the attack’s validity was also increased to fully penetrate the enterprise. The attack did not succeed in the zero-trust network because the attacker cannot pass the User Account Control (UAC) to gain the NT authority.
Edge-to-Cloud Adaptive Offloading for Next-Generation Services
Authors: M. Al-Tuhafi Ola , H. Al-Hemiary Emad
Published: September 2023

Due to the continuous growth of user traffic demands, there is a need to cope with the increased processing and storage requirements. The increased number of connected end devices causes a problem with carrying the generated loads efficiently. Edge and cloud computing and storage are real solutions to overcome the limitations of end devices on many prospective including computation capabilities, storage capabilities, and power consumption. Terminal devices offload their overflow tasks to the cloud for processing, analysis, and storage. This paper aims to improve computation offloading from edge nodes to the cloud in Internet of Things networks by making efficient decisions using an adaptive offloading algorithm. Offloading is controlled by a processing time offloading threshold value, which is determined automatically by edge nodes based on their traffic intensity and adaptively increased or decreased in loads. The proposed algorithm had been programmed and simulated; experimental evaluations show that the proposed adaptive offloading algorithm minimizes the edge mean response time by up to 58% and the cloud mean response time by up to 25% compared to the existing fixed, pre-defined offloading threshold value.
TgF344-AD Rat Model of Alzheimer’s Disease: Spatial Disorientation and Asymmetry in Hemispheric Neurodegeneration
Authors: Sagalajev Boriss , Lennartz Lina , Vieth Lukas , Gunawan Cecilia Tasya , Neumaier Bernd , Drzezga Alexander , Visser-Vandewalle Veerle , Endepols Heike , Sesia Thibaut
Published: September 2023

Background:

The TgF344-AD ratline represents a transgenic animal model of Alzheimer’s disease. We previously reported spatial memory impairment in TgF344-AD rats, yet the underlying mechanism remained unknown. We, therefore, set out to determine if spatial memory impairment in TgF344-AD rats is attributed to spatial disorientation. Also, we aimed to investigate whether TgF344-AD rats exhibit signs of asymmetry in hemispheric neurodegeneration, similar to what is reported in spatially disoriented AD patients. Finally, we sought to examine how spatial disorientation correlates with working memory performance.

Methods:

TgF344-AD rats were divided into two groups balanced by sex and genotype. The first group underwent the delayed match-to-sample (DMS) task for the assessment of spatial orientation and working memory, while the second group underwent positron emission tomography (PET) for the assessment of glucose metabolism and microglial activity as in-vivo markers of neurodegeneration. Rats were 13 months old during DMS training and 14–16 months old during DMS testing and PET.

Results:

In the DMS task, TgF344-AD rats were more likely than their wild-type littermates to display strong preference for one of the two levers, preventing working memory testing. Rats without lever-preference showed similar working memory, regardless of their genotype. PET revealed hemispherically asymmetric clusters of increased microglial activity and altered glucose metabolism in TgF344-AD rats.

Conclusions:

TgF344-AD rats display spatial disorientation and hemispherically asymmetrical neurodegeneration, suggesting a potential causal relationship consistent with past clinical research. In rats with preserved spatial orientation, working memory remains intact.
Normative Data for Single-Letter Controlled Oral Word Association Test in Older White Australians and Americans, African-Americans, and Hispanic/Latinos
Authors: Zhou Aoshuang , Britt Carlene , Woods Robyn L. , Orchard Suzanne G. , Murray Anne M. , Shah Raj C. , Rajan Ramesh , McNeil John J. , Chong Trevor T.-J. , Storey Elsdon , Ryan Joanne
Published: September 2023

Background:

The Controlled Oral Word Association Test (COWAT) is a commonly used measure of verbal fluency. While a normal decline in verbal fluency occurs in late adulthood, significant impairments may indicate brain injury or diseases such as Alzheimer’s disease. Normative data is essential to identify when test performance falls below expected levels based on age, gender, and education level.

Objective:

This study aimed to establish normative performance data on single-letter COWAT for older community-dwelling adults.

Methods:

Over 19,000 healthy men and women, without a diagnosis of dementia or a Modified Mini-Mental State Examination score below 77/100, were recruited for the ASPREE trial. Neuropsychological assessments, including the COWAT with letter F, were administered at study entry.

Results:

Median participant age was 75 years (range 65–98), with 56.5% being women. The majority of participants had 9–11 years of education in Australia and over 12 years in the U.S. The COWAT performance varied across ethno-racial groups and normative data were thus presented separately for 16,335 white Australians, 1,084 white Americans, 896 African-Americans, and 316 Hispanic/Latinos. Women generally outperformed men in the COWAT, except for Hispanic/Latinos. Higher education levels consistently correlated with better COWAT performance across all groups, while the negative association with age was weaker.

Conclusions:

This study provides comprehensive normative data for the COWAT stratified by ethno-racial groups in Australia and the U.S., considering age, gender, and education level. These norms can serve as reference standards for screening cognitive impairments in older adults in both clinical and research settings.
Advancing Clinical Trial Design for Non-Muscle Invasive Bladder Cancer
Authors: Chang Elaine , Hahn Noah M. , Lerner Seth P. , Fallah Jaleh , Agrawal Sundeep , Kamat Ashish M. , Bhatnagar Vishal , Svatek Robert S. , Jaigirdar Adnan A. , Bross Peter , Shore Neal , Kates Max , Sachse Karen , Brewer Jamie R. , O’Donnell Michael A. , Steinberg Gary D. , Viviano Charles J. , Bloomquist Erik , Ribal Maria J. , Galsky Matthew D. , Oliver Richard , Black Peter C. , Al-Ahmadie Hikmat , Brothers Kenneth , Pohar Kamal , Dinney Colin P. , Feng Zhou , Downs Tracy M. , Porten Sima P. , Smith Angela B. , Bangs Rick , Psutka Sarah P. , Agarwal Neeraj , Amiri-Kordestani Laleh , Suzman Daniel L. , Pazdur Richard , Kluetz Paul G. , Weinstock Chana
Published: September 2023

BACKGROUND:

Despite recent drug development for non-muscle invasive bladder cancer (NMIBC), few therapies have been approved by the US Food and Drug Administration (FDA), and there remains an unmet clinical need. Bacillus Calmette-Guerin (BCG) supply issues underscore the importance of developing safe and effective drugs for NMIBC.

OBJECTIVE:

On November 18–19, 2021, the FDA held a public virtual workshop to discuss NMIBC research needs and potential trial designs for future development of effective therapies.

METHODS:

Representatives from various disciplines including urologists, oncologists, pathologists, statisticians, basic and translational scientists, and the patient advocacy community participated. The workshop format included invited lectures, panel discussions, and opportunity for audience discussion and comment.

RESULTS:

In a pre-workshop survey, 92% of urologists surveyed considered the development of alternatives to BCG as a high drug development priority for BCG-naïve high-risk patients. Key topics discussed included definitions of disease states; trial design for BCG-naïve NMIBC, BCG-unresponsive carcinoma in situ, and BCG-unresponsive papillary carcinoma; strengths and limitations of single-arm trial designs; assessing patient-reported outcomes; and considerations for assessing avoidance of cystectomy as an efficacy measure.

CONCLUSIONS:

The workshop discussed several important opportunities for trial design refinement in NMIBC. FDA encourages sponsors to meet with the appropriate review division to discuss trial design proposals for NMIBC early in drug development.
The Multifaceted Effects of Flavonoids on Neuroplasticity
Authors: Rivi Veronica , Batabyal Anuradha , Lukowiak Ken
Published: September 2023

There has been a significant increase in the incidence of multiple neurodegenerative and terminal diseases in the human population with life expectancy increasing in the current times. This highlights the urgent need for a more comprehensive understanding of how different aspects of lifestyle, in particular diet, may affect neural functioning and consequently cognitive performance as well as in enhancing overall health. Flavonoids, found in a variety of fruits, vegetables, and derived beverages, provide a new avenue of research that shows a promising influence on different aspects of brain function. However, despite the promising evidence, most bioactive compounds lack strong clinical research efficacy. In the current scoping review, we highlight the effects of Flavonoids on cognition and neural plasticity across vertebrates and invertebrates with special emphasis on the studies conducted in the pond snail, Lymnaea stagnalis, which has emerged to be a functionally dynamic model for studies on learning and memory. In conclusion, we suggest future research directions and discuss the social, cultural, and ethnic dependencies of bioactive compounds that influence how these compounds are used and accepted globally. Bridging the gap between preclinical and clinical studies about the effects of bioactive natural compounds on brain health will surely lead to lifestyle choices such as dietary Flavonoids being used complementarily rather than as replacements to classical drugs bringing about a healthier future.
Effects of digital education on human resource development
Authors: Siyi Chen , Yu Qi , Al-Samawi Amjad
Published: September 2023

BACKGROUND: The process of Digitizing Education has experienced significant growth in recent times, particularly under the background of COVID-19. Enterprises have ushered in new transformation needs, and digital education is the foundation of digital management. OBJECTIVE: Based on the entropy value method, it indicates the prominent factors affecting the progress of digital education. Give suggestions on human resource development and educational digitization. METHODS: Using panel data for 32 countries from 2015 to 2022. This study integrates digital technology, digital education economic environment, digital skills, and information literacy to establish an evaluation index system for assessing the level of digital education. RESULTS: The entropy value indicates that digital technology holds a prominent role in affecting the progress of human resources. Well-developed digital education can promote human resource management. CONCLUSIONS: The proposed digital technology has an important impact on the development of digital education and human resource management. Enterprises should pay more attention to the introduction of high-quality information talents to realize the digital transformation of enterprise management. The results open up several avenues for digital education in human resource management in future research.
An Alternative View of Familial Alzheimer’s Disease Genetics
Authors: Lardelli Michael
Published: September 2023

Probabilistic and parsimony-based arguments regarding available genetics data are used to propose that Hardy and Higgin’s amyloid cascade hypothesis is valid but is commonly interpreted too narrowly to support, incorrectly, the primacy of the amyloid-β peptide (Aβ) in driving Alzheimer’s disease pathogenesis. Instead, increased activity of the βCTF (C99) fragment of AβPP is the critical pathogenic determinant altered by mutations in the APP gene. This model is consistent with the regulation of APP mRNA translation via its 5’ iron responsive element. Similar arguments support that the pathological effects of familial Alzheimer’s disease mutations in the genes PSEN1 and PSEN2 are not exerted directly via changes in AβPP cleavage to produce different ratios of Aβ length. Rather, these mutations likely act through effects on presenilin holoprotein conformation and function, and possibly the formation and stability of multimers of presenilin holoprotein and/or of the γ-secretase complex. All fAD mutations in APP, PSEN1, and PSEN2 likely find unity of pathological mechanism in their actions on endolysosomal acidification and mitochondrial function, with detrimental effects on iron homeostasis and promotion of “pseudo-hypoxia” being of central importance. Aβ production is enhanced and distorted by oxidative stress and accumulates due to decreased lysosomal function. It may act as a disease-associated molecular pattern enhancing oxidative stress-driven neuroinflammation during the cognitive phase of the disease.
Association Between Olfactory Test Data with Multiple Levels of Odor Intensity and Suspected Cognitive Impairment: A Cross-Sectional Study
Authors: Sato Shuichi , Imaeda Takao , Mugikura Shunji , Mori Naoko , Takanashi Masaki , Hayakawa Kazumi , Saito Tomo , Taira Makiko , Narita Akira , Kogure Mana , Chiba Ippei , Hatanaka Rieko , Nakaya Kumi , Kanno Ikumi , Ishiwata Ryosuke , Nakamura Tomohiro , Motoike Ikuko N. , Nakaya Naoki , Koshiba Seizo , Kinoshita Kengo , Kuriyama Shinichi , Ogishima Soichi , Nagami Fuji , Fuse Nobuo , Hozawa Atsushi
Published: September 2023

Background: Olfactory function decline has recently been reported to be associated with a risk of cognitive impairment. Few population-based studies have included younger adults when examining the association between olfactory test data with multiple odor intensities and suspected cognitive impairment. Objective: We investigated the association between high-resolution olfactory test data with fewer odors and suspected cognitive impairments. We also examined the differences between older and younger adults in this association. Methods: The Japanese version of the Montreal Cognitive Assessment (MoCA-J) was administered to 1,450 participants, with three odor-intensity-level olfactometry using six different odors. Logistic regressions to discriminate suspected cognitive impairment were conducted to examine the association, adjusted for age, sex, education duration, and smoking history. Data were collected from the Program by Tohoku University Tohoku Medical Megabank Organization, with an additional olfactory test conducted between 2019 and 2021. Results: We generally observed that the lower the limit of distinguishable odor intensity was, the higher the MoCA-J score was. The combination of spearmint and stuffy socks contributed most to the distinction between suspected and unsuspected cognitive impairment. Furthermore, the association was significant in women aged 60–74 years (adjusted odds ratio 0.881, 95% confidence interval [0.790, 0.983], p = 0.024). Conclusions: The results indicate an association between the limit of distinguishable odor intensity and cognitive function. The olfactory test with multiple odor intensity levels using fewer odors may be applicable for the early detection of mild cognitive impairment, especially in older women aged 60–74 years.
Long-Term Safety, Tolerability, and Efficacy of a Transdermal Donepezil Patch in Patients with Severe Alzheimer’s Disease
Authors: Nakamura Yu , Narita Kohei , Kim Rei , Nishiyama Kenichi , Kikuchi Takashi , Ishikawa Ichiro , Aoki Hiroshi
Published: September 2023

Background: Oral formulations are not suitable for demented patients with dysphagia, those refuse to take tablets, or those with drug compliance problem. However, only oral formulations of donepezil hydrochloride are approved for the treatment of severe Alzheimer’s disease in Japan. Objective: To evaluate the safety, tolerability, and efficacy of long-term application of a 55.0 mg transdermal donepezil patch switched from a 10 mg oral donepezil hydrochloride tablet, for the treatment of patients with severe Alzheimer’s disease. Methods: A 52-week, multicenter, open-label, uncontrolled (phase III) study (jRCT2080224612) was conducted in Japan between April 2019 and August 2021. A 10 mg donepezil hydrochloride tablet was administered once a day for four weeks; a 55.0 mg donepezil patch was then applied once a day for 52 weeks in patients with severe Alzheimer’s disease. Results: Of 64 patients received the patch, 45 completed the 52-week period. The overall discontinuation rate was 29.7% (19/64). Among the 19 patients discontinued, six patients 9.4% (6/64) discontinued due to adverse events. The incidence of adverse events at application sites was 67.2% (43/64), including application site erythema 29.7% (19/64), application site pruritus 25.0% (16/64), and contact dermatitis 20.3% (13/64). Adverse events were mild and did not increase with time, demonstrating a favorable safety profile. Cognitive function, measured using the Mini-Mental State Examination, was maintained for up to 24 weeks. Conclusions: Adverse events were considered manageable in a clinical setting. The long-term application of a 55.0 mg donepezil patch once a day was feasible treatment in patients with severe Alzheimer’s disease.
SHMAD: A Smart Health Care System to Monitor Alzheimer’s Disease Patients
Authors: Ziyad Shabana R. , Altulyan May , Alharbi Meshal
Published: September 2023

Background: In the digital era monitoring the patient’s health status is more effective and consistent with smart healthcare systems. Smart health care facilitates secure and reliable maintenance of patient data. Sensors, machine learning algorithms, Internet of things, and wireless technology has led to the development of Artificial Intelligence-driven Internet of Things models. Objective: This research study proposes an Artificial Intelligence driven Internet of Things model to monitor Alzheimer’s disease patient condition. The proposed Smart health care system to monitor and alert caregivers of Alzheimer’s disease patients includes different modules to monitor the health parameters of the patients. This study implements the detection of fall episodes using an artificial intelligence model in Python. Methods: The fall detection model is implemented with data acquired from the IMU open dataset. The ensemble machine learning algorithm AdaBoost performs classification of the fall episode and daily life activity using the feature set of each data sample. The common machine learning classification algorithms are compared for their performance on the IMU fall dataset. Results: AdaBoost ensemble classifier exhibits high performance compared to the other machine learning algorithms. The AdaBoost classifier shows 100% accuracy for the IMU dataset. This high accuracy is achieved as multiple weak learners in the ensemble model classify the data samples in the test data accurately. Conclusions: This study proposes a smart healthcare system for monitoring Alzheimer’s disease patients. The proposed model can alert the caregiver in case of fall detection via mobile applications installed in smart devices.
Detecting Anosognosia from the Prodromal Stage of Alzheimer’s Disease
Authors: Guieysse Thomas , Lamothe Roxane , Houot Marion , Razafimahatratra Solofo , Medani Takfarinas , Lejeune François-Xavier , Dreyfus Gérard , Klarsfeld André , Pantazis Dimitrios , Koechlin Etienne , Andrade Katia
Published: September 2023

Background: Though not originally developed for this purpose, the Healthy Aging Brain Care Monitor (HABC-M) seems a valuable instrument for assessing anosognosia in Alzheimer’s disease (AD). Objectives: Our study aimed at 1) investigating the validity of the HABC-M (31 items), and its cognitive, psychological, and functional subscales, in discriminating AD patients from controls; 2) exploring whether the HABC-M discrepancy scores between the self-reports of patients/controls in these different domains and the respective ratings provided by their caregivers/informants correlate with an online measure of self-awareness; 3) determining whether the caregiver burden level, also derived from the HABC-M, could add additional support for detecting anosognosia. Methods: The HABC-M was administered to 30 AD patients and 30 healthy controls, and to their caregivers/informants. A measure of online awareness was established from subjects’ estimation of their performances in a computerized experiment. Results: The HABC-M discrepancy scores distinguished AD patients from controls. The cognitive subscale discriminated the two groups from the prodromal AD stage, with an AUC of 0.88 [95% CI: 0.78;0.97]. Adding the caregiver burden level raised it to 0.94 [0.86;0.99]. Significant correlations between the HABC-M and online discrepancy scores were observed in the patients group, providing convergent validity of these methods. Conclusions: The cognitive HABC-M (six items) can detect anosognosia across the AD spectrum. The caregiver burden (four items) may corroborate the suspicion of anosognosia. The short-hybrid scale, built from these 10 items instead of the usual 31, showed the highest sensitivity for detecting anosognosia from the prodromal AD stage, which may further help with timely diagnosis.
Malignant Brain Aging: The Formidable Link Between Dysregulated Signaling Through Mechanistic Target of Rapamycin Pathways and Alzheimer’s Disease (Type 3 Diabetes)
Authors: de la Monte Suzanne M.
Published: September 2023

Malignant brain aging corresponds to accelerated age-related declines in brain functions eventually derailing the self-sustaining forces that govern independent vitality. Malignant brain aging establishes the path toward dementing neurodegeneration, including Alzheimer’s disease (AD). The full spectrum of AD includes progressive dysfunction of neurons, oligodendrocytes, astrocytes, microglia, and the microvascular systems, and is mechanistically driven by insulin and insulin-like growth factor (IGF) deficiencies and resistances with accompanying deficits in energy balance, increased cellular stress, inflammation, and impaired perfusion, mimicking the core features of diabetes mellitus. The underlying pathophysiological derangements result in mitochondrial dysfunction, abnormal protein aggregation, increased oxidative and endoplasmic reticulum stress, aberrant autophagy, and abnormal post-translational modification of proteins, all of which are signature features of both AD and dysregulated insulin/IGF-1-mechanistic target of rapamycin (mTOR) signaling. This article connects the dots from benign to malignant aging to neurodegeneration by reviewing the salient pathologies associated with initially adaptive and later dysfunctional mTOR signaling in the brain. Effective therapeutic and preventive measures must be two-pronged and designed to 1) address complex and shifting impairments in mTOR signaling through the re-purpose of effective anti-diabetes therapeutics that target the brain, and 2) minimize the impact of extrinsic mediators of benign to malignant aging transitions, e.g., inflammatory states, obesity, systemic insulin resistance diseases, and repeated bouts of general anesthesia, by minimizing exposures or implementing neuroprotective measures.
Deletion of the Homocysteine Thiolactone Detoxifying Enzyme Bleomycin Hydrolase, in Mice, Causes Memory and Neurological Deficits and Worsens Alzheimer’s Disease-Related Behavioral and Biochemical Traits in the 5xFAD Model of Alzheimer’s Disease
Authors: Witucki Łukasz , Borowczyk Kamila , Suszyńska-Zajczyk Joanna , Warzych Ewelina , Pawlak Piotr , Jakubowski Hieronim
Published: September 2023

Background: Bleomycin hydrolase (BLMH), a homocysteine (Hcy)-thiolactone detoxifying enzyme, is attenuated in Alzheimer’s disease (AD) brains. Blmh loss causes astrogliosis in mice while the loss of histone demethylase Phf8, which controls mTOR signaling, causes neuropathy in mice and humans. Objective: To examine how Blmh gene deletion affects the Phf8/H4K20me1/mTOR/autophagy pathway, amyloid-β (Aβ) accumulation, and cognitive/neuromotor performance in mice. Methods: We generated a new mouse model of AD, the Blmh-/-5xFAD mouse. Behavioral assessments were conducted by cognitive/neuromotor testing. Blmh and Phf8 genes were silenced in mouse neuroblastoma N2a-APPswe cells by RNA interference. mTOR- and autophagy-related proteins, and AβPP were quantified by western blotting and the corresponding mRNAs by RT-qPCR. Aβ was quantified by western blotting (brains) and by confocal microscopy (cells). Results: Behavioral testing showed cognitive/neuromotor deficits in Blmh-/- and Blmh-/-5xFAD mice. Phf8 was transcriptionally downregulated in Blmh-/- and Blmh-/-5xFAD brains. H4K20me1, mTOR, phospho-mTOR, and AβPP were upregulated while autophagy markers Becn1, Atg5, and Atg7 were downregulated in Blmh-/- and Blmh-/-5xFAD brains. Aβ was elevated in Blmh-/-5xFAD brains. These biochemical changes were recapitulated in Blmh-silenced N2a-APPswe cells, which also showed increased H4K20me1-mTOR promoter binding and impaired autophagy flux (Lc3-I, Lc3-II, p62). Phf8-silencing or treatments with Hcy-thiolactone or N-Hcy-protein, metabolites elevated in Blmh-/- mice, induced biochemical changes in N2a-APPswe cells like those induced by the Blmh-silencing. However, Phf8-silencing elevated Aβ without affecting AβPP. Conclusions: Our findings show that Blmh interacts with AβPP and the Phf8/H4K20me1/mTOR/autophagy pathway, and that disruption of those interactions causes Aβ accumulation and cognitive/neuromotor deficits.