bluuebunny/crossref_metadata_2025 huggingface dataset:
Inosine triphosphate pyrophosphatase: A guardian of the cellular nucleotide pool and potential mediator of RNA function
Authors: Schroader Jacob H. , Handley Mark T. , Reddy Kaalak
Published: April 2023

Inosine triphosphate pyrophosphatase (ITPase), encoded by the ITPA gene in humans, is an important enzyme that preserves the integrity of cellular nucleotide pools by hydrolyzing the noncanonical purine nucleotides (deoxy)inosine and (deoxy)xanthosine triphosphate into monophosphates and pyrophosphate. Variants in the ITPA gene can cause partial or complete ITPase deficiency. Partial ITPase deficiency is benign but clinically relevant as it is linked to altered drug responses. Complete ITPase deficiency causes a severe multisystem disorder characterized by seizures and encephalopathy that is frequently associated with fatal infantile dilated cardiomyopathy. In the absence of ITPase activity, its substrate noncanonical nucleotides have the potential to accumulate and become aberrantly incorporated into DNA and RNA. Hence, the pathophysiology of ITPase deficiency could arise from metabolic imbalance, altered DNA or RNA regulation, or from a combination of these factors. Here, we review the known functions of ITPase and highlight recent work aimed at determining the molecular basis for ITPA‐associated pathogenesis which provides evidence for RNA dysfunction.

This article is categorized under:

RNA in Disease and Development > RNA in Disease

RNA in Disease and Development > RNA in Development
Training and capacity building of young water professionals—role of an innovative and transformative program for sustainable water futures
Authors: Maheshwari Basant
Published: April 2023

Water management has become quite a complex task because of population pressure, climate change, and urbanization. Future young water professionals (YWPs) need to be capable of working with real‐world situations, and they need to be trained suitably so that they can effectively communicate with decision‐makers and enable innovative ideas to be adopted in policy development and actions on the ground. To get the ideas converted into actions, we need YWPs who are well‐trained not only in water science and engineering but also in social, economic, governance, policy, and other related aspects. Overall, well‐designed transdisciplinary training can help YWPs to bring new thinking and leadership in their workplace, including water governance, stakeholder involvement, critical thinking, problem analysis, and effective communication in various situations. Furthermore, such training can help YWPs develop their vision and capacity for more effective planning, design, implementation, and management of water projects and initiatives. As part of their training, YWPs need to develop their competencies, namely, problem‐solving, transdisciplinary and systemic thinking, and effective communication, through working on real‐world projects of selected clients. The next issue of World Water Policy Journal will be a Special Issue focusing on the work of YWPs involved in two initiatives in South Asia. Activities through the Australia–India Water Centre Program for capacity building for Indian YWPs in Sustainable Water Futures will be one of the initiatives presented.
Past, present, and future of water governance—a reflective walk on advances and failures since 1977
Authors: Neto Susana
Published: April 2023

There has been a plethora of world water conferences, workshops, and other initiatives over the last four decades. Initially, the focus was on localized water and environmental problems. As environmental issues began to cross borders and became more complex, a new phase of international initiatives emerged, which incorporated environmental objectives with other water related ones. More recently, a focus on international water initiatives has been on improving water governance and transboundary cooperation. The first United Nations conference specifically devoted to water was held in the city of Mar del Plata in Argentina (1977). The increased demand for water across the planet, the degrading anthropic actions, and the development models that exclude the more vulnerable communities, indicate the beginning of a crisis that should be addressed by an integrated water resources management approach. Thus, the Mar del Plata Action Plan was drawn up. Forty‐six years after, another high‐level UN Conference took place in New York. From 22 to 24 last March this year, governments, organizations, and stakeholders from all over the world got together under the major objective to not miss the opportunity to chart a path to water security for the future.
The Widening Road: Constructions of Gay Japanese Men on YouTube
Authors: Furukawa Gavin
Published: April 2023

This chapter examines the discourses found in Japanese gay vlog entries to see how such streaming contents are used as sites of contact between gays and straights in Japan. Early internet sites created safe public spaces for sexual minority members to meet and socialize where straights previously seldom had access or were expressly unwelcome. Using a collection of coming out and Q and A videos, the chapter will also explore the use of vlogging discourse for social change in Japan. More recently, sites like YouTube have created new contact spaces where straights are welcomed and can interact with gay content creators more directly. This chapter analyzes the ways in which Japanese gay men construct themselves as well as other gay and straight people around them in these videos. Utilizing membership categorization and indexicality the analysis will show how notions of family and gayness along with associated bound predicates are used to discursively resist heteronormativity. The discourse also shows how these videos focus on the purposes of informing and educating over phatic communication. The analysis will also demonstrate how the concept of internationalization has become semiotically relevant to the gay Japanese male category, constructing an image of masculine interculturality, contrasted against overly feminine mass-mediated stereotypes. Possibilities for further change and social justice in Japan through such sites of contact will also be discussed.
Boys’ Love, Transmedia Storytelling, and LGBT Awareness in Contemporary Japan
Authors: Nozawa Emiko
Published: April 2023

With the recent “LGBT Boom,” the media coverage of individuals, activism, the news, and films and dramas related to LGBT people is increasing in Japan. There are several hit movies and TV dramas about so-called LGBT people, where male-male romantic relationships are often depicted, and some are based on Boys’ Love manga (BL). BL is a distinct genre involving the intense descriptions of male-male intimate relations, where both authors and readers are predominantly heterosexual ciswomen. With the market success of these films and TV dramas, BL representations are becoming available to large audiences and are sometimes regarded as a source for the public to learn about LGBT issues, although many authors acknowledge that the representations in BL do not necessarily reflect the actuality of gay people. Some scholars and gay commentators have claimed that the dissemination of unrealistic descriptions by heterosexual female writers is discriminative, which would further marginalize and rhetorically appropriate sexual minorities. This chapter analyzes how BL is located in Japanese society amid the rise of LGBT awareness. It examines the representations of same-sex relationships in BL manga, the recent growth of the genre into forms of transmedia storytelling, and the debates on the representations of same-sex relations. Drawing on these analyses, I will argue that BL transmedia storytelling is a valuable space for creators from diverse media to collaboratively explore new forms of narratives and interpretations; but it could simultaneously disseminate distorted representations of same-sex relationships if they failed to adequately understand the nature of BL.
Migration Policy and Welfare Chauvinism in the United Kingdom: European Divergence or Trend-Setting?
Authors: D’Angelo Alessio
Published: April 2023

Growing hostility towards large-scale immigration following the EU enlargement (2004) and, later, the increase in South-North flows due to the global financial crisis (2008), played a major role in the Brexit referendum of 2016. This marked the departure of the United Kingdom from the European Union and from its mechanisms of “free movement”. Such hostility was not framed simply in terms of xenophobia but, rather, as “welfare chauvinism”. This chapter critically examines the last few decades of policy and political debates around intra-European migration in the United Kingdom, the key trends that have led to the (not so) unpredictable Brexit referendum, and the scenarios which have been set in motion with the UK-EU Agreement of 2020. In spite of the strong sense of British exceptionalism which has informed UK discussions, some of the fundamentals underpinning this process have much in common with what we are witnessing elsewhere in Europe, with the stratification of (welfare) rights for different categories of migrants being used as a pragmatic – if not cynical – mechanism to regulate entry and settlement. In fact, what at political and institutional level appears yet as the major rapture within the European framework, may end up revealing itself as part of a wider trend among both Northern and Southern European regimes: the restrictionist reconfiguration of the welfare-migration nexus. This race to the welfare bottom is not only affecting newly arrived migrants, but eroding the rights of the wider population.
Challenges and Ambiguities of the Policies for Immigrants’ Regularisation: The Portuguese Case in Context
Authors: Malheiros Jorge , Peixoto João
Published: April 2023

The idea that most immigrant receiving countries face a crisis of control has become pervasive since the 1990s, when neoliberal globalisation, as well as securitarian and nationalist policies, gained space. Due to the several contradictions and inefficiencies of the global circulation framework, most countries are exposed to uncontrolled migration, including the North and South European ones. The challenge is stronger when borders separate regions with uneven development levels and the economic cycle is expanding. When irregular migration occurs, the basic ex-post policy choices are limited to ignore the problem, enact deportation strategies or create mechanisms for regularisation.

In Southern European countries, irregular immigration became endemic. Until the mid-2000s, the most frequent policy approach adopted in these migration regimes was the enactment of extraordinary regularisation processes. Since then, some nations adopted an ongoing regularisation model. Using Portugal as a reference, we intend to examine how such processes were implemented and why they have been enacted. Because the features of the Portuguese case share elements with other countries, some comparative analysis is developed and positioned at the global European level, to evaluate the convergence or divergence hypothesis and the blurring of migration regimes’ boundaries.
Knowledge Production Through Regularisation and Ex-Post Regulation Strategies: Italy and Germany Compared
Authors: Finotelli Claudia
Published: April 2023

This chapter addresses the use of regularisations and ex-post regulation measures as an instrument to produce knowledge on social problems. Regularisations, more than other migration regulation tools, were addressed to highlight the “efficacy gap” existing between Northern and Southern European control regimes and were the object of several confrontations between Northern and Southern European Member States. Especially in times of migration crises, the use of regularisations seemed to strengthen the stereotype on “weak” Southern European migration regimes, in which chaotic and unplanned regulation mechanisms dominate. Yet, in this chapter it is argued that the function of regularisations should be assessed beyond the dichotomic distinction between “weak” and “strong” migration control regimes in Southern and Northern Europe. Regularisations and ex-post regulation strategies should rather be observed as an instrument to overcome weak internal controls and to produce knowledge on the presence of irregular migrants. To this end, the Italian and German immigration regimes will be used as comparative examples since they represent two opposed migration patterns in Europe with opposed approaches to unauthorised residence. The aim of the comparison is not only to discuss how very different migration regimes produce knowledge on unauthorised residence on their territory, but also to highlight the importance of these measures for the stabilisation of precarious immigrant populations.
Correlation Between Endoglin and Malignant Phenotype in Human Melanoma Cells: Analysis of hsa-mir-214 and hsa-mir-370 in Cells and Their Extracellular Vesicles
Authors: Ruiz-Llorente Lidia , Ruiz-Rodríguez María Jesús , Savini Claudia , González-Muñoz Teresa , Riveiro-Falkenbach Erica , Rodríguez-Peralto José L. , Peinado Héctor , Bernabeu Carmelo
Published: April 2023

Endoglin (CD105) is an auxiliary receptor of transforming growth factor (TGF)-β family members that is expressed in human melanomas. It is heterogeneously expressed by primary and metastatic melanoma cells, and endoglin targeting as a therapeutic strategy for melanoma tumors is currently been explored. However, its involvement in tumor development and malignancy is not fully understood. Here, we find that endoglin expression correlates with malignancy of primary melanomas and cultured melanoma cell lines. Next, we have analyzed the effect of ectopic endoglin expression on two miRNAs (hsa-mir-214 and hsa-mir-370), both involved in melanoma tumor progression and endoglin regulation. We show that compared with control cells, overexpression of endoglin in the WM-164 melanoma cell line induces; (i) a significant increase of hsa-mir-214 levels in small extracellular vesicles (EVs) as well as an increased trend in cells; and (ii) significantly lower levels of hsa-mir-370 in the EVs fractions, whereas no significant differences were found in cells. As hsa-mir-214 and hsa-mir-370 are not just involved in melanoma tumor progression, but they can also target endoglin-expressing endothelial cells in the tumor vasculature, these results suggest a complex and differential regulatory mechanism involving the intracellular and extracellular signaling of hsa-mir-214 and hsa-mir-370 in melanoma development and progression.
Constructing operator basis in supersymmetry: a Hilbert series approach
Authors: Delgado Antonio , Martin Adam , Wang Runqing
Published: April 2023

Abstract

In this paper we introduce a Hilbert series approach to build the operator basis for a N = 1 supersymmetry theory with chiral superfields. We give explicitly the form of the corrections that remove redundancies due to the equations of motion and integration by parts. In addition, we derive the maps between the correction spaces. This technique allows us to calculate the number of independent operators involving chiral and antichiral superfields to arbitrarily high mass dimension. Using this method, we give several illustrative examples.
Mean-Field Limits for Entropic Multi-Population Dynamical Systems
Authors: Almi Stefano , D’Eramo Claudio , Morandotti Marco , Solombrino Francesco
Published: April 2023

The well-posedness of a multi-population dynamical system with an entropy regularization and its convergence to a suitable mean-field approximation are proved, under a general set of assumptions. Under further assumptions on the evolution of the labels, the case of different time scales between the agents’ locations and labels dynamics is considered. The limit system couples a mean-field-type evolution in the space of positions and an instantaneous optimization of the payoff functional in the space of labels.
Nonlesional epilepsy—a case report in adult epileptology
Authors: Sheybani Laurent , Spinelli Laurent , Egervari Kristof , Garibotto Valentina , Vargas Maria Isabel , Seeck Margitta , Vulliemoz Serge
Published: April 2023

We report the case of a patient with nonlesional, pharmacoresistant epilepsy. Bilateral synchronous discharges as well as focal discharges were identified on electroencephalogram (EEG). After non-invasive and invasive presurgical evaluation, a probable epileptogenic zone was identified with concordant results of focal origin involvement of the left temporal pole. Resective epilepsy surgery provided seizure freedom (last follow-up at 12 months). The case nicely illustrates that bilateral synchronous discharges or/and a lack of lesions on neuroimaging are not contraindications to presurgical evaluation of epilepsy, which on the contrary should be offered to all patients with pharmacoresistant epilepsy. The case also illustrates the importance of combining electrophysiological, imaging, and neuropsychological information to guide intracranial EEG placement and improve postsurgical outcome.
The Impact of Fruit Ripeness on the Lower Oxygen Limit, Chlorophyll Fluorescence and Fermentation Behavior in Apples
Authors: Schlie Tim-Pascal , Rath Thomas , Köpcke Dirk , Dierend Werner
Published: April 2023

Dynamic Controlled Atmosphere-Chlorophyll Fluorescence storage (DCA-CF) uses a fluorescence-based measurement method to detect fermentation in apples (Malus × domestica BORKH.) caused by low-oxygen levels at an early stage. In recent years, it has been observed that individual apples of the same variety and origin can exhibit different fermentation behavior when stored under completely identical conditions. The causes of the different fermentation behavior must be found in order to be able to use DCA storage optimally. This study aimed to find the causes of the different fermentation behaviors of individual apples. Our results show that fruit ripeness can affect the lower oxygen limit (LOL), especially immediately after harvest, when the starch degradation in the fruit is not yet complete. A significant increase in the LOL was observed in ‘Elstar’ (2020: 0.3 kPa, 0.6 kPa, 0.9 kPa; 2021: 0.3 kPa, 0.4 kPa, 0.6 kPa). ‘Braeburn’ also exhibited this behavior regarding the LOL at a lower level. The LOL could not be identified for some of the fruit (varying from 12.5% to 41.7% of the examined apples) previously stored in Ultra Low Oxygen (ULO) storage for 4 months. Also, the chlorophyll content in the apple skin influences the fluorescence measurement method. Within 2 weeks, the chlorophyll content in the apple skin was halved. If the chlorophyll content drops, the reliability of the fluorescence measurement also decreases. It turned out that apples with an Fv/Fm < 0.7 were unsuitable for valid LOL identification.
A Bayesian model of legal syllogistic reasoning
Authors: Constant Axel
Published: April 2023

Bayesian approaches to legal reasoning propose causal models of the relation between evidence, the credibility of evidence, and ultimate hypotheses, or verdicts. They assume that legal reasoning is the process whereby one infers the posterior probability of a verdict based on observed evidence, or facts. In practice, legal reasoning does not operate quite that way. Legal reasoning is also an attempt at inferring applicable rules derived from legal precedents or statutes based on the facts at hand. To make such an inference, legal reasoning follows syllogistic logic and first order transitivity. This paper proposes a Bayesian model of legal syllogistic reasoning that complements existing Bayesian models of legal reasoning using a Bayesian network whose variables correspond to legal precedents, statutes, and facts. We suggest that legal reasoning should be modelled as a process of finding the posterior probability of precedents and statutes based on available facts.
(mis)-Targeting of SWI/SNF complex(es) in cancer
Authors: Reddy Divya , Bhattacharya Saikat , Workman Jerry L.
Published: April 2023

The ATP-dependent chromatin remodeling complex SWI/SNF (also called BAF) is critical for the regulation of gene expression. During the evolution from yeast to mammals, the BAF complex has evolved an enormous complexity that contains a high number of subunits encoded by various genes. Emerging studies highlight the frequent involvement of altered mammalian SWI/SNF chromatin-remodeling complexes in human cancers. Here, we discuss the recent advances in determining the structure of SWI/SNF complexes, highlight the mechanisms by which mutations affecting these complexes promote cancer, and describe the promising emerging opportunities for targeted therapies.
GABAA receptor-mediated seizure liabilities: a mixed-methods screening approach
Authors: Bampali Konstantina , Koniuszewski Filip , Vogel Florian D. , Fabjan Jure , Andronis Christos , Lekka Eftychia , Virvillis Vassilis , Seidel Thomas , Delaunois Annie , Royer Leandro , Rolf Michael G. , Giuliano Chiara , Traebert Martin , Roussignol Gautier , Fric-Bordat Magali , Mazelin-Winum Ludmilla , Bryant Sharon D. , Langer Thierry , Ernst Margot
Published: April 2023

GABAA receptors, members of the pentameric ligand-gated ion channel superfamily, are widely expressed in the central nervous system and mediate a broad range of pharmaco-toxicological effects including bidirectional changes to seizure threshold. Thus, detection of GABAA receptor-mediated seizure liabilities is a big, partly unmet need in early preclinical drug development. This is in part due to the plethora of allosteric binding sites that are present on different subtypes of GABAA receptors and the critical lack of screening methods that detect interactions with any of these sites. To improve in silico screening methods, we assembled an inventory of allosteric binding sites based on structural data. Pharmacophore models representing several of the binding sites were constructed. These models from the NeuroDeRisk IL Profiler were used for in silico screening of a compiled collection of drugs with known GABAA receptor interactions to generate testable hypotheses. Amoxapine was one of the hits identified and subjected to an array of in vitro assays to examine molecular and cellular effects on neuronal excitability and in vivo locomotor pattern changes in zebrafish larvae. An additional level of analysis for our compound collection is provided by pharmacovigilance alerts using FAERS data. Inspired by the Adverse Outcome Pathway framework, we postulate several candidate pathways leading from specific binding sites to acute seizure induction. The whole workflow can be utilized for any compound collection and should inform about GABAA receptor-mediated seizure risks more comprehensively compared to standard displacement screens, as it rests chiefly on functional data.
Country differentiation in the global environmental context: Who is ‘developing’ and according to what?
Authors: Farias Deborah Barros Leal
Published: April 2023

Several multilateral treaties and International Governmental Organizations have introduced different legal obligations for countries based on the developing/developed (or equivalent) dichotomy. Such differentiation can (re)produce a range of material and symbolic consequences for those labelled developing or developed. Much has been researched about this topic in the environmental regime yet an important gap remains: what does this differentiation look like empirically? This article answers this question through a qualitative analysis that compares about two dozen multilateral environmental agreements (MEAs) on (1) how they specify what makes a country be developing (or not) and (2) the result of this choice, that is, exactly which countries are labelled developing under each MEA. The research reveals at least four important points: (1) the absence of any converging approach to classifying countries in the global environmental context; (2) almost 1 out of 4 countries in the world have mixed classification (developing or developed depending on the MEA); (3) ‘switching’ groups is relatively infrequent, but can be both moving to or away from the developing label; and (4) most countries with mixed classifications appear to be comfortable in the situation. This research contributes to a finer-grained understanding of differentiation in global environmental governance.
Clinical and laboratory key performance indicators in IVF: A consensus between the Italian Society of Fertility and Sterility and Reproductive Medicine (SIFES-MR) and the Italian Society of Embryology, Reproduction and Research (SIERR)
Authors: Vaiarelli Alberto , Zacà Carlotta , Spadoni Valentina , Cimadomo Danilo , Conforti Alessandro , Alviggi Carlo , Palermo Roberto , Bulletti Carlo , De Santis Lucia , Pisaturo Valerio , Vigiliano Vincenzo , Scaravelli Giulia , Ubaldi Filippo Maria , Borini Andrea
Published: April 2023

Purpose

Infertility is increasing worldwide, and many couples seek IVF. Clinical management and laboratory work are fundamental in the IVF journey. Therefore, the definition of reliable key performance indicators (KPIs) based on clinical and laboratory parameters, is essential for internal quality control (IQC). Laboratory performance indicators have been identified and a first attempt to also determine clinical ones has been recently published. However, more detailed indicators are required.

Methods

An Italian group of experts in Reproductive Medicine from both public and private clinics on behalf of SIFES-MR and SIERR was established to define IVF indicators to monitor clinical performance.

Results

The working group built a consensus on a list of KPIs, performance indicators (PIs) and recommendation indicators (RIs). When deemed necessary, the reference population was stratified by woman age, response to ovarian stimulation and adoption of preimplantation genetic testing for aneuploidies (PGT-A). Each indicator was scored with a value from 1 to 5 and a weighted average formula – considering all the suggested parameters—was defined. This formula generates a center performance score, indicating low, average, good, or excellent performance.

Conclusion

This study is intended to provide KPIs, PIs and RIs that encompass several essential aspects of a modern IVF clinic, including quality control and constant monitoring of clinical and embryological features. These indicators could be used to assess the quality of each center with the aim of improving efficacy and efficiency in IVF.
The Cuticular Hydrocarbons of Dasineura Oleae Show Differences Between Sex, Adult Age and Mating Status
Authors: Caselli Alice , Favaro Riccardo , Petacchi Ruggero , Valicenti Marta , Angeli Sergio
Published: April 2023

In insects, cuticular lipids prevent water loss and act as semiochemicals. Because of their ecological function, the profile change across the insects’ sex and development offers insight into insect biology and possible tools for pest management. Here, the first work on cecidomyiid cuticular extracts is proposed considering Dasineura oleae (Diptera: Cecidomyiidae) males and females at different adult ages (0–12 h, 12–24 h, 24–36 h) and distinct sexual conditions (virgin and mated). A set of 49 compounds were recorded (12 alkanes, 1 monomethyl alkane, 11 fatty acids, 4 esters, 1 aldehyde, 1 allylbenzene, 1 amine, 1 flavonoid, 1 ketone, 1 phenol, 1 steradiene, 1 sterol, 1 terpene, 1 triterpene and 11 unknown compounds), and 18 of them showed significant differences between groups. Among alkanes, hexacosane (nC26) exhibited a decreasing trend from the youngest to the oldest females, while pentacosane (nC25) and nonacosane (nC29) showed a decreasing trend from 0 to 12 h to 12–24 h virgin females. In addition, nonadecane (nC19) was significantly more abundant in the youngest males compared to older males and females. The alkanes nC25, nC26 and nC29 have been reported to be age-related also in other dipterans, while nC19 has been described as gender-specific chemical cue for platygastrid parasitoids. Further behavioural trials and analyses are required to assign the specific ecological roles to the characterized compounds. Our results may contribute to develop new low-impact control strategies relying on the manipulation of D. oleae’s chemical communication (e.g. disruption of mating or species recognition).

Highlights

• Cuticular hydrocarbons are often involved in dipteran intraspecific communication.

• We explored the cuticular profile of D. oleae at different age, sex, mating condition.

• Five alkanes and one mono-methyl alkane showed differences among groups.

• Linoleic acid is the most abundant compound in virgins, absent in mated insects.

• Eleven compounds disappear in mated insects, but were present in all virgins.

Graphical Abstract
Moral knowledge and the existence of god
Authors: McKay Noah D.
Published: April 2023

In this essay, I argue that, all else being equal, theism is more probable than naturalism on the assumption that human beings are able to arrive at a body of moral knowledge that is largely accurate and complete. I put forth this thesis on grounds that, if naturalism is true, the explanation of the content of our moral intuitions terminates either in biological-evolutionary processes or in social conventions adopted for pragmatic reasons; that, if this is so, our moral intuitions were selected for their utility, not their truth; and that, if our moral intuitions were so selected, they are probably false. I defend the argument against three objections: first, that the argument amounts to a generic skeptical challenge; second, that ethical naturalism explains how our moral intuitions could have been selected for their truth; and third, that there is a pre-established harmony between the utility of moral beliefs and their truth-values.
Teleology and mechanism: a dialectical approach
Authors: Gambarotto Andrea
Published: April 2023

The paper proposes a dialectical approach to our understanding of the relation between teleology and mechanism. This approach is dialectical both in form and content. Inform, it proposes a contemporary interpretation of Hegel’s metaphysical account of teleology. This account is grounded in a dialectical methodology, which consists in scrutinizing the inherent limitations of a theoretical position that lead it to suppress itself and evolve into a better one. I apply the same methodology to the function debate. For Hegel, teleology can be understood in three main variants, which can be fruitfully mapped onto the three main positions in the function debate, the key conceptual distinction being whether teleological principles are understood as extrinsic or intrinsic. When it comes to autonomous systems, i.e. systems that embody the regime ofGeist, extrinsic functionality must be grounded in intrinsic functionality. My approach is dialectical also incontent, insofar as it concludes that intrinsic functional ascriptions rely on the relation of co-determination between the parts and the whole of a system, as well as between the system and its environment.
A long distance telesurgical demonstration on robotic surgery phantoms over 5G
Authors: Moustris George , Tzafestas Costas , Konstantinidis Konstantinos
Published: April 2023

Purpose

Using robotic technology and communications infrastructure to remotely perform surgery has been a persistent goal in medical research in the past three decades. The recent deployment of the Fifth-Generation Wireless Networks has revitalized the research efforts in the telesurgery paradigm. Offering low latency and high bandwidth communication, they are well suited for applications that require real-time data transmission and can allow smoother communication between surgeon and patient, making it possible to remotely perform complex surgeries. In this paper, we investigate the effects of the 5 G network on surgical performance during a telesurgical demonstration where the surgeon and the robot are separated by nearly 300 km.

Methods

The surgeon performed surgical exercises on a robotic surgery training phantom using a novel telesurgical platform. The master controllers were connected to the local site on a 5 G network, teleoperating the robot remotely in a hospital. A video feed of the remote site was also streamed. The surgeon performed various tasks on the phantom such as cutting, dissection, pick-and-place and ring tower transfer. To assess the usefulness, usability and image quality of the system, the surgeon was subsequently interviewed using three structured questionnaires.

Results

All tasks were completed successfully. The low latency and high bandwidth of the network resulted into a latency of 18 ms for the motion commands while the video delay was about 350 ms. This enabled the surgeon to operate smoothly with a high-definition video from about 300 km away. The surgeon viewed the system’s usability in a neutral to positive way while the video image was rated as of good quality.

Conclusion

5 G networks provide significant advancement in the field of telecommunications, offering faster speeds and lower latency than previous generations of wireless technology. They can serve as an enabling technology for telesurgery and further advance its application and adoption.
Identifying Gut Microbiota associated with Gastrointestinal Symptoms upon Roux-en-Y Gastric Bypass
Authors: Wijdeveld Madelief , van Olst Nienke , van der Vossen Eduard W. J. , de Brauw Maurits , Acherman Yair I. Z. , de Goffau Marcus C. , Gerdes Victor E. A. , Nieuwdorp Max
Published: April 2023

Purpose

Roux-en-Y gastric bypasses (RYGB) are frequently accompanied by long-term gastrointestinal (GI) symptoms. Direct mechanistic insight into the causation of these symptoms is lacking, but changes in the intestinal microbiome have been proposed to play a role. With this study, we aimed to investigate whether a microbial predisposition exists before RYGB which is associated with GI symptoms during follow-up and to evaluate which microbial groups are involved.

Materials and Methods

In total, 67 RYGB patients were included. Shotgun metagenomic sequencing was performed on fecal samples obtained just before and 1 year after surgery. To assess GI symptoms, patients filled out Gastrointestinal Quality of Life Index (GIQLI) questionnaires and were divided into groups based on their total GIQLI score and change in score (postsurgery versus baseline). Extremely randomized tree predictor models were used to identify the most distinctive microbial species associated with postoperative GI symptoms.

Results

Beta diversity differed significantly between baseline and 1-year post-surgery samples, with the post-surgery microbiome resembling a more dysbiotic profile. The most predictive species regarding total GIQLI (AUC 0.77) or delta GIQLI score (AUC 0.83) were identified. Many of these species are known butyrate producers or species known to support them and/or species with anti-inflammatory properties, including Coprococcus eutactus, Faecalibacterium prausnitzii, and Ruminococcus callidus.

Conclusion

Beneficial commensal gut microbiota related to a high GI score were associated to adequate intestinal fermentative capacity, suggesting these species might have protective properties against postoperative GI malfunctioning.

Graphical Abstract
Whole-Genome Sequencing Among Kazakhstani Children with Early-Onset Epilepsy Revealed New Gene Variants and Phenotypic Variability
Authors: Bayanova Mirgul , Bolatov Aidos K. , Bazenova Assiya , Nazarova Lyazzat , Nauryzbayeva Alissa , Tanko Naanlep Matthew , Rakhimova Saule , Satvaldina Nazerke , Samatkyzy Diana , Kozhamkulov Ulan , Kairov Ulykbek , Akilzhanova Ainur , Sarbassov Dos
Published: April 2023

In Kazakhstan, there is insufficient data on genetic epilepsy, which has its own clinical and management implications. Thus, this study aimed to use whole genome sequencing to identify and evaluate genetic variants and genetic structure of early onset epilepsy in the Kazakhstani pediatric population. In this study, for the first time in Kazakhstan, whole genome sequencing was carried out among epilepsy diagnosed children. The study involved 20 pediatric patients with early onset epilepsy and no established cause of the disease during the July–December, 2021. The average age at enrolment was 34.5 months, with a mean age at seizure onset of 6 months. Six patients (30%) were male, and 7 were familial cases. We identified pathogenic and likely pathogenic variants in 14 (70%) cases, among them, 6 novel disease gene variants (KCNQ2, CASK, WWOX, MT-CO3, GRIN2D, and SLC12A5). Other genes associated with the disease were SCN1A (x2), SLC2A1, ARX, CACNA1B, PCDH19, KCNT1, and CHRNA2. Identification of the genetic causes in 70% of cases confirms the general structure of the etiology of early onset epilepsy and the necessity of using NGS in diagnostics. Moreover, the study describes new genotype-phenotypic correlations in genetic epilepsy. Despite certain limitations of the study, it can be concluded that the genetic etiology of pediatric epilepsy in Kazakhstan is very broad and requires further research.
1 Analysis of dietary intake and biliary tract cancer risk in 638,860 Chinese and European adults in three cohort studies
Authors: Gunchick Valerie , Zheng Wei
Published: April 2023

OBJECTIVES/GOALS: Biliary tract cancer is an uncommon, aggressive malignancy. Incidence varies geographically and is highest in East Asia and South America and lowest in Western countries. Previous dietary risk evaluations have primarily been case-control studies. We evaluated associations of dietary intakes with BTC risk in three cohort studies in two countries. METHODS/STUDY POPULATION: We evaluated 638,860 adults in China and the United Kingdom enrolled in the Shanghai Women’s Health Study (SWHS), Shanghai Men’s Health Study (SMHS), or UK Biobank (UKB). Dietary intake information was obtained from study participants at baseline using food frequency questionnaires previously validated for these studies. Dietary intakes of major food groups and macronutrients were divided into low, middle, and high intake tertiles. Cox regression was used to estimate hazard ratios and 95% CIs for biliary tract cancer risk associated with major food groups in all three cohorts and macronutrients in the SWHS and SMHS. Participants were excluded if, at enrollment, they had a history of cancer, CHD, stroke, a total daily Kcal count below 500 or exceeding 3500, or developed cancer or died within one year after enrollment. RESULTS/ANTICIPATED RESULTS: The analyzed cohort includes 558,372 participants: 66,945 SWHS, 55,750 SMHS, and 435,677 UKB participants with median enrollment ages of 49, 52, and 57 years old and median follow-up times of 18.1, 12.3, and 10.3 years, respectively. The SWHS observed 205 eligible BTC cases, SMHS 97, and UKB 366. SWHS and SMHS participants were combined for dietary evaluation and the highest tertile of fruit intake showed an inverse association with biliary tract cancer risk when compared to the lowest tertile: HR 0.74 (95% CI, 0.55-0.99); p-trend 0.044. In UKB, the highest tertile of fish intake was associated with a reduced risk when compared to the lowest tertile: HR 0.76 (95% CI, 0.59-0.98); p-trend 0.034. DISCUSSION/SIGNIFICANCE: High dietary fruit intake was associated with a reduced risk of biliary tract cancer only in SWHS and SMHS. High fish intake was associated with a reduced risk of biliary tract cancer only in UKB. Our findings reflect geographic-based BTC risk variation which we will further explore in our next model accounting for population-specific risk factors.
21 Epidemiology of Infectious Keratitis at University of Rochester Medical Center
Authors: Maretz Caroline , Wozniak Rachel
Published: April 2023

OBJECTIVES/GOALS: Infectious keratitis is a potentially sight-threatening disease. Its epidemiology has been considered on various national and regional levels, which demonstrates unique patterns in patient risk factors, causative organisms, antimicrobial resistance and clinical outcomes. This study will examine the patterns specific to the Rochester, NY area. METHODS/STUDY POPULATION: This project will be a ten-year retrospective study, examining all patients who were diagnosed with infectious keratitis at the University of Rochester Medical Center between 2011 and 2021. The study population is selected from a compiled list of those patients with an ICD diagnosis code including ’keratitis’ in the eRecord that falls within our chosen date range. Participants were excluded if the patient’s physician documented that the keratitis is most likely not infectious in etiology. If eligible for the study, there is documentation of patient demographics, clinical risk factors, clinical course, culture data from corneal scraping and antimicrobial resistance patterns, if available. Once data is collected, it will be analyzed and compared to pre-existing regional and national data. RESULTS/ANTICIPATED RESULTS: Between 2011 and 2021, there were 1652 patients with ICD diagnoses of keratitis at the University of Rochester Medical Center. Of these patients, we anticipate approximately 1,200 to meet our inclusion criteria. Some of the major risk factors for developing infectious keratitis in this population include contact lens use, immunocompromised state (elderly, diseased or iatrogenic) and corneal trauma. Clinical complications include progression to endophthalmitis, need for interventional surgery, or failure to improve on clinical exam after 2 weeks of antimicrobials. Causative organisms are most often bacterial. Certain organisms are associated with specific risk factors while other organisms predict greater risk of complications. We also anticipate patterns of antimicrobial resistance to emerge. DISCUSSION/SIGNIFICANCE: This study will provide insights into the risk factors and clinical course of infectious keratitis according to causative organisms in the Rochester, NY area. This can help us mitigate risk factors and help prognosticate for patients, once diagnosed. Also, patterns of antimicrobial resistance can inform empiric antimicrobial recommendations.
28 Mental health and antipsychotic prescription receipt among youth: A nation-wide healthcare insurance claims study
Authors: Sepe-Forrest Linnea , Meraz Richard , D’Onofrio Brian M. , Quinn Patrick D.
Published: April 2023

OBJECTIVES/GOALS: In 2010, an estimated 65% of antipsychotic prescriptions were given to youth for off-label indications. It is unclear whether subsequent calls for reduced pediatric prescribing led to a decrease in off-label use. This study examined the diagnostic characteristics of the current pediatric population using antipsychotics in the United States. METHODS/STUDY POPULATION: Data from the Clinformatics Data Mart, a database containing longitudinal patient information between 2010-2019 from commercial healthcare insurance claims in the United States was used in this study. We conducted a case-control study, in which antipsychotic initiators were matched 1:1 to non-initiators on age, sex, and insurance enrollment. There were 26,375 included antipsychotic initiators with matched non-initiator controls between the ages of 6-17. Conditional logistic regression was used to examine the odds of being an antipsychotic user among those with past-year psychiatric diagnoses that have been previously found to be associated with antipsychotic use. RESULTS/ANTICIPATED RESULTS: Disorders with psychotic features were associated with the greatest differences in odds of antipsychotic prescription receipt. Specifically, children with bipolar or manic disorders had 145-fold greater odds of antipsychotic receipt than did those without bipolar or manic disorders (OR = 145.45, 95% CI = [95.64, 221.22]), whereas those with schizophrenia had 106-fold greater odds (OR = 105.89, CI = [67.40, 166.37]). However, these disorders occurred in only 12% and 8%, respectively, of the antipsychotic recipients. The most common disorders among those with antipsychotic receipt were depressive disorders and ADHD, which occurred in 46% and 43% of the recipients, respectively. Additionally, conduct disorder was present in 20% of recipients. DISCUSSION/SIGNIFICANCE: As expected, bipolar disorder and schizophrenia were strongly associated with initiation of pediatric antipsychotic treatment. Yet, most initiators did not have a diagnosis for either psychotic disorder or any other FDA-approved indications. This study highlights the critical need for further research on antipsychotic use among youth.
43 Random Forest Model Approaches to Build Prediction Models of Cognitive Impairment Using the National Alzheimer’s Coordinating Center database
Authors: Moon Chooza , Wang Boxiang , Gardner Sue , Geerling Joel , Hoth Karn
Published: April 2023

OBJECTIVES/GOALS: Our goal is to explore the complex, the non-linear interplay among chronic conditions collectively contributing to a greater detrimental impact on the progression of Alzheimer’s disease (AD) than a single chronic condition alone in individuals with normal cognition, MCI, and AD. METHODS/STUDY POPULATION: We used longitudinal data from National Alzheimer Coordinating Center (n = 41,437) and focused on individuals with normal cognition (n =16,884, mean age (SD) = 70.72 (9.7)). Random forest models were used to predict newly developed MCI or AD from baseline to the most recent visits. We used self-reported baseline data on 50 chronic conditions and comprehensive clinical and demographic information (e.g., age, sex, APOE status, mini-mental status exam (MMSE) scores, education, BMI, and depressive symptoms). A binomial random forest was used to identify significant interactions (with p-values RESULTS/ANTICIPATED RESULTS: Our model demonstrated an AUC of 0.708 and a classification error rate of 25.4%. Variables of importance for predicting MCI or dementia were age, coronary artery bypass, depression, APOE status, smoking, and depressive symptoms. Two-way interactions, such as age X MMSE score, age X depressive symptoms, and age X BMI, were significant. Three-way interactions, including age X depressive symptoms X MMSE score, or depressive symptoms X BMI X MMSE score, were significant. However, when we explored the random forest model using only the chronic condition data, we found an AUC of 0.602 and an error rate of 27.15%. We found that depression, anxiety, hypercholesterolemia, stroke, and the interaction between BMI and anxiety were significant. DISCUSSION/SIGNIFICANCE: Random Forest models indicate that not only known factors including age, baseline cognitive status, and APOE status, but also chronic conditions like depression, anxiety, hypercholesterolemia, and stroke may predict cognitive impairment.