bluuebunny/crossref_metadata_2025 huggingface dataset:
PRScalc, a privacy-preserving calculation of raw polygenic risk scores from direct-to-consumer genomics data
Authors: Sandoval Lorena , Jafri Saleet , Balasubramanian Jeya Balaji , Bhawsar Praphulla , Edelson Jacob L , Martins Yasmmin , Maass Wolfgang , Chanock Stephen J , Garcia-Closas Montserrat , Almeida Jonas S
Published: October 2023

Motivation

Currently, the Polygenic Score (PGS) Catalog curates over 400 publications on over 500 traits corresponding to over 3000 polygenic risk scores (PRSs). To assess the feasibility of privately calculating the underlying multivariate relative risk for individuals with consumer genomics data, we developed an in-browserPRS calculator for genomic data that does not circulate any data or engage in any computation outside of the user's personal device.

Results

A prototype personal risk score calculator, created for research purposes, was developed to demonstrate how the PGS Catalog can be privately and readily applied to readily available direct-to-consumer genetic testing services, such as 23andMe. No software download, installation, or configuration is needed. The PRS web calculator matches individual PGS catalog entries with an individual's 23andMe genome data composed of 600k to 1.4 M single-nucleotide polymorphisms (SNPs). Beta coefficients provide researchers with a convenient assessment of risk associated with matched SNPs. This in-browser application was tested in a variety of personal devices, including smartphones, establishing the feasibility of privately calculating personal risk scores with up to a few thousand reference genetic variations and from the full 23andMe SNP data file (compressed or not).

Availability and implementation

The PRScalc web application is developed in JavaScript, HTML, and CSS and is available at GitHub repository (https://episphere.github.io/prs) under an MIT license. The datasets were derived from sources in the public domain: [PGS Catalog, Personal Genome Project].
Peyote as Earth Medicine: Examining How Symbolic Meanings Shape Experiences With Psychedelics
Authors: Copes Heith , Ragland Jared
Published: October 2023

Narrative criminology prioritizes personal narratives for explaining past behaviours and shaping future decisions. Using this perspective, we rely on data from a photo-ethnography with people who use peyote in religious ceremonies to understand how their discourses about peyote shape their experiences with it. We find that participants define peyote as an ‘earth medicine’ that helps with healing (physical, spiritual and psychological) and thus should be respected. This narrative dictates how and when they use it (e.g. with intention and not recreationally), distances from other drugs (which are regarded as harmful) and directs their physiological experiences. Findings suggest that the symbolic meaning associated with specific drugs justifies using it and directs and encourages continued use. Thus, understanding drug use requires examining how discourse about specific drugs are incorporated into personal narratives.
Characteristics and prognosis of first-time hospitalized patients with generalized pustular psoriasis: insights from national databases
Authors: Haugaard Jeanette Halskou , Thein David , Egeberg Alexander
Published: October 2023

In a Danish nationwide population-based study, we found that the mortality rate for patients with first-time hospitalization for generalized pustular psoriasis was zero during hospitalization but increased to 7% within the first 12 months following discharge. The study period spanned 2008–2017; in this period, the most frequently prescribed pharmacotherapy during hospitalization was acitretin, followed by methotrexate.
Structural and Socio-Political Barriers to Providing Services to Arab-Palestinian Young Women: Social Workers’ Perspectives
Authors: Elias Haneen , Alnabilsy Raghda , Pagorek-Eshel Shira , Levin Lia
Published: October 2023

The aim of the study was to understand structural and socio-political barriers faced by social workers to providing services to Arab-Palestinian young women abused in childhood, considering their multiple marginalisation. The literature has addressed the structural barriers in terms of the written policy and the social services provided to the Arab-Palestinian minority. However, little is known about how these barriers affect the provision of services to Arab-Palestinian young women abused in childhood from the perspective of service providers. To address this gap, twenty-one social workers were interviewed in depth. The findings revealed two main themes: (i) structural discrimination and the socio-political context of Arab Palestinians in Israel; (ii) challenges and structural barriers at the level of social policy. Our findings shed light on the oppressive othering of Arab-Palestinian young women, who feel invisible vis- à-vis governmental organisations. Thus, social workers working in the field should examine the needs of the young women and work in collaboration with senior government officials to promote culture- and gender-adapted programmes.
Temporal manipulation of the Scn1a gene reveals its essential role in adult brain function
Authors: Di Berardino Claudia , Mainardi Martina , Brusco Simone , Benvenuto Elena , Broccoli Vania , Colasante Gaia
Published: October 2023

Dravet syndrome is a severe epileptic encephalopathy, characterized by drug-resistant epilepsy, severe cognitive and behavioural deficits, with increased risk of sudden unexpected death (SUDEP). It is caused by haploinsufficiency of SCN1A gene encoding for the α-subunit of the voltage-gated sodium channel Nav1.1. Therapeutic approaches aiming to upregulate the healthy copy of SCN1A gene to restore its normal expression levels are being developed. However, whether Scn1a gene function is required only during a specific developmental time-window or, alternatively, if its physiological expression is necessary in adulthood is untested up to now.

We induced Scn1a gene haploinsufficiency at two ages spanning postnatal brain development (P30 and P60) and compared the phenotypes of those mice to Scn1a perinatally induced mice (P2), recapitulating all deficits of Dravet mice.

Induction of heterozygous Nav1.1 mutation at P30 and P60 elicited susceptibility to the development of both spontaneous and hyperthermia-induced seizures and SUDEP rates comparable to P2-induced mice, with symptom onset accompanied by the characteristic GABAergic interneuron dysfunction. Finally, delayed Scn1a haploinsufficiency induction provoked hyperactivity, anxiety and social attitude impairment at levels comparable to age matched P2-induced mice, while it was associated with a better cognitive performance, with P60-induced mice behaving like the control group.

Our data show that maintenance of physiological levels of Nav1.1 during brain development is not sufficient to prevent Dravet symptoms and that long-lasting restoration of Scn1a gene expression would be required to grant optimal clinical benefit in patients with Dravet syndrome.
Effective connectivity between deep brain stimulation targets in individuals with treatment-resistant depression
Authors: Amiri Saba , Arbabi Mohammad , Rahimi Milad , Parvaresh-Rizi Mansour , Mirbagheri Mehdi M
Published: October 2023

The therapeutic effect of deep brain stimulation on patients with treatment-resistant depression is strongly dependent on the connectivity of the stimulation region with other regions associated with depression. The aims of this study are to characterize the effective connectivity between the brain regions playing important roles in depression and further investigate the underlying pathophysiological mechanisms of treatment-resistant depression and the mechanisms involving deep brain stimulation. Thirty-three individuals with treatment-resistant depression and 29 healthy control subjects were examined. All subjects underwent resting-state functional MRI scanning. The coupling parameters reflecting the causal interactions among deep brain stimulation targets and medial prefrontal cortex were estimated using spectral dynamic causal modelling. Our results showed that compared to the healthy control subjects, in the left hemisphere of treatment-resistant depression patients, the nucleus accumbens was inhibited by the inferior thalamic peduncle and excited the ventral caudate and the subcallosal cingulate gyrus, which in turn excited the lateral habenula. In the right hemisphere, the lateral habenula inhibited the ventral caudate and the nucleus accumbens, both of which inhibited the inferior thalamic peduncle, which in turn inhibited the cingulate gyrus. The ventral caudate excited the lateral habenula and the cingulate gyrus, which excited the medial prefrontal cortex. Furthermore, these effective connectivity links varied between males and females, and the left and right hemispheres. Our findings suggest that intrinsic excitatory/inhibitory connections between deep brain stimulation targets are impaired in treatment-resistant depression patients, and that these connections are sex dependent and hemispherically lateralized. This knowledge can help to better understand the underlying mechanisms of treatment-resistant depression, and along with tractography, structural imaging, and other relevant clinical information, may assist to determine the appropriate region for deep brain stimulation therapy in each treatment-resistant depression patient.
A blunted TH17 cytokine signature in women with mild cognitive impairment: insights from inflammatory profiling of a community-based cohort of older adults
Authors: Bachstetter Adam D , Lutshumba Jenny , Winford Edric , Abner Erin L , Martin Barbra J , Harp Jordan P , Van Eldik Linda J , Schmitt Frederick A , Wilcock Donna M , Stowe Ann M , Jicha Gregory A , Nikolajczyk Barbara S
Published: October 2023

People with dementia have an increase in brain inflammation, caused in part by innate and adaptive immune cells. However, it remains unknown whether dementia-associated diseases alter neuro-immune reflex arcs to impact the systemic immune system. We examined peripheral immune cells from a community-based cohort of older adults to test if systemic inflammatory cytokine signatures associated with early stages of cognitive impairment. Human peripheral blood mononuclear cells were cultured with monocyte or T-cell-targeted stimuli, and multiplex assays quantitated cytokines in the conditioned media. Following T-cell-targeted stimulation, cells from women with cognitive impairment produced lower amounts of TH17 cytokines compared with cells from cognitively healthy women, while myeloid-targeted stimuli elicited similar amounts of cytokines from cells of both groups. This TH17 signature correlated with the proportion of circulating CD4+ and CD8+ T cells and plasma glial fibrillary acidic protein and neurofilament light concentrations. These results suggest that decreases in TH17 cytokines could be an early systemic change in women at risk for developing dementia. Amelioration of TH17s cytokines in early cognitive impairment could, in part, explain the compromised ability of older adults to respond to vaccines or defend against infection.
How embodied is cognition? fMRI and behavioral evidence for common neural resources underlying motor planning and mental rotation of bodily stimuli
Authors: Doganci Naz , Iannotti Giannina Rita , Coll Sélim Yahia , Ptak Radek
Published: October 2023

Functional neuroimaging shows that dorsal frontoparietal regions exhibit conjoint activity during various motor and cognitive tasks. However, it is unclear whether these regions serve several, computationally independent functions, or underlie a motor “core process” that is reused to serve higher-order functions. We hypothesized that mental rotation capacity relies on a phylogenetically older motor process that is rooted within these areas. This hypothesis entails that neural and cognitive resources recruited during motor planning predict performance in seemingly unrelated mental rotation tasks. To test this hypothesis, we first identified brain regions associated with motor planning by measuring functional activations to internally-triggered vs externally-triggered finger presses in 30 healthy participants. Internally-triggered finger presses yielded significant activations in parietal, premotor, and occipitotemporal regions. We then asked participants to perform two mental rotation tasks outside the scanner, consisting of hands or letters as stimuli. Parietal and premotor activations were significant predictors of individual reaction times when mental rotation involved hands. We found no association between motor planning and performance in mental rotation of letters. Our results indicate that neural resources in parietal and premotor cortex recruited during motor planning also contribute to mental rotation of bodily stimuli, suggesting a common core component underlying both capacities.
Graded brain fMRI response to somatic and visual acupuncture stimulation
Authors: Yoon Da-Eun , Lee Seoyoung , Kim Jundong , Kim Kyuseok , Park Hi-Joon , Napadow Vitaly , Lee In-Seon , Chae Younbyoung
Published: October 2023

Increased stimulation can enhance acupuncture clinical response; however, the impact of acupuncture stimulation as “dosage” has rarely been studied. Furthermore, acupuncture can include both somatic and visual components. We assessed both somatic and visual acupuncture dosage effects on sensory ratings and brain response. Twenty-four healthy participants received somatic (needle inserted, manually stimulated) and visual (needle video, no manual stimulation) acupuncture over the leg at three different dosage levels (control, low-dose, and high-dose) during functional magnetic resonance imaging (fMRI). Participants reported the perceived deqi sensation for each acupuncture dose level. Blood-oxygen-level dependent imaging data were analyzed by general linear model and multivariate pattern analysis. For both somatic and visual acupuncture, reported deqi sensation increased with increased dosage of acupuncture stimulation. Brain fMRI analysis demonstrated that higher dosage of somatic acupuncture produced greater brain responses in sensorimotor processing areas, including anterior and posterior insula and secondary somatosensory cortex. For visual acupuncture, higher dosage of stimulation produced greater brain responses in visual-processing areas, including the middle temporal visual areas (V5/MT+) and occipital cortex. Psychophysical and psychophysiological responses to both somatic and visual acupuncture were graded in response to higher doses. Our findings suggest that acupuncture response may be enhanced by the dosage of needling-specific and nonspecific components, represented by different neural mechanisms.
EEG-based assessment of temporal fine structure and envelope effect in mandarin syllable and tone perception
Authors: Ni Guangjian , Xu Zihao , Bai Yanru , Zheng Qi , Zhao Ran , Wu Yubo , Ming Dong
Published: October 2023

In recent years, speech perception research has benefited from low-frequency rhythm entrainment tracking of the speech envelope. However, speech perception is still controversial regarding the role of speech envelope and temporal fine structure, especially in Mandarin. This study aimed to discuss the dependence of Mandarin syllables and tones perception on the speech envelope and the temporal fine structure. We recorded the electroencephalogram (EEG) of the subjects under three acoustic conditions using the sound chimerism analysis, including (i) the original speech, (ii) the speech envelope and the sinusoidal modulation, and (iii) the fine structure of time and the modulation of the non-speech (white noise) sound envelope. We found that syllable perception mainly depended on the speech envelope, while tone perception depended on the temporal fine structure. The delta bands were prominent, and the parietal and prefrontal lobes were the main activated brain areas, regardless of whether syllable or tone perception was involved. Finally, we decoded the spatiotemporal features of Mandarin perception from the microstate sequence. The spatiotemporal feature sequence of the EEG caused by speech material was found to be specific, suggesting a new perspective for the subsequent auditory brain-computer interface. These results provided a new scheme for the coding strategy of new hearing aids for native Mandarin speakers.

Highlights
Molecular mechanisms underlying human spatial cognitive ability revealed with neurotransmitter and transcriptomic mapping
Authors: Yang Jia , Chen Kexuan , Zhang Junyu , Ma Yingzi , Chen Meiling , Shao Heng , Zhang Xing , Fan Defang , Wang Zhengbo , Sun Zhenglong , Wang Jiaojian
Published: October 2023

Mental rotation, one of the cores of spatial cognitive abilities, is closely associated with spatial processing and general intelligence. Although the brain underpinnings of mental rotation have been reported, the cellular and molecular mechanisms remain unexplored. Here, we used magnetic resonance imaging, a whole-brain spatial distribution atlas of 19 neurotransmitter receptors, transcriptomic data from Allen Human Brain Atlas, and mental rotation performances of 356 healthy individuals to identify the genetic/molecular foundation of mental rotation. We found significant associations of mental rotation performance with gray matter volume and fractional amplitude of low-frequency fluctuations in primary visual cortex, fusiform gyrus, primary sensory-motor cortex, and default mode network. Gray matter volume and fractional amplitude of low-frequency fluctuations in these brain areas also exhibited significant sex differences. Importantly, spatial correlation analyses were conducted between the spatial patterns of gray matter volume or fractional amplitude of low-frequency fluctuations with mental rotation and the spatial distribution patterns of neurotransmitter receptors and transcriptomic data, and identified the related genes and neurotransmitter receptors associated with mental rotation. These identified genes are localized on the X chromosome and are mainly involved in trans-synaptic signaling, transmembrane transport, and hormone response. Our findings provide initial evidence for the neural and molecular mechanisms underlying spatial cognitive ability.
Connecting the dots: harnessing dual-site transcranial magnetic stimulation to quantify the causal influence of medial frontal areas on the motor cortex
Authors: Neige Cécilia , Vassiliadis Pierre , Ali Zazou Abdelkrim , Dricot Laurence , Lebon Florent , Brees Thomas , Derosiere Gerard
Published: October 2023

Dual-site transcranial magnetic stimulation has been widely employed to investigate the influence of cortical structures on the primary motor cortex. Here, we leveraged this technique to probe the causal influence of two key areas of the medial frontal cortex, namely the supplementary motor area and the medial orbitofrontal cortex, on primary motor cortex. We show that supplementary motor area stimulation facilitates primary motor cortex activity across short (6 and 8 ms) and long (12 ms) inter-stimulation intervals, putatively recruiting cortico-cortical and cortico-subcortico-cortical circuits, respectively. Crucially, magnetic resonance imaging revealed that this facilitatory effect depended on a key morphometric feature of supplementary motor area: individuals with larger supplementary motor area volumes exhibited more facilitation from supplementary motor area to primary motor cortex for both short and long inter-stimulation intervals. Notably, we also provide evidence that the facilitatory effect of supplementary motor area stimulation at short intervals is unlikely to arise from spinal interactions of volleys descending simultaneously from supplementary motor area and primary motor cortex. On the other hand, medial orbitofrontal cortex stimulation moderately suppressed primary motor cortex activity at both short and long intervals, irrespective of medial orbitofrontal cortex volume. These results suggest that dual-site transcranial magnetic stimulation is a fruitful approach to investigate the differential influence of supplementary motor area and medial orbitofrontal cortex on primary motor cortex activity, paving the way for the multimodal assessment of these fronto-motor circuits in health and disease.
Food and Drug Administration Public Workshop Summary—Addressing Challenges in Inhaled Antifungal Drug Development
Authors: Jjingo Caroline J , Bala Shukal , Waack Ursula , Needles Mark , Bensman Timothy J , McMaster Owen , Smith Thomas , Blakely Brandon , Chan Irene Z , Puthawala Khalid , Dixon Cheryl , Kim Yongman , Lim Robert , Colangelo Philip , St. Clair Christopher , Nambiar Sumathi , Moss Richard B , Botgros Radu , Bazaz Rohit , Denning David W , Marr Kieren A , Husain Shahid , Berman Lance , Christensen Dale J , Keywood Charlotte , Clayton Russell G , Walsh Thomas J , Song Hyo Sook E , Shukla Sunita J , Farley John
Published: October 2023

Allergic bronchopulmonary aspergillosis and invasive fungal diseases represent distinct infectious entities that cause significant morbidity and mortality. Currently, administered inhaled antifungal therapies are unapproved, have suboptimal efficacy, and are associated with considerable adverse reactions. The emergence of resistant pathogens is also a growing concern. Inhaled antifungal development programs are challenged by inadequate nonclinical infection models, highly heterogenous patient populations, low prevalence rates of fungal diseases, difficulties defining clinical trial enrollment criteria, and lack of robust clinical trial endpoints. On 25 September 2020, the US Food and Drug Administration (FDA) convened a workshop with experts in pulmonary medicine and infectious diseases from academia, industry, and other governmental agencies. Key discussion topics included regulatory incentives to facilitate development of inhaled antifungal drugs and combination inhalational devices, limitations of existing nonclinical models and clinical trial designs, patient perspectives, and industry insights.
3D Shape Marks: A 360-Degree Analysis
Authors: Fhima Ilanah
Published: October 2023

Today’s consumers use a range of cues to identify product origin, including brand names, logos, colours and shapes. The range of registrable marks has therefore expanded, but this brings a risk that features which others have a legitimate competitive need to use will fall under the exclusive control of a single undertaking. Registration may also be used to extend the finite duration of other IP rights that the owner has already enjoyed. Consequently, trade mark law contains functionality limitations on registration designed to protect these competitive concerns. This piece considers how well those limitations are working. The CJEU has also seemed to apply stricter distinctiveness rules to shape marks based on the assumption that consumers are not used to seeing shapes as origin indicators. Some have assumed this means that it is almost impossible to register shape marks—this research examines whether this is really so. How functionality and distinctiveness work in practice is examined through an empirical analysis over a 5-year period of all shape mark applications to the European Union Intellectual Property Office. This piece considers which types of marks are being registered, which are being refused and why. It reveals that distinctiveness, rather than functionality, is having the biggest impact on shape mark registration, and in fact a larger number of shape marks than expected are registered: often because of the addition of non-3D matter. However, are a significant number of marks comprised just of product shapes. It concludes with a discussion of competitive and policy challenges identified by this research.
SPAW-SMOTE: Space Partitioning Adaptive Weighted Synthetic Minority Oversampling Technique For Imbalanced Data Set Learning
Authors: Zhang Qiang , He Junjiang , Li Tao , Lan Xiaolong , Fang Wenbo , Li Yihong
Published: October 2023

The problem of data imbalance is common in reality, which greatly affects the performance of classifiers. Most of the solutions are to balance the data set by generating new minority class samples, which are faced with the problems of selecting the appropriate area for generating samples, fuzzy classification boundary and uneven distribution of samples. To solve these problems, we propose a novel oversampling algorithm named space partitioning adaptive weighted synthetic minority oversampling technique (SPAW-SMOTE). We first divide the data space into boundary space and non-boundary space based on spatial partitioning techniques. The number of samples to be generated is assigned to different spaces by the designed adaptive weighting algorithm, which is used to solve the problems of uneven distribution of samples and easy to blur the classification boundary. Finally, we also endeavor to develop a new generation algorithm to reduce the probability of overlapping samples generated when synthesizing new samples and to ensure the diversity of new samples. Experimental results on 18 real-world data sets show that the average performance (G-mean, F1-measure and Area Under Curve) of SPAW-SMOTE is significantly better than other existing oversampling techniques.
A novel in vitro model of the small intestinal epithelium in co-culture with ‘gut-like’ dendritic cells
Authors: Johnston Luke J , Barningham Liam , Campbell Eric L , Cerovic Vuk , Duckworth Carrie A , Luu Lisa , Wastling Jonathan , Derricott Hayley , Coombes Janine L
Published: October 2023

Cross-talk between dendritic cells (DCs) and the intestinal epithelium is important in the decision to mount a protective immune response to a pathogen or to regulate potentially damaging responses to food antigens and the microbiota. Failures in this decision-making process contribute to the development of intestinal inflammation, making the molecular signals that pass between DCs and intestinal epithelial cells potential therapeutic targets. Until now, in vitro models with sufficient complexity to understand these interactions have been lacking. Here, we outline the development of a co-culture model of in vitro differentiated ‘gut-like’ DCs with small intestinal organoids (enteroids). Sequential exposure of murine bone marrow progenitors to Flt3L, granulocyte macrophage colony-stimulating factor (GM-CSF) and all-trans-retinoic acid (RA) resulted in the generation of a distinct population of conventional DCs expressing CD11b+SIRPα+CD103+/− (cDC2) exhibiting retinaldehyde dehydrogenase (RALDH) activity. These ‘gut-like’ DCs extended transepithelial dendrites across the intact epithelium of enteroids. ‘Gut-like’ DC in co-culture with enteroids can be utilized to define how epithelial cells and cDCs communicate in the intestine under a variety of different physiological conditions, including exposure to different nutrients, natural products, components of the microbiota, or pathogens. Surprisingly, we found that co-culture with enteroids resulted in a loss of RALDH activity in ‘gut-like’ DCs. Continued provision of GM-CSF and RA during co-culture was required to oppose putative negative signals from the enteroid epithelium. Our data contribute to a growing understanding of how intestinal cDCs assess environmental conditions to ensure appropriate activation of the immune response.
A novel, small-volume subcutaneous furosemide formulation delivered by an abdominal patch infusor device in patients with heart failure: results of two phase I studies
Authors: Osmanska Joanna , Brooksbank Katriona , Docherty Kieran F , Robertson Stacy , Wetherall Kirsty , McConnachie Alex , Hu Jerry , Gardner Roy S , Clark Andrew L , Squire Iain B , Kalra Paul R , Jhund Pardeep S , Muntendam Pieter , McMurray John J V , Petrie Mark C , Campbell Ross T
Published: October 2023

Aims

Subcutaneous (SC) furosemide has potential advantages over intravenous (IV) furosemide by enabling self-administration or administration by a lay caregiver, such as facilitating early discharge, preventing hospitalizations, and in palliative care. A high-concentration, pH-neutral furosemide formulation has been developed for SC administration via a small patch infusor pump. We aimed to compare the bioavailability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of a new SC furosemide formulation with conventional IV furosemide and describe the first use of a bespoke mini-pump to administer this formulation.

Methods and results

A novel pH-neutral formulation of SC furosemide containing 80 mg furosemide in ∼2.7 mL (infused over 5 h) was investigated. The first study was a PK/PD study of SC furosemide compared with 80 mg IV furosemide administered as a bolus in ambulatory patients with heart failure (HF). The primary outcome was absolute bioavailability of SC compared with IV furosemide. The second study investigated the same SC furosemide preparation delivered by a patch infusor in patients hospitalized with HF. Primary outcome measures were treatment-emergent adverse events, infusion site pain, device performance, and PK measurements.

The absolute bioavailability of SC furosemide in comparison to IV furosemide was 112%, resulting in equivalent diuresis and natriuresis. When SC furosemide was administered via the patch pump, there were no treatment-emergent adverse events and 95% of participants reported no/minor discomfort at the infusion site.

Conclusion

The novel preparation of SC furosemide had similar bioavailability to IV furosemide. Administration via a patch pump was feasible and well tolerated.
Is Digital Credit Filling a Hole or Digging a Hole? Evidence from Malawi
Authors: Brailovskaya Valentina , Dupas Pascaline , Robinson Jonathan
Published: October 2023

Digital credit has expanded rapidly in Africa, with opaque loan terms amidst low consumer financial literacy. Rich data from Malawi shows substantial demand for a digital loan with a base interest rate of 10% over 15 days, yet most borrowers are not aware of loan terms, repay late and incur substantial late fees. Regression discontinuity analyses show no evidence that access to small digital loans harms consumers’ perceived well-being. A short, randomised, phone-based financial literacy intervention improved knowledge, but did not increase timely loan repayment and modestly increased loan demand, ultimately increasing the likelihood of ever defaulting.
Technology Shocks and Predictable Minsky Cycles
Authors: L’Huillier Jean-Paul , Phelan Gregory , Wieman Hunter
Published: October 2023

Big technological improvements in a new, secondary sector lead to a period of excitement about the future prospects of the overall economy, generating boom-bust dynamics propagating through credit markets. Increased future capital prices relax collateral constraints today, leading to a boom before the realisation of the shock. But reallocation of capital toward the secondary sector when the shock hits leads to a bust going forward. These cycles are perfectly foreseen in our model, making them markedly different from the typical narrative about unexpected financial shocks used to explain crises. Our dynamics obtain without a departure from rational expectations. In fact, these cycles echo Minsky’s original narrative for financial cycles, according to which ‘financial trauma occur [sic] as normal functioning events in a capitalistic economy’ (Minsky, 1980, p. 21).
Parental Investments and Intra-household Inequality in Child Human Capital: Evidence from a Survey Experiment
Authors: Giannola Michele
Published: October 2023

Intra-household inequality explains 40% of child human capital variation in the developing world. I study how parents’ investment contributes to this inequality. To mitigate the identification problem posed by observational data, I design a survey experiment with parents in India that allows me to identify beliefs about the human capital production function, preferences for inequality in outcomes and the role of resources. I find that investments are driven by efficiency considerations: as parents perceive investment and ability as complements, they invest more in higher-achieving children and more so when constrained. Simulations indicate that interventions have intra-household distributional impacts through parental responses.
Mavacamten: a first-in-class myosin inhibitor for obstructive hypertrophic cardiomyopathy
Authors: Braunwald Eugene , Saberi Sara , Abraham Theodore P , Elliott Perry M , Olivotto Iacopo
Published: October 2023

Mavacamten is a first-in-class, targeted, cardiac-specific myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic New York Heart Association Classes II and III obstructive hypertrophic cardiomyopathy (oHCM). Mavacamten was developed to target the hyper-contractile phenotype, which plays a critical role in the pathophysiology of the disease. In Phase 2 and 3 clinical trials, mavacamten was well tolerated, reduced left ventricular outflow tract gradients, improved exercise capacity and symptoms, and was associated with improvements in other clinically relevant parameters, such as patient-reported outcomes and circulating biomarkers. In addition, treatment with mavacamten was associated with evidence of favourable cardiac remodelling in multi-modality imaging studies. Mavacamten substantially reduced guideline eligibility for septal reduction therapy candidates with oHCM and drug-refractory symptoms. In this article, the available efficacy and safety data from completed and ongoing clinical studies of mavacamten in patients with symptomatic oHCM are reviewed. Longer term extension studies may help address questions related to the positioning of mavacamten in current oHCM management algorithms, interactions with background therapy, as well as the potential for disease modification beyond symptomatic relief of left ventricular outflow tract obstruction.
Structural genomic variation and migratory behavior in a wild songbird
Authors: Delmore Kira E , Van Doren Benjamin M , Ullrich Kristian , Curk Teja , van der Jeugd Henk P , Liedvogel Miriam
Published: October 2023

Structural variants (SVs) are a major source of genetic variation; and descriptions in natural populations and connections with phenotypic traits are beginning to accumulate in the literature. We integrated advances in genomic sequencing and animal tracking to begin filling this knowledge gap in the Eurasian blackcap. Specifically, we (a) characterized the genome-wide distribution, frequency, and overall fitness effects of SVs using haplotype-resolved assemblies for 79 birds, and (b) used these SVs to study the genetics of seasonal migration. We detected >15 K SVs. Many SVs overlapped repetitive regions and exhibited evidence of purifying selection suggesting they have overall deleterious effects on fitness. We used estimates of genomic differentiation to identify SVs exhibiting evidence of selection in blackcaps with different migratory strategies. Insertions and deletions dominated the SVs we identified and were associated with genes that are either directly (e.g., regulatory motifs that maintain circadian rhythms) or indirectly (e.g., through immune response) related to migration. We also broke migration down into individual traits (direction, distance, and timing) using existing tracking data and tested if genetic variation at the SVs we identified could account for phenotypic variation at these traits. This was only the case for 1 trait—direction—and 1 specific SV (a deletion on chromosome 27) accounted for much of this variation. Our results highlight the evolutionary importance of SVs in natural populations and provide insight into the genetic basis of seasonal migration.
Successful cultivation of black morel, Morchella sp. in Japan
Authors: Narimatsu Maki , Sato Shiho , Sakamoto Yuichi
Published: October 2023

True morels (Morchella spp.) are economically important edible fungi cultivated mainly in China. Japan is one of the top importers of morels, but there are no reports on the distribution of major cultivated species. To investigate the possibility of black morel cultivation in Japan, phylogenetic analysis, mating-type analysis, and field cultivation tests were conducted using domestically collected strains. A total of 172 strains were isolated from the spores of wild ascomata collected from 15 locations. Mating-type analysis for 118 strains revealed 28 strains had only MAT1-1-1, 40 strains had only MAT1-2-1, and 48 strains had both MAT genes. Seven strains were inoculated in March 2020 at the field cultivation test site. Mycelial growth and conidial layer formation were observed within a month. Ascomata were observed in April 2021 for one of the tested strains. Phylogenetic analysis revealed that both the observed ascomata and fruited strains were Morchella sp. Mel-21, which is one of the cultivated species in China. Moreover, no antagonism was observed in the somatic incompatibility test between strains isolated from observed ascomata and spawn strain. These results suggest that the ascomata originated in the inoculated spawn, a finding that will contribute to commercial morel cultivation in Japan.
Effect of BRAF mutation on the prognosis for patients with colorectal cancer undergoing cytoreductive surgery for synchronous peritoneal metastasis
Authors: Wu Zhijie , Qin Xiusen , Zhang Yuanxin , Luo Jian , Luo Rui , Cai Zonglu , Wang Hui
Published: October 2023

Background

KRAS/BRAF mutations (mutKRAS/mutBRAF) are unfavorable prognostic factors for colorectal cancer (CRC) metastases to the liver and lungs. However, their effects on the prognosis for patients with synchronous peritoneal metastasis (S-PM) of CRC after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are controversial. In the study, we aimed to determine the effects of mutKRAS/mutBRAF on the prognosis for patients with S-PM who received CRS.

Methods

A total of 142 patients diagnosed with S-PM between July 2007 and July 2019 were included in this study. The demographics, mutKRAS/mutBRAF status, overall survival (OS), and progression-free survival (PFS) of the patients were evaluated. The Kaplan–Meier method and log-rank test were used to estimate the difference in survival between groups.

Results

Among 142 patients, 68 (47.9%) showed mutKRAS and 42 (29.5%) showed mutBRAF. The median OS values were 8.4 and 34.3 months for patients with mutBRAF and BRAF wild-type, respectively (P < 0.01). However, KRAS status was not significantly associated with median OS (P = 0.76). Multivariate analysis revealed carcinoembryonic antigen, CRS, HIPEC, and mutBRAF as independent predictors for OS. Based on these findings, a nomogram was constructed. The C-index was 0.789 (95% confidence interval, 0.742–0.836), indicating good predictive ability of the model. Furthermore, the 1- and 2-year survival calibration plots showed good agreement between the predicted and actual OS rates. The area under curves of the 1- and 2-year survival predictions based on the nomogram were 0.807 and 0.682, respectively. Additionally, mutBRAF was significantly associated with lower PFS (P < 0.001).

Conclusions

mutBRAF is an independent prognostic risk factor for S-PM. The established nomogram predicted the OS of patients with CRC having S-PM with high accuracy, indicating its usefulness as a valuable prognostic tool for the designated patient cohort.
Incidence of Dementia and Alzheimer’s Disease, Genetic Susceptibility, and Grip Strength Among Older Adults
Authors: Kim Youngwon , Wang Mengyao , Sharp Stephen J , Au Yeung Shiu Lun , Luo Shan , Jang Haeyoon , Jiesisibieke Zhu Liduzi , Shi Qiaoxin , Chen Ziyuan , Brage Soren
Published: October 2023

Background

Grip strength has prognostic value for aging-related health outcomes. Whether the associations of grip strength with the risk of dementia and Alzheimer’s disease (AD) vary by the genetic risk of AD and related dementias (ADD) is unknown.

Methods

This study included 148 659 older adults of white British ancestry (aged ≥60 years) participating in UK Biobank with no dementia, and self-reported poor health status at baseline. Polygenic risk scores (PRS) for ADD were calculated based on 64 genetic variants. Grip strength was measured by hand dynamometers.

Results

The hazard ratios (HR) of dementia (n = 4 963) and AD (n = 2 373) for high genetic risk of ADD were 2.36 (95% confidence interval [CI]: 2.15–2.59) and 3.00 (95% CI: 2.61–3.44), respectively, compared with low genetic risk. Compared with the bottom tertile of grip strength, the top tertile of grip strength had a hazard ratio (HR) of 0.69 (95% CI: 0.64–0.74) for incident dementia, and 0.74 (95% CI: 0.66–0.82) for incident AD, after adjustment for confounders and PRS for ADD. The risk of dementia and AD was lower with the top grip strength tertile within each level of genetic susceptibility to ADD. There was no evidence of multiplicative interaction between grip strength and genetic susceptibility to ADD for both dementia (p value: .241) and AD (p value: .314).

Conclusions

Older adults with higher PRS for ADD are at higher risk of developing dementia and AD. The risk of dementia and AD was lower in individuals with higher grip strength, regardless of their level of genetic susceptibility to ADD.
The Third Annual Symposium of the Midwest Aging Consortium
Authors: Keller Andrea , Bai Hua , Budinger Scott , Eliazer Susan , Hansen Malene , Konopka Adam R , Morales-Nebreda Luisa , Najt Charles P , Prahlad Veena , Victorelli Stella , Vorland Colby J , Yuan Rong , Rhoads Timothy W , Mihaylova Maria M
Published: October 2023

The geroscience hypothesis suggests that addressing the fundamental mechanisms driving aging biology will prevent or mitigate the onset of multiple chronic diseases, for which the largest risk factor is advanced age. Research that investigates the root causes of aging is therefore of critical importance given the rising healthcare burden attributable to age-related diseases. The third annual Midwest Aging Consortium symposium was convened as a showcase of such research performed by investigators from institutions across the Midwestern United States. This report summarizes the work presented during a virtual conference across topics in aging biology, including immune function in the lung—particularly timely given the Corona Virus Immune Disease-2019 pandemic—along with the role of metabolism and nutrient-regulated pathways in cellular function with age, the influence of senescence on stem cell function and inflammation, and our evolving understanding of the mechanisms underlying observation of sex dimorphism in aging-related outcomes. The symposium focused on early-stage and emerging investigators, while including keynote presentations from leaders in the biology of aging field, highlighting the diversity and strength of aging research in the Midwest.
How, why and for whom does a basic income contribute to health and wellbeing: a systematic review
Authors: McKay Fiona H , Bennett Rebecca , Dunn Matthew
Published: October 2023

Ensuring that people have a sufficient income to meet their basic needs and that it keeps pace with costs of living are important when considering ways to reduce health inequities. Many have argued that providing a basic income is one way to do this. The aim of this review is to provide an overview of the existing peer reviewed evidence on the health and wellbeing impacts of basic income interventions. A systematic search of ten electronic databases was conducted in June 2022. Eligible publications examined any effect on health and wellbeing from unconditional cash transfers. All study designs were included, and no limitations were placed on duration of cash transfer trials, location of study, study population or on amount of money provided through the cash transfer. Ten studies were included in this review. Studies employed a range of methods. All studies reported on a trial of Universal Basic Income in either a region or a town. Studies explored a range of health and wellbeing related outcomes including crime, quality of life, employment, subjective wellbeing, tuberculosis and hospitalization. Basic income programs can mitigate poverty in a time of economic upheaval and have the potential to become a powerful policy tool to act upon the determinants of health and reduce health inequality. This review found a small number of trials indicating a positive impact on health and wellbeing. More trials which track recipients over a longer period are needed to provide more robust evidence for the impact of basic income programs.
Dysregulation of alternative splicing in spinocerebellar ataxia type 1
Authors: Olmos Victor , Thompson Evrett N , Gogia Neha , Luttik Kimberly , Veeranki Vaishnavi , Ni Luhan , Sim Serena , Chen Kelly , Krause Diane S , Lim Janghoo
Published: October 2023

Spinocerebellar ataxia type 1 is caused by an expansion of the polyglutamine tract in ATAXIN-1. Ataxin-1 is broadly expressed throughout the brain and is involved in regulating gene expression. However, it is not yet known if mutant ataxin-1 can impact the regulation of alternative splicing events. We performed RNA sequencing in mouse models of spinocerebellar ataxia type 1 and identified that mutant ataxin-1 expression abnormally leads to diverse splicing events in the mouse cerebellum of spinocerebellar ataxia type 1. We found that the diverse splicing events occurred in a predominantly cell autonomous manner. A majority of the transcripts with misregulated alternative splicing events were previously unknown, thus allowing us to identify overall new biological pathways that are distinctive to those affected by differential gene expression in spinocerebellar ataxia type 1. We also provide evidence that the splicing factor Rbfox1 mediates the effect of mutant ataxin-1 on misregulated alternative splicing and that genetic manipulation of Rbfox1 expression modifies neurodegenerative phenotypes in a Drosophila model of spinocerebellar ataxia type 1 in vivo. Together, this study provides novel molecular mechanistic insight into the pathogenesis of spinocerebellar ataxia type 1 and identifies potential therapeutic strategies for spinocerebellar ataxia type 1.
CYP2A6associates with respiratory disease risk and younger age of diagnosis: a phenome-wide association Mendelian Randomization study
Authors: Giratallah Haidy , Chenoweth Meghan J , Pouget Jennie G , El-Boraie Ahmed , Alsaafin Alaa , Lerman Caryn , Knight Jo , Tyndale Rachel F
Published: October 2023

CYP2A6, a genetically variable enzyme, inactivates nicotine, activates carcinogens, and metabolizes many pharmaceuticals. Variation in CYP2A6 influences smoking behaviors and tobacco-related disease risk. This phenome-wide association study examined associations between a reconstructed version of our weighted genetic risk score (wGRS) for CYP2A6 activity with diseases in the UK Biobank (N = 395 887). Causal effects of phenotypic CYP2A6 activity (measured as the nicotine metabolite ratio: 3′-hydroxycotinine/cotinine) on the phenome-wide significant (PWS) signals were then estimated in two-sample Mendelian Randomization using the wGRS as the instrument. Time-to-diagnosis age was compared between faster versus slower CYP2A6 metabolizers for the PWS signals in survival analyses. In the total sample, six PWS signals were identified: two lung cancers and four obstructive respiratory diseases PheCodes, where faster CYP2A6 activity was associated with greater disease risk (Ps < 1 × 10−6). A significant CYP2A6-by-smoking status interaction was found (Psinteraction < 0.05); in current smokers, the same six PWS signals were found as identified in the total group, whereas no PWS signals were found in former or never smokers. In the total sample and current smokers, CYP2A6 activity causal estimates on the six PWS signals were significant in Mendelian Randomization (Ps < 5 × 10−5). Additionally, faster CYP2A6 metabolizer status was associated with younger age of disease diagnosis for the six PWS signals (Ps < 5 × 10−4, in current smokers). These findings support a role for faster CYP2A6 activity as a causal risk factor for lung cancers and obstructive respiratory diseases among current smokers, and a younger onset of these diseases. This research utilized the UK Biobank Resource.