bluuebunny/crossref_metadata_2025 huggingface dataset:
Macroprudential Policies and Global Finance
Authors: Claessens Stijn , Mehrotra Aaron , Shim Ilhyock
Published: September 2023

Macroprudential policy involves using mainly prudential but sometimes also monetary and fiscal tools to reduce systemic risk and achieve financial stability. It is motivated by externalities associated with the buildup of systemic risk over time due to strategic complementarities, fire sales and credit crunches related to a generalized sell-off of assets, and strong cross-institutional interconnectedness. Macroprudential tools apply to both banks and nonbank financial institutions and to different classes of borrowers to the extent that they come with systemic risks.

Both advanced economies (AEs) and emerging market economies (EMEs) have steadily increased their use of macroprudential measures since the mid-1990s. Empirical evidence suggests that tighter macroprudential policy has improved banking system resilience and that tools such as lower caps on loan-to-value or debt service ratios have helped reduce housing credit and price growth. Evidence shows that while tightening macroprudential policy is generally effective, relaxing it is less so. By moderating fluctuations in general bank credit, housing/household credit, or house prices, macroprudential policy tends to reduce the severity and likelihood of future crises as well as the volatility of growth, but recent studies also show that it slows output growth.

As financial globalization progresses, macroprudential policy may become less effective due to regulatory arbitrage and cross-border leakages, especially in financially more open AEs and EMEs, also given the limited scope for international coordination and the lack of an internationally agreed-upon macroprudential framework. To deal with the associated externally driven risks, many EMEs use foreign exchange (FX)-related macroprudential tools, e.g., FX liability-based reserve requirements, limits on currency mismatch or FX positions, and FX liquidity requirements. In EMEs, FX intervention can also play a macroprudential role. In contrast, AEs rarely use such instruments but use macroprudential capital buffers more actively than EMEs. Recent evidence suggests both positive and negative international spillover effects of these and other macroprudential policies.

These and other findings point to the need to build formal models that have a macro-financial stability framework (MFSF) at their core. The framework incorporates the relevant policy tools, their individual effects, and interactions, and captures the channels of financial risk-taking and their implications for global and domestic financial conditions. Such an MFSF includes monetary policy to ensure macroeconomic stability and assist with financial stability, fiscal policy to guarantee fiscal sustainability and limit cyclical economic fluctuations, and macroprudential policy to complement monetary and fiscal policies by strengthening the resilience of the financial system and limiting the buildup of financial imbalances. Research is underway to develop such models, but considerable scope for further work in this area exists.
Phoenix
Authors: Shermer Elizabeth Tandy
Published: September 2023

Phoenix, the capital of the state of Arizona, exemplifies the ways Sun Belt cities dramatically grew after World War II. Phoenix was best described as a small trading town in 1912, when Arizona became the last territory to achieve statehood in the continental United States. Although Phoenix was a capital city located in an area with little rainfall and high summer temperatures, its economy depended heavily on the sale of cotton and copper as well as tourists attracted to the Salt River valley’s warm winters. But members of the local Chamber of Commerce, like many small-town boosters across the US South and West, wanted to attract manufacturers by the 1930s, when the Great Depression upended the agricultural, mining, and tourism markets. The Chamber’s White male leaders (including future Senator Barry Goldwater) succeeded during World War II. They lobbied for wartime investment that transformed Phoenix into one of the many boom towns that dotted the South and West. That success fueled postwar efforts to attract industry by building a favorable “business climate.” Local leaders, business executives, and industry experts used that seemingly benign phrase to describe cities that guaranteed investors low taxes, weak unions, few government regulations, and other policies that maximized profits and undermined 1930s reforms. Phoenix stood out in what reporters called the “Second War between the States” for industry. General Electric, Motorola, and Sperry Rand had all opened branch plants by 1960, when Phoenix was already one of the largest US cities. It also stood out in 1969, when Republican strategist Kevin Phillips drew attention to the “Sun Belt phenomenon” that seemed to be the metropolitan core of a new conservative politics dedicated to free enterprise and poised to spread across the rapidly deindustrializing Northeast and Midwest. But growth undermined the Chamber’s power. By the 1970s, citizens questioned putting business first, and investors began shifting manufacturing overseas, which left residents to deal with the environmental, fiscal, and political damage the business climate ideal had wrought.
Palestinian Muslim Communities in Colombia
Authors: Gutiérrez Felipe Medina , David Odette Yidi
Published: September 2023

Arabic-speaking peoples, including Palestinians mostly Christian from Ottoman-controlled lands and later living under European mandates in greater Syria, migrated to the Americas, during the last quarter of the 19th century and until the end of the World War II. The creation of the State of Israel in May 1948 meant the expulsion and forced migration of yet more Palestinians, some settling in refugee camps in the region and others moving to distant countries, such as Colombia. This new wave of Palestinian immigrants was overwhelmingly Muslim. The Palestinian diaspora in the 21st century comprises about ten million people around the world and is highly diverse in terms of religious identity. Some communities have organized around supporting the development of their host countries and homeland; nonetheless, not many people are aware of these stories. Also, it is common in the “West” to witness accusations that Palestinians, Muslims, and Arabs in general are violent by nature, as a result of a series of orientalist misconceptions about a people and a religion that, despite exceeding 1,600 billion believers around the world, remains misunderstood. Something similar happens with the Palestinian diaspora in Colombia, where little research has been undertaken to historicize their presence and interactions. Primary and secondary sources illustrate how the Palestinian Muslim immigrant community in Colombia has integrated into the local society and strengthened its ties on a social level beyond the political and economic issues, with consideration of its religious identity and minority condition.
The Welsh Colony in Patagonia
Authors: Gavirati Marcelo
Published: September 2023

In July of 1865, some 160 Welsh immigrants settled in the valley of the Chubut River, located in the middle of a Patagonian territory controlled by the Indigenous Tehuelche. This was to be the beginning of a unique colonization process. Unlike many other migratory experiences, the colonizing effort promoted by a group of Welsh nationalist leaders was aimed at liberating their compatriots from the oppression to which they felt they had been subjected in the United Kingdom. Their utopian objective was to establish a “New Wales,” in which they could work their own land, freely practice their language (Cymraeg, in Welsh) and the religion of their nonconformist denominations, and achieve a certain degree of political autonomy.

In spite of facing an unknown and arid territory, the Welsh managed to produce wheat irrigated by canals. What is more, they would overcome prejudices about the “savage” nature of the Indigenous peoples, eventually working with the Pampa and Tehuelche tribes to develop a model of peaceful coexistence based on complementary economic practices, providing a unique example of relations between Europeans and Native Americans.

Economic development allowed the arrival of additional contingents of settlers. During the first decades, Welsh was the language of daily life, in social, political, economic, cultural, and religious contexts. The valley of the Chubut River became dotted with chapels. But in 1885, after the military campaigns that deprived the Indigenous peoples of their territories, the Argentine government materialized its sovereign presence over Patagonia. Although in 1891 Argentina made possible the creation of a new Welsh settlement in a valley of the Andean foothills, the process of nationalization and assimilation was underway. Influences within the political and educational spheres, as well as the arrival of immigrants of other nationalities, allowed the national government to gradually displace the Welsh from their position of primacy in the Chubut territory.

Although the autonomous Welsh Utopia did not flourish, some traces remain. More than 155 years after the arrival of the first contingent, there are still Welsh speakers and students in Patagonia. The eisteddfod and the arrival of the first immigrants’ ship are celebrated every July 28, a date officially considered to be the founding of the current province of Chubut.
The History of Variationist Germanic Linguistics
Authors: Gregersen Frans
Published: September 2023

The history of variationist linguistics (also known as variationist sociolinguistics or language variation and change) shows that over the years it has entered into competition and collaboration with a number of disciplines. It is in competition with Chomskyan theoretical linguistics, diverging from this hegemonic trend in methods, data, and types of analysis: variationist linguistics favors observation and dismisses introspection; it builds on everyday conversations with more speakers than one; and it uses quantitative methods in all analyses. Variationism collaborates with or is compatible with other types of analyses of language use and is sometimes seen as part of a larger sociolinguistic field also encompassing interactional linguistics, discourse analysis, critical discourse analysis, conversation analysis, and functional grammar, and systemic functional linguistics may complement or in other ways be used in otherwise mainly variationist enterprises. Indeed since one of the central variationist types of data is the sociolinguistic interview, variationist data may be analyzed by all of these disciplines.

The article is organized along the following historical framework: It circumscribes three periods ranging from approximately 1960 to ca. 2010: The founder period establishes the approach at the various European universities by producing a number of exemplary studies, primary among them William Labov’s dissertation and later book, The Social Stratification of English in New York City. In focusing on an urban environment, Labov identified a moot point in the dialectological tradition, which otherwise is not only compatible with variationism but would also, gradually, be profoundly transformed by it. He also studied a community whose sheer size makes sampling and concomitant discussions of representativity necessary. These are central discussions for any urban sociology.

The history of variationism in general plays out differently in the various countries or regions of Germanic-speaking Europe, but in the second period it is characteristic that variationist linguistics gets a more or less favored place in a broader canvas of disciplines studying spoken language in use. The disciplines may take their cue from sociology (ethnomethodology, conversation analysis), philosophy (speech-act theory), or social psychology (accommodation theory). Thus, we have labeled this period the period of fragmentation.

The third period distinguished here is a period of larger corpora, when studies of variation may be carried out in tandem with, or indeed in collaboration with, other analyses; thus, in a way, modifying the previous period of fragmentation—at least institutionally.

The three periods happen at various points in time in the various countries discussed, and it could be argued that the two later periods overlap, but the framework used here nevertheless makes it possible to organize their overall history.
Dangel, Richard
Authors: Mindel Charles H.
Published: September 2023

Richard Dangel (1949–2021) was a researcher, practitioner and spokesman for the prevention and treatment of child and sexual abuse. He practiced one on one with abused children and later developed treatment practice model that allowed organizations to identify and prevent abuse in their own organizations.
New horizons in schizophrenia in older people
Authors: Meesters Paul D
Published: September 2023

People aged 65 years and older will soon constitute more than a quarter of the total population with schizophrenia, challenging the existing systems of care. For a long time, research into schizophrenia in later life was very limited. However, recent years have seen an encouraging surge in novel and high-quality studies related to this stage of life. Older people with schizophrenia consist of those who had an early onset and aged with the disorder, and of a smaller but sizeable group with a late onset or a very late onset. With ageing, physical needs gain importance relative to psychiatric needs. Medical comorbidity contributes to a markedly higher mortality compared to the general population. In many persons, symptoms and functioning fluctuate with time, leading to deterioration in some but improvement in others. Of note, a substantial number of older people may experience subjective well-being in spite of ongoing symptoms and social impairments. The majority of individuals with schizophrenia reside in the community, but when institutionalization is required many are placed in residential or nursing homes where staff is often ill-equipped to address their complex needs. There is a clear need for implementation of new models of care in which mental health and general health systems cooperate. This review provides a state-of-the-art overview of current knowledge in late life schizophrenia and related disorders, with a focus on themes with clinical relevance.
Is the automated Elecsys tacrolimus assay on the Roche cobas e 602 analyzer an acceptable replacement for a liquid chromatography–tandem mass spectrometry–based assay?
Authors: Gant Kanegusuku Anastasia , Yeo Kiang-Teck J
Published: September 2023

Objectives

This study evaluated the suitability and accuracy of the automated Roche Elecsys tacrolimus electrochemiluminescence immunoassay (ECLIA) by comparing it with a current laboratory-developed test by liquid chromatography–tandem mass spectrometry (LC-MS/MS).

Methods

The tacrolimus ECLIA was evaluated for precision, linearity, interference, and postextraction stability. Accuracy was compared with LC-MS/MS.

Results

The tacrolimus ECLIA assay is precise, exhibits a measuring range of 0.75 to 30 ng/mL, and is tolerant of significant interferences (plasma indices: hemolysis <2306, icterus <55, lipemia <1427, and biotin <1200 ng/mL). Comparison with LC-MS/MS revealed a 26% proportional bias in patient samples evaluated for tacrolimus concentration (y = 1.26x + 0.08; r2 = 0.97; Sy/x = 0.94; n = 43) and an absolute mean (SD) bias of 2.2 (1.7) ng/mL. Postextraction studies confirmed that samples were stable for up to 30 minutes under routine laboratory conditions.

Conclusions

The 2 major challenges for implementation of the tacrolimus ECLIA assay are the postextraction sample stability and the significant proportional bias observed compared with the LC-MS/MS reference method. The 30-minute window for analysis of extracted samples is a practical challenge to the routine workflow of the core laboratory. In addition, disagreement between the immunoassay and LC-MS/MS methods can lead to discordant clinical interpretations and ultimately affect patient care.
Note: The Heirs of Pausimachus v City of Kalymnos arbitration
Authors: Paschalidis Paschalis
Published: September 2023

The so-called ‘Knidian arbitration’ between the heirs of the banker Pausimachus and the city-State of Kalymnos has been the subject of much debate amongst historians and archaeologists. However, it seems to have escaped the attention of arbitration practictioners, despite the fact that it constitutes, in essence, a commercial proto-arbitration against a State. The present contribution aims at correcting this omission. The award is a treasure trove of information about the conduct of ancient arbitrations. While arbitrations have become increasingly sophisticated procedures, this ancient award also helps identify essential aspects of the arbitral process that transcend time. To do so, this contribution provides both an overview and commentary of the award as well as a translation of the surviving fragments.
Tcbf: a novel user-friendly tool for pan-3D genome analysis of topologically associating domain in eukaryotic organisms
Authors: He Xin , Huang Xianhui , Long Yuexuan , Liu Zhenping , Chang Xing , Zhang Xianlong , Wang Maojun
Published: September 2023

TAD boundaries are essential for organizing the chromatin spatial structure and regulating gene expression in eukaryotes. However, for large-scale pan-3D genome research, identifying conserved and specific TAD boundaries across different species or individuals is computationally challenging. Here, we present Tcbf, a rapid and powerful Python/R tool that integrates gene synteny blocks and homologous sequences to automatically detect conserved and specific TAD boundaries among multiple species, which can efficiently analyze huge genome datasets, greatly reduce the computational burden and enable pan-3D genome research.

Availability and implementation

Tcbf is implemented by Python/R and is available at https://github.com/TcbfGroup/Tcbf under the MIT license.
Genital coupling and copulatory wounding in the interspecific mating of theDrosophila aurariaspecies complex (Diptera: Drosophilidae)
Authors: Onuma Moe , Kamimura Yoshitaka , Sawamura Kyoichi
Published: September 2023

Structural matching of genitalia between sexes of the same species would guarantee a stable mating posture and tight genital coupling that minimizes the reproductive cost in females. Interspecific mating might cause mismatches in genital structures between sexes, leading to an unstable mating posture, abnormal genital coupling, enhanced risk of wounding to the genitalia, and reduced mating duration. In this study, copulation duration, mating posture, genital coupling and copulatory wounding were analysed in reciprocal combinations of interspecific mating between Drosophila auraria and Drosophila triauraria and between Drosophila biauraria and Drosophila subauraria. Interspecific mating exhibited a large variation in copulation duration, and copulatory wounds were produced in females at positions that lacked the corresponding fold structures, although the frequency of copulatory wounds was sometimes lower than in intraspecific mating. The angle of the aedeagus insertion during mating and positions of the copulatory wounds after interspecific mating were as expected from the male species, suggesting that males attempt to tighten genital coupling and stabilize copulation using the genitalia regardless of the female species. As in other groups of Drosophila studied to date, the species-specific structures in female genitalia contact the conspecific male organs during copulation, and the results suggest that they might have functions related to sexual conflict or sexual selection.
SMAD signaling pathway is disrupted by BPA via the AMH receptor in bovine granulosa cells
Authors: Patel Rushi H , Truong Vivien B , Sabry Reem , Acosta Julianna E , McCahill Kiera , Favetta Laura A
Published: September 2023

Significant events that determine oocyte competence occur during follicular growth and oocyte maturation. The anti-Mullerian hormone, a positive predictor of fertility, has been shown to be affected by exposure to endocrine disrupting compounds, such as bisphenol A and S. However, the interaction between bisphenols and SMAD proteins, mediators of the anti-Mullerian hormone pathway, has not yet been elucidated. AMH receptor (AMHRII) and downstream SMAD expression was investigated in bovine granulosa cells treated with bisphenol A, bisphenol S, and then competitively with the anti-Mullerian hormone. Here, we show that 24-h bisphenol A exposure in granulosa cells significantly increased SMAD1, SMAD4, and SMAD5 mRNA expression. No significant changes were observed in AMHRII or SMADs protein expression after 24-h treatment. Following 12-h treatments with bisphenol A (alone or with the anti-Mullerian hormone), a significant increase in SMAD1 and SMAD4 mRNA expression was observed, while a significant decrease in SMAD1 and phosphorylated SMAD1 was detected at the protein level. To establish a functional link between bisphenols and the anti-Mullerian hormone signaling pathway, antisense oligonucleotides were utilized to suppress AMHRII expression with or without bisphenol exposure. Initially, transfection conditions were optimized and validated with a 70% knockdown achieved. Our findings show that bisphenol S exerts its effects independently of the anti-Mullerian hormone receptor, while bisphenol A may act directly through the anti-Mullerian hormone signaling pathway providing a potential mechanism by which bisphenols may exert their actions to disrupt follicular development and decrease oocyte competence.
An eigenvector-assisted estimation framework for signal-plus-noise matrix models
Authors: Xie Fangzheng , Wu Dingbo
Published: September 2023

In this paper, we develop an eigenvector-assisted estimation framework for a collection of signal-plus-noise matrix models arising in high-dimensional statistics and many applications. The framework is built upon a novel asymptotically unbiased estimating equation using the leading eigenvectors of the data matrix. However, the estimator obtained by directly solving the estimating equation could be numerically unstable in practice and lacks robustness against model misspecification. We propose to use the quasi-posterior distribution by exponentiating a criterion function whose maximizer coincides with the estimating equation estimator. The proposed framework can incorporate heteroskedastic variance information, but does not require the complete specification of the sampling distribution and is also robust to the potential misspecification of the distribution of the noise matrix. Computationally, the quasi-posterior distribution can be obtained via a Markov chain Monte Carlo sampler, which exhibits superior numerical stability over some of the existing optimization-based estimators and is straightforward for uncertainty quantification. Under mild regularity conditions, we establish the large sample properties of the quasi-posterior distributions. In particular, the quasi-posterior credible sets have the correct frequentist nominal coverage probability provided that the criterion function is carefully selected. The validity and usefulness of the proposed framework are demonstrated through the analysis of synthetic datasets and the real-world ENZYMES network datasets.
Situating defaunation in an operational framework to advance biodiversity conservation
Authors: Poulsen John R , Maicher Vincent , Malinowski Halina , DeSisto Camille
Published: September 2023

Anthropogenic pressures are causing the widespread loss of wildlife species and populations, with adverse consequences for ecosystem functioning. This phenomenon has been widely but inconsistently referred to as defaunation. A cohesive, quantitative framework for defining and evaluating defaunation is necessary for advancing biodiversity conservation. Likening defaunation to deforestation, we propose an operational framework for defaunation that defines it and related terms, situates defaunation relative to intact communities and faunal degradation, and encourages quantitative, ecologically reasonable, and equitable measurements. We distinguish between defaunation, the conversion of an ecosystem from having wild animals to not having wild animals, and faunal degradation, the process of losing animals or species from an animal community. The quantification of context-relevant defaunation boundaries or baselines is necessary to compare faunal communities over space and time. Situating a faunal community on the degradation curve can promote Global Biodiversity Framework targets, advancing the 2050 Vision for Biodiversity.
The influence of aggressive exercise on responses to self-perceived and others’ pain
Authors: Wei Zilong , Huang Yujuan , Li Xiong , Shao Min , Qian Huiling , He Bojun , Meng Jing
Published: September 2023

Previous studies have reported relationships between exercise and pain. However, little is known about how aggressive exercise modulates individuals’ responses to their own and others’ pain. This present study addresses this question by conducting 2 studies employing event-related potential (ERP). Study 1 included 38 participants whose self-perceived pain was assessed after intervention with aggressive or nonaggressive exercises. Study 2 recruited 36 participants whose responses to others’ pain were assessed after intervention with aggressive or nonaggressive exercise. Study 1’s results showed that P2 amplitudes were smaller, reaction times were longer, and participants’ judgments were less accurate in response to self-perceived pain stimuli, especially to high-pain stimuli, after intervention with aggressive exercise compared to nonaggressive exercise. Results of study 2 showed that both P3 and LPP amplitudes to others’ pain were larger after intervention with aggressive exercise than with nonaggressive exercise. These results suggest that aggressive exercise decreases individuals’ self-perceived pain and increases their empathic responses to others’ pain.
Drugs with a negative impact on cognitive functions (Part 2): drug classes to consider while prescribing in CKD patients
Authors: Hafez Gaye , Malyszko Jolanta , Golenia Aleksandra , Klimkowicz-Mrowiec Aleksandra , Ferreira Ana Carina , Arıcı Mustafa , Bruchfeld Annette , Nitsch Dorothea , Massy Ziad A , Pépin Marion , Capasso Giovambattista , Mani Laila-Yasmin , Liabeuf Sophie ,   CONNECT Action (Cognitive Decline in Nephro-Neurology European Cooperative Target), Capasso Giovambattista , Andrade Alexandre , Bachmann Maie , Bumblyte Inga , Covic Adrian Constantin , Delgado Pilar , Endlich Nicole , Engvig Andreas , Fouque Denis , Franssen Casper , Frische Sebastian , Garneata Liliana , Gesualdo Loreto , Giannakou Konstantinos , Goumenos Dimitrios , Kartal Ayşe Tuğba , Liabeuf Sophie , Mani Laila-Yasmin , Marti Hans-Peter , Mayer Christopher , Nielsen Rikke , Pešić Vesna , Rroji (Molla) Merita , Sakkas Giorgos , Spasovski Goce , Stevens Kate , Vazelov Evgueniy , Viggiano Davide , Zacharia Lefteris , Ferreira Ana Carina , Malyszko Jolanta , Hoorn Ewout , Figurek Andreja , Unwin Robert , Wagner Carsten , Wanner Christoph , Bruchfeld Annette , Pepin Marion , Wiecek Andrzej , Nitsch Dorothea , Fridolin Ivo , Hafez Gaye , Romeo Maria José Soler , Barbieri Michelangela , Batinić Bojan , Carrasco Laura , Carriazo Sol , Gansevoort Ron , Martino Gianvito , Raso Francesco Mattace , Nistor Ionut , Ortiz Alberto , Paolisso Giuseppe , Rastenytė Daiva , Stefan Gabriel , Tedeschi Gioacchino , Massy Ziad , Bikbov Boris , Endlich Karl Hans , Godefroy Olivier , Kossioni Anastassia , Kurganaite Justina , Perico Norberto , Remuzzi Giuseppe , Grodzicki Tomasz , Trepiccione Francesco , Zoccali Carmine , Arici Mustafa , Blankestijn Peter , Eckardt Kai-Uwe , Fliser Danilo , Jiménez Eugenio Gutiérrez , Konig Maximilian , Rychlik Ivan , Deleidi Michela , Reusz George , Farisco Michele , Perico Norberto , Silva Pedro Imenez , Bobot Mickaël , Golenia Aleksandra , Perna Alessandra , Idrizi Alma , Hansen Brian , Simeoni Mariadelina
Published: September 2023

There is growing evidence that chronic kidney disease (CKD) is an independent risk factor for cognitive impairment, especially due to vascular damage, blood–brain barrier disruption and uremic toxins. Given the presence of multiple comorbidities, the medication regimen of CKD patients often becomes very complex. Several medications such as psychotropic agents, drugs with anticholinergic properties, GABAergic drugs, opioids, corticosteroids, antibiotics and others have been linked to negative effects on cognition. These drugs are frequently included in the treatment regimen of CKD patients. The first review of this series described how CKD could represent a risk factor for adverse drug reactions affecting the central nervous system. This second review will describe some of the most common medications associated with cognitive impairment (in the general population and in CKD) and describe their effects.
Systematic Minigene-Based Splicing Analysis and Tentative Clinical Classification of 52 CHEK2 Splice-Site Variants
Authors: Sanoguera-Miralles Lara , Valenzuela-Palomo Alberto , Bueno-Martínez Elena , Esteban-Sánchez Ada , Lorca Víctor , Llinares-Burguet Inés , García-Álvarez Alicia , Pérez-Segura Pedro , Infante Mar , Easton Douglas F , Devilee Peter , Vreeswijk Maaike P G , de la Hoya Miguel , Velasco-Sampedro Eladio A
Published: September 2023

Background

Disrupted pre-mRNA splicing is a frequent deleterious mechanism in hereditary cancer. We aimed to functionally analyze candidate spliceogenic variants of the breast cancer susceptibility gene CHEK2 by splicing reporter minigenes.

Methods

A total of 128 CHEK2 splice-site variants identified in the Breast Cancer After Diagnostic Gene Sequencing (BRIDGES) project (https://cordis.europa.eu/project/id/634935) were analyzed with MaxEntScan and subsetted to 52 variants predicted to impact splicing. Three CHEK2 minigenes, which span all 15 exons, were constructed and validated. The 52 selected variants were then genetically engineered into the minigenes and assayed in MCF-7 (human breast adenocarcinoma) cells.

Results

Of 52 variants, 46 (88.5%) impaired splicing. Some of them led to complex splicing patterns with up to 11 different transcripts. Thirty-four variants induced splicing anomalies without any trace or negligible amounts of the full-length transcript. A total of 89 different transcripts were annotated, which derived from different events: single- or multi-exon skipping, alternative site-usage, mutually exclusive exon inclusion, intron retention or combinations of the abovementioned events. Fifty-nine transcripts were predicted to introduce premature termination codons, 7 kept the original open-reading frame, 5 removed the translation start codon, 6 affected the 5′UTR (Untranslated Region), and 2 included missense variations. Analysis of variant c.684-2A > G revealed the activation of a non-canonical TG-acceptor site and exon 6 sequences critical for its recognition.

Conclusions

Incorporation of minigene read-outs into an ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology)-based classification scheme allowed us to classify 32 CHEK2 variants (27 pathogenic/likely pathogenic and 5 likely benign). However, 20 variants (38%) remained of uncertain significance, reflecting in part the complex splicing patterns of this gene.
Alzheimer Disease Biomarkers: Moving from CSF to Plasma for Reliable Detection of Amyloid and tau Pathology
Authors: Kang Ju Hee , Korecka Magdalena , Lee Edward B , Cousins Katheryn A Q , Tropea Thomas F , Chen-Plotkin Alice A , Irwin David J , Wolk David , Brylska Magdalena , Wan Yang , Shaw Leslie M
Published: September 2023

Background

Development of validated biomarkers to detect early Alzheimer disease (AD) neuropathology is needed for therapeutic AD trials. Abnormal concentrations of “core” AD biomarkers, cerebrospinal fluid (CSF) amyloid beta1–42, total tau, and phosphorylated tau correlate well with neuroimaging biomarkers and autopsy findings. Nevertheless, given the limitations of established CSF and neuroimaging biomarkers, accelerated development of blood-based AD biomarkers is underway.

Content

Here we describe the clinical significance of CSF and plasma AD biomarkers to detect disease pathology throughout the Alzheimer continuum and correlate with imaging biomarkers. Use of the AT(N) classification by CSF and imaging biomarkers provides a more objective biologically based diagnosis of AD than clinical diagnosis alone. Significant progress in measuring CSF AD biomarkers using extensively validated highly automated assay systems has facilitated their transition from research use only to approved in vitro diagnostics tests for clinical use. We summarize development of plasma AD biomarkers as screening tools for enrollment and monitoring participants in therapeutic trials and ultimately in clinical care. Finally, we discuss the challenges for AD biomarkers use in clinical trials and precision medicine, emphasizing the possible ethnocultural differences in the levels of AD biomarkers.

CSF AD biomarker measurements using fully automated analytical platforms is possible. Building on this experience, validated blood-based biomarker tests are being implemented on highly automated immunoassay and mass spectrometry platforms. The progress made developing analytically and clinically validated plasma AD biomarkers within the AT(N) classification scheme can accelerate use of AD biomarkers in therapeutic trials and routine clinical practice.
Technological change, training, and within-firm wage inequality in Germany
Authors: Müller Christoph
Published: September 2023

Technological change increases the demand for higher skills and fosters wage inequality. Studies on technological change often emphasize the importance of training to adapt workers’ skills to technology use and mitigate inequality. However, we know little about firms’ training activities and their consequences for inequality in the context of technological change. This article investigates, first, whether firms’ decisions to invest in information technology (IT) are associated with skill bias in firms’ training activities, whether this is conditional on the job tasks of workers, and, whether the relationship between IT investments and training activities affects the wage gap within firms. Using linked employer–employee data containing detailed information about investments and training, I show that firms’ IT investments have a large positive effect on the training participation of high-skilled workers. In contrast, the positive effect on low-skilled workers is smaller, short lasting and conditional on workers job tasks. Additional investigations show that the training of high-skilled workers mediates approximately 5 per cent of the effect of IT investments on wage inequality within firms. In the conclusions, I highlight the broader implications of these findings for the effects of technological change for inequality in training opportunities.
Evolution along allometric lines of least resistance: morphological differentiation in Pristurus geckos
Authors: Tejero-Cicuéndez Héctor , Menéndez Iris , Talavera Adrián , Mochales-Riaño Gabriel , Burriel-Carranza Bernat , Simó-Riudalbas Marc , Carranza Salvador , Adams Dean C
Published: September 2023

Species living in distinct habitats often experience unique ecological selective pressures, which can drive phenotypic divergence. However, how ecophenotypic patterns are affected by allometric trends and trait integration levels is less well understood. Here we evaluate the role of allometry in shaping body size and body form diversity in Pristurus geckos utilizing differing habitats. We found that patterns of allometry and integration in body form were distinct in species with different habitat preferences, with ground-dwelling Pristurus displaying the most divergent allometric trend and high levels of integration. There was also strong concordance between intraspecific allometry across individuals and evolutionary allometry among species, revealing that differences in body form among individuals were predictive of evolutionary changes across the phylogeny at macroevolutionary scales. This suggested that phenotypic evolution occurred along allometric lines of least resistance, with allometric trajectories imposing a strong influence on the magnitude and direction of size and shape changes across the phylogeny. When viewed in phylomorphospace, the largest rock-dwelling species were most similar to the smallest ground-dwelling species, and vice versa. Thus, in Pristurus, phenotypic evolution along the differing habitat-based allometric trajectories resulted in similar body forms at differing body sizes in distinct ecological habitats.
Factors Associated With Response to Rescue Therapy in Acute Severe Ulcerative Colitis
Authors: Li Wai Suen Christopher F D , Seah Dean , Choy Matthew C , De Cruz Peter
Published: September 2023

Background

Acute severe ulcerative colitis (ASUC) is a medical emergency for which colectomy is required in patients who do not respond to rescue therapy. While previous studies have predominantly focused on predicting outcome to first-line corticosteroid therapy, there is a need to understand the factors associated with response to rescue therapies in order to improve clinical outcomes. We reviewed the evidence regarding factors associated with response to rescue therapy in adults with ASUC and identified future directions for research.

Methods

A systematic search of the literature was conducted, and 2 reviewers independently assessed studies for inclusion.

Results

Of 3509 records screened, 101 completed studies were eligible for inclusion. We identified 42 clinical, hematological, biochemical, endoscopic, or pharmacological factors associated with response to rescue therapy. Older age (≥50 years), thiopurine experience, and cytomegalovirus or Clostridioides difficile infection were associated with a higher risk of nonresponse to rescue therapy. Biochemical factors associated with poorer response included an elevated C-reactive protein (CRP) ≥30mg/L on admission, hypoalbuminemia and an elevated ratio of CRP to albumin. Severe endoscopic findings, including a Mayo endoscopic score of 3 or Ulcerative Colitis Endoscopic Index of Severity ≥5, portended poorer outcomes. The role of fecal calprotectin and therapeutic value of measuring infliximab drug levels in ASUC remain to be defined.

Conclusions

Response to rescue therapy can be predicted by several specific factors, which would aid clinical decision-making. Existing and emerging factors should be integrated within predictive and prognostic models to help improve clinical outcomes.
Implementation Behaviours and a Strength-Based Approach to Equality and Human Rights Implementation
Authors: Barrett David
Published: September 2023

The introduction of the Public Sector Equality Duty (PSED) and the Human Rights Act were intended to establish an equality and human rights culture within public authorities. However, so far this culture has failed to take hold. Both utilise an enforcement pyramid model of regulation, where penalties increasingly progress until non-compliers comply. Using original empirical data this article explores the implementation of equality and human rights law within public authorities via semi-structured interviews. It finds three different implementation profiles: strong implementation (where individuals make the most of the resources they have and drive ever deeper implementation), mixed implementation (where individuals oscillate between deeper and perfunctory implementation), and weak implementation (where individuals avoid taking meaningful action due to feeling overwhelmed and in need of rescue). On the basis of these behaviours, it is argued that an alternative strength-based model of regulation is needed to supplement the enforcement pyramid and truly establish an equality and human rights culture within public authorities.
Simultaneous Determination of Estradiol Cypionate and Medroxyprogesterone Acetate Hormones in Injectable Suspension by UV Spectrophotometry Based on Least-Squares Support Vector Machine and Fuzzy Inference System: Comparison with HPLC
Authors: Valizadeh Maryam , Ameri Braki Zahra , Smiley Erfan
Published: September 2023

Background

The combination of estradiol cypionate (ECA) and medroxyprogesterone acetate (MPA) is used to prevent pregnancy in women. The analysis of the ECA and MPA combination reveals a challenge due to the strong overlap of the spectra of these compounds.

Objective

Spectrophotometry techniques along with chemometrics methods are simple, fast, precise, and low-cost for the simultaneous determination of ECA and MPA in a combined pharmaceutical dosage form.

Methods

Two developed approaches, the least-squares support vector machine (LSSVM) and fuzzy inference system (FIS), along with a spectrophotometric method were proposed to solve such a challenging overlap.

Results

Based on the cross-validation method, the regularization parameter (γ) and width of the function (σ) in the LSSVM model were optimized and the root mean square error (RMSE) values were found to be 0.3957 and 0.2839 for ECA and MDA, respectively. The mean recovery values were 99.87 and 99.63% for ECA and MDA, respectively. The FIS coupled with principal component analysis (PCA) showed mean recovery percentages equal to 99.05 and 99.50% for ECA and MDA, respectively. Also, the RMSE of both components was lower than 0.3.

Conclusion

The analysis results of a real sample (injection suspension) using the proposed methods were compared with HPLC by a one-way analysis of variance (ANOVA) test, and no significant differences were found in the results.

Highlights

Intelligent methods were proposed for the simultaneous determination of ECA and MPA. The least-squares support vector machine and fuzzy inference system along with spectrophotometry were used. HPLC as a reference method was performed and compared with chemometrics methods. The benefits of the proposed approaches are that they are rapid, simple, low-cost, and accurate.
What Evidence for a Cholera Vaccine? Jaime Ferrán’s Submissions to the Prix Bréant
Authors: Uzcanga Clara , Teira David
Published: September 2023

This article analyses how the French Academy of Sciences assessed Jaime Ferrán’s cholera vaccine submitted for the Prix Bréant in the 1880s. Ferrán, a Spanish independent physician, discovered the treatment in 1884 and tried it on thousands of patients during the cholera outbreak in Valencia the following year. His evaluation sparked a controversy in Spain and abroad on the vaccine’s efficacy. The Bréant jury did not see any evidence for it in Ferrán’s submission, a decision usually interpreted in terms of French scientific nationalism (or simple chauvinism): an outsider from the scientific periphery could not be awarded the Bréant. Drawing on the archival records of the award, we suggest that Ferrán failed instead to provide data that the Academy could consider unbiased, according to the contemporary standards for data presentation. We will illustrate these standards at work in the assessment of another submission from Spain, by Philip Hauser, who received the Bréant for the thoroughness of his statistical endeavour.
The maize transcription factor CCT regulates drought tolerance by interacting with Fra a 1, E3 ligase WIPF2, and auxin response factor Aux/IAA8
Authors: Zhang Zhaoheng , Qu Jiayue , Lu Min , Zhao Xinyu , Xu Yang , Wang Li , Liu Zhongjia , Shi Yingying , Liu Chaotian , Li Yipu , Wang Chao , Xu Mingliang , Nan Zhangjie , Cao Qingqin , Pan Jinbao , Liu Wende , Li Xinrui , Sun Qingpeng , Wang Weixiang
Published: September 2023

Plants are commonly exposed to abiotic stressors, which can affect their growth, productivity, and quality. Previously, the maize transcription factor ZmCCT was shown to be involved in the photoperiod response, delayed flowering, and quantitative resistance to Gibberella stalk rot. In this study, we demonstrate that ZmCCT can regulate plant responses to drought. ZmCCT physically interacted with ZmFra a 1, ZmWIPF2, and ZmAux/IAA8, which localized to the cell membrane, cytoplasm, and nucleus, respectively, both in vitro and in vivo in a yeast two-hybrid screen in response to abiotic stress. Notably, ZmCCT recruits ZmWIPF2 to the nucleus, which has strong E3 self-ubiquitination activity dependent on its RING-H2 finger domain in vitro. When treated with higher indole-3-acetic acid/abscisic acid ratios, the height and root length of Y331-ΔTE maize plants increased. Y331-ΔTE plants exhibited increased responses to exogenously applied auxin or ABA compared to Y331 plants, indicating that ZmCCT may be a negative regulator of ABA signalling in maize. In vivo, ZmCCT promoted indole-3-acetic acid biosynthesis in ZmCCT-overexpressing Arabidopsis. RNA-sequencing and DNA affinity purification-sequencing analyses showed that ZmCCT can regulate the expression of ZmRD17, ZmAFP3, ZmPP2C, and ZmARR16 under drought. Our findings provide a detailed overview of the molecular mechanism controlling ZmCCT functions and highlight that ZmCCT has multiple roles in promoting abiotic stress tolerance.
Analysis of the features of 105 confirmed CRISPR loci in 487 Klebsiella variicola
Authors: Xi Yanyan , Zhao Jiaxue , Zhang Jiangfeng , Jin Yuefei , Yang Haiyan , Duan Guangcai , Chen Shuaiyin , Long Jinzhao
Published: September 2023

Klebsiella variicola, an emerging human pathogen, poses a threat to public health. The horizontal gene transfer (HGT) of plasmids is an important driver of the emergence of multiple antibiotic-resistant K. variicola. Clustered regularly interspersed short palindromic repeats (CRISPR) coupled with CRISPR-associated genes (CRISPR/Cas) constitute an adaptive immune system in bacteria, and can provide acquired immunity against HGT. However, the information about the CRISPR/Cas system in K. variicola is still limited. In this study, 487 genomes of K. variicola obtained from the National Center for Biotechnology Information database were used to analyze the characteristics of CRISPR/Cas systems. Approximately 21.56% of genomes (105/487) harbor at least one confirmed CRISPR array. Three types of CRISPR/Cas systems, namely the type I-E, I-E*, and IV-A systems, were identified among 105 strains. Spacer origin analysis further revealed that approximately one-third of spacers significantly match plasmids or phages, which demonstrates the implication of CRISPR/Cas systems in controlling HGT. Moreover, spacers in K. variicola tend to target mobile genetic elements from K. pneumoniae. This finding provides new evidence of the interaction of K. variicola and K. pneumoniae during their evolution. Collectively, our results provide valuable insights into the role of CRISPR/Cas systems in K. variicola.
POSSESSION AND CONSUMPTION: CLARICE LISPECTOR AND THE ETHICS OF MYSTICISM
Authors: Denne Sarah
Published: September 2023

Many critics have called Clarice Lispector a mystic. Lispector, however, was not a religious figure, but rather a 20th-century Brazilian writer who was influenced by both her Jewish background and her Catholic Brazilian context. There are various forms of Jewish and Christian mysticism that reject transcendent union with God and, by referencing them, I elucidate the complexity of Lispector’s mystical fiction. By looking at challenges to mystical union in these traditions, I aim to show the ethical complexity of this concept and how that complexity is deepened through Lispector’s writing as she problematises blurred boundaries between self and Other.