bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional variations in the management of primary hyperparathyroidism in Sweden: population-based case-control study
Authors: Thorsteinsson David , Granath Fredrik , Bränström Robert , Koman Anna , Zedenius Jan , Nilsson Inga-Lena
Published: February 2024

Background

Substantial disparities in the utilization of parathyroidectomy for primary hyperparathyroidism have been reported. This study aimed to analyse regional variations in parathyroidectomy incidence with respect to the patient's disease burden and socioeconomic status.

Methods

A population-based case-control study included all patients with primary hyperparathyroidism who underwent parathyroidectomy in Sweden between 2008 and 2017 and 10 matched controls. Data on demographic and socioeconomic variables, co-morbidities and drug prescriptions were collected from relevant national registers. Conditional logistic regression was used to analyse predictors of parathyroidectomy.

Results

A total of 8626 patients with primary hyperparathyroidism (77% women) underwent parathyroidectomy during the study interval. The annual incidence of parathyroidectomy was 9.0 per 100 000 persons. The annual age-adjusted regional incidences of parathyroidectomy varied between 3.3 and 16.9 operations per 100 000 inhabitants. Except for a small underrepresentation of patients with lower education, no effect of socioeconomic variables was observed. Compared with matched controls, the parathyroidectomy group had increased odds ratios of having developed classical symptoms of primary hyperparathyroidism and being prescribed medication against cardiovascular disorders and psychiatric illness at the time of parathyroidectomy. Increased risks of kidney stones and osteoporosis were observed 5 years before parathyroidectomy. Patients with primary hyperparathyroidism selected for parathyroidectomy from regions with a low incidence of operations had a higher prevalence of kidney stones, osteoporosis and hypertension, as well as larger adenomas and higher calcium levels at the time of parathyroidectomy compared with patients in high-incidence regions.

Conclusion

The considerable variation in parathyroidectomy seems more likely associated with different clinical thresholds for detection of primary hyperparathyroidism and referral to surgery than socioeconomic disparities.
Tau accumulation and its spatial progression across the Alzheimer’s disease spectrum
Authors: St-Onge Frédéric , Chapleau Marianne , Breitner John C S , Villeneuve Sylvia , Pichet Binette Alexa
Published: February 2024

The accumulation of tau abnormality in sporadic Alzheimer’s disease is believed typically to follow neuropathologically defined Braak staging. Recent in-vivo PET evidence challenges this belief, however, as accumulation patterns for tau appear heterogeneous among individuals with varying clinical expressions of Alzheimer’s disease. We, therefore, sought a better understanding of the spatial distribution of tau in the preclinical and clinical phases of sporadic Alzheimer’s disease and its association with cognitive decline. Longitudinal tau-PET data (1370 scans) from 832 participants (463 cognitively unimpaired, 277 with mild cognitive impairment and 92 with Alzheimer’s disease dementia) were obtained from the Alzheimer’s Disease Neuroimaging Initiative. Among these, we defined thresholds of abnormal tau deposition in 70 brain regions from the Desikan atlas, and for each group of regions characteristic of Braak staging. We summed each scan’s number of regions with abnormal tau deposition to form a spatial extent index. We then examined patterns of tau pathology cross-sectionally and longitudinally and assessed their heterogeneity. Finally, we compared our spatial extent index of tau uptake with a temporal meta-region of interest—a commonly used proxy of tau burden—assessing their association with cognitive scores and clinical progression. More than 80% of amyloid-beta positive participants across diagnostic groups followed typical Braak staging, both cross-sectionally and longitudinally. Within each Braak stage, however, the pattern of abnormality demonstrated significant heterogeneity such that the overlap of abnormal regions across participants averaged less than 50%, particularly in persons with mild cognitive impairment. Accumulation of tau progressed more rapidly among cognitively unimpaired and participants with mild cognitive impairment (1.2 newly abnormal regions per year) compared to participants with Alzheimer’s disease dementia (less than 1 newly abnormal region per year). Comparing the association of tau pathology and cognitive performance our spatial extent index was superior to the temporal meta-region of interest for identifying associations with memory in cognitively unimpaired individuals and explained more variance for measures of executive function in patients with mild cognitive impairments and Alzheimer’s disease dementia. Thus, while participants broadly followed Braak stages, significant individual regional heterogeneity of tau binding was observed at each clinical stage. Progression of the spatial extent of tau pathology appears to be fastest in cognitively unimpaired and persons with mild cognitive impairment. Exploring the spatial distribution of tau deposits throughout the entire brain may uncover further pathological variations and their correlation with cognitive impairments.
Synergistic effect of phthalocyanine and pyrochlore-type oxide catalysts to enhance activity of electrochemical carbon dioxide reduction
Authors: Maruyama Ren , Takase Satoko , Shimizu Youichi
Published: February 2024

Electrochemical CO2 reduction has been attracting attention due to its potential to improve the environment. In this study, we found that the combination of Co-phthalocyanine and pyrochlore-type Bi2Sn2O7 catalyst gave high catalytic activity for CO2 reduction, and devised a new electrocatalyst that combines them for their synergistic effects.
Spin–spin interaction in a highly stable neutral diradical: σ-boned dimer of trioxotriangulene
Authors: Murata Tsuyoshi , Ukai Shusaku , Yamaguchi Sawa , Furukawa Ko , Morita Yasushi
Published: February 2024

A σ-bonded dimer of 4,8,10-trioxotriangulene (TOT) was newly synthesized and its electronic spin structure was characterized. The neutral diradical had a singlet ground state due to the strong antiferromagnetic interaction through the σ-bond. The strong intramolecular interaction within the σ-dimer caused a near-infrared photoabsorption of around 700–1,000 nm, which is close to that of the π-stacked dimer of TOT monoradical.
Urine Albumin Measurements in Clinical Diagnostics
Authors: Seegmiller Jesse C , Bachmann Lorin M
Published: February 2024

Background

Measurement of urine albumin is critical for diagnosis, risk classification, and monitoring of chronic kidney disease (CKD). Guidelines recommend clinical decision cutoffs for the urine albumin-to-creatinine ratio (ACR) of 30 and 300 mg/g (3 and 30 mg/mmol). However, differences among manufacturers’ routine urine albumin measurement procedures have been found to exceed 40%, suggesting CKD diagnosis and risk classification may vary depending upon the specific measurement procedure implemented in the laboratory.

Content

This review discusses urine albumin pathophysiology and clinical practice guideline recommendations for CKD. The review also provides recommendations for urine specimen collection and storage, and results reporting for the ACR. Recent advances in measurement techniques and development of reference systems intended to facilitate standardization of urine albumin measurements are reviewed.

Urine albumin is an important measurement procedure used for diagnosis, risk classification, and management of CKD. Urine albumin results should be reported as the ACR using quantitative measurement procedures. Random urine collections used for albuminuria screening should be followed by confirmation with first morning void collections to reduce variation and increase diagnostic accuracy for urine albumin measurement. Most measurement procedures utilize immunoturbidimetric or immunonephelometric techniques. However, results vary significantly among measurement procedures, potentially resulting in differences in classification or risk assessment for CKD. The National Institute for Standards and Technology (NIST) and other laboratories are developing reference systems, including liquid chromatography–tandem mass spectrometry candidate reference measurement procedures and reference materials, to enable standardization of routine measurement procedures.
Competence-based language curricula: implementation challenges in Africa
Authors: Atuhura Dorothy , Nambi Rebecca
Published: February 2024

Drawing on a case study design, this article examines the real-life adaptive challenges secondary school teachers of English in Uganda face while implementing the 2020 English language competence-based curriculum innovation. Findings indicate that scarcity of instructional materials, time constraints and large class sizes, limited planning and stakeholders’ support, dissonance between local culture and learning styles significantly underlie complications ESL teachers face adapting and implementing competence-based curricula innovations in English language classrooms in low-income contexts in the global south. The experiences of teachers in Uganda resonate across most global south ESL educational contexts. They illustrate the universality of challenges teachers face and are likely to face when implementing competence-based curricula in sub-Saharan Africa and the wider global south where the teaching and learning of English is premised on facilitating acquisition of English language for meaningful interaction.
Lack of paternal silencing and ecotype-specific expression in head and body lice hybrids
Authors: Marshall Hollie , de la Filia Andrés G , Cavalieri Ross , Mallon Eamonn B , Clark John M , Ross Laura
Published: February 2024

Paternal genome elimination (PGE) is a non-Mendelian inheritance system, described in numerous arthropod species, in which males develop from fertilized eggs, but their paternally inherited chromosomes are eliminated before or during spermatogenesis. Therefore, PGE males only transmit their maternally inherited set of chromosomes to their offspring. In addition to the elimination of paternal chromosomes, diverse PGE species have also repeatedly evolved the transcriptional silencing of the paternal genome, making males effectively haploid. However, it is unclear if this paternal chromosome silencing is mechanistically linked to the chromosome elimination or has evolved at a later stage, and if so, what drives the haploidization of males under PGE. In order to understand these questions, here we study the human louse, Pediculus humanus, which represents an ideal model system, as it appears to be the only instance of PGE where males eliminate, but not silence their paternal chromosomes, although the latter remains to be shown conclusively. In this study, we analyzed parent-of-origin allele-specific expression patterns in male offspring of crosses between head and body lice ecotypes. We show that hybrid adult males of P. humanus display biparental gene expression, which constitutes the first case of a species with PGE in which genetic activity of paternal chromosomes in the soma is not affected by embryonic silencing or (partial or complete) elimination. We did however also identify a small number of maternally biased genes (potentially imprinted genes), which may be involved in the elimination of paternal chromosomes during spermatogenesis. Finally, we have identified genes that show ecotype-specific expression bias. Given the low genetic diversity between ecotypes, this is suggestive for a role of epigenetic processes in ecotype differences.
Learning a microlocal prior for limited-angle tomography
Authors: Rautio Siiri , Murthy Rashmi , Bubba Tatiana A , Lassas Matti , Siltanen Samuli
Published: February 2024

Limited-angle tomography is a highly ill-posed linear inverse problem. It arises in many applications, such as digital breast tomosynthesis. Reconstructions from limited-angle data typically suffer from severe stretching of features along the central direction of projections, leading to poor separation between slices perpendicular to the central direction. In this paper, a new method is introduced, based on machine learning and geometry, producing an estimate for interfaces between regions of different X-ray attenuation. The estimate can be presented on top of the reconstruction, indicating more reliably the separation between features. The method uses directional edge detection, implemented using complex wavelets and enhanced with morphological operations. By using convolutional neural networks, the visible part of the singular support is first extracted and then extended to the full domain, filling in the parts of the singular support that would otherwise be hidden due to the lack of measurement directions.
Mediating effects of hypertension in association between household wealth disparities and diabetes among women of reproductive age: analysis of eight countries in sub-Saharan Africa
Authors: Nyarko Samuel H , Addo Isaac Y , Ayebeng Castro , Dickson Kwamena S , Acquah Evelyn
Published: February 2024

Background

Diabetes prevalence appears to be increasing in low- and middle-income countries, yet little is known about how hypertension status mediates the association between household wealth and diabetes. This study examined the mediation effects of hypertension in associations between household wealth and diabetes in eight sub-Saharan African (SSA) countries.

Methods

This is a cross-sectional study of 71 577 women from recent Demographic and Health Surveys for eight SSA countries. Sample-weighted logistic regression and causal mediation analyses were conducted.

Results

Of the 71 577 women, 1.1% (782) reported ever being diagnosed with diabetes. Women with diabetes were more likely to have hypertension compared with those without diabetes (54.9% vs 9.9%). The odds of diabetes were significantly higher among women with hypertension (adjusted odds ratio [OR] 5.71 [95% confidence interval {CI} 4.62 to 7.05]) and women from rich households (adjusted OR 1.65 [95% CI 1.23 to 2.22]) compared with their respective counterparts. Hypertension status mediated 27.4% of the association between household wealth and diabetes status.

Conclusions

Hypertension status partly contributes to the associations between household wealth disparities and diabetes status among women in the selected countries. Further research and targeted interventions are needed to explore specific mechanisms and confounding factors related to household wealth disparities, hypertension status and diabetes prevalence in this population.
The Practice of Engagement without Recognition under International Law: A Tool for Combatting Human Trafficking
Authors: Hadjigeorgiou Nasia
Published: February 2024

This article argues that, even in the absence of international recognition, international law can make a real and meaningful impact in de facto states. Such impact can come about through engagement without recognition, which should be understood, not as a shadowy practice that takes place in the fringes of international law, but as a strategy that is fully compatible with international legal standards. The article makes this argument by relying on a detailed analysis of relevant case law of the European Court of Human Rights. It further proposes that reconceptualizing engagement without recognition can have important practical consequences in the fight against human trafficking, which has received regrettably limited attention by policymakers in de facto states.
Practice Contestation in and between Communities of Practice: From Top-Down to Inclusive Policymaking at the World Bank
Authors: Sondarjee Maïka
Published: February 2024

By focusing on like-mindedness, community of practice (CoP) scholars are often accused of downgrading issues of power and contestation. This article theorizes practice contestation as an integral part of participation in a community. Building on a relational ontology and the concept of epistemic power, I define practice contestation as tacit (practical) or discursive interventions challenging the shared background knowledge of a CoP. This process is bidirectional (pushing for and against change) and happens at two levels (within a CoP and at the boundaries with other CoPs). This framework leads to four types of practice contestation: internal disruption, internal resistance, external pressure, and external resistance. These concomitant types of contestation participate in the constant fluctuations of international practices and social orders. Methodologically, this article looks at the CoP of World Bank’s senior managers and their boundaries with other communities, and it builds on interview material and archival documents collected between 2017 and 2020.
Cultivating Communities of Practice: From Institutions to Practices
Authors: Bicchi Federica
Published: February 2024

Where do communities of practice (CoPs) come from? What relationship do they entertain with institutions within or across which they develop? To what extent can institutions actually create CoPs? These questions are crucial, if only because of the benefits that CoPs are expected to bring, from innovation to learning to shared best practices. This article suggests that the most important relationship is between the CoP and its founding practice, which is ontologically prior to the CoP. The coming into existence of a CoP thus depends on the pre-existence of a founding practice and practical alignments. This argument counterbalances the two prevailing positions in the literature on CoPs, which focus on institutions instead of practices. In most IR literature on the topic, scholars have viewed CoPs as emerging “organically” and informally at the margins of institutions in a bottom-up fashion and from there often coming back to influence institutions bottom-up. Knowledge management scholars and institutional actors themselves have instead embraced a more agential and performative top-down approach by which CoPs can and should be cultivated to foster knowledge creation in business and international institutions alike. The article explores these positions with the help of examples drawn mainly from the European Union’s experience, including the Joint Research Centre’s attempt to cultivate CoPs from 2016 onwards.
Delegation of Economic Statecraft to Private Enterprises: Russia, China, and Turkey in Africa
Authors: Laryš Martin , Svoboda Karel
Published: February 2024

The literature on economic statecraft, defined as the use of economic means to achieve strategic ends, deals primarily with direct state instruments (sanctions, embargoes, and loans), or delegation to state-owned enterprises. However, states as principals also frequently delegate to private enterprises, which leads to the puzzling question of why some principals delegate economic statecraft to private enterprises instead of state-owned enterprises. In the classic literature on principal–agent theory, the principal delegates to agents because of the agents’ experience, the principal’s poor relationship with the target subject, or inability to participate in every step of the process. Arguably, the reasons for the principal’s delegation to private enterprises in economic statecraft might differ. The contribution of this article is two-fold. First, it introduces a three-tiered model of the economic statecraft’s delegation based on deniability and control. It consists of direct state interventions, delegation to the state-owned enterprises, and delegation to the private-owned enterprises. Second, it aims to close the gap in the existing literature by focusing on the principal’s preference of the delegation to private instead of state-owned enterprises in the context of Russian, Chinese, and Turkish geopolitical goals in Africa.
Linezolid brain penetration in neurointensive care patients
Authors: Hosmann Arthur , Moser Miriam M , van Os Wisse , Gramms Leon , al Jalali Valentin , Sanz Codina Maria , Plöchl Walter , Lier Constantin , Kees Frieder , Dorn Christoph , Rössler Karl , Reinprecht Andrea , Zeitlinger Markus
Published: February 2024

Background

Linezolid exposure in critically ill patients is associated with high inter-individual variability, potentially resulting in subtherapeutic antibiotic exposure. Linezolid exhibits good penetration into the CSF, but its penetration into cerebral interstitial fluid (ISF) is unknown.

Objectives

To determine linezolid penetration into CSF and cerebral ISF of neurointensive care patients.

Patients and methods

Five neurocritical care patients received 600 mg of linezolid IV twice daily for treatment of extracerebral infections. At steady state, blood and CSF samples were collected from arterial and ventricular catheters, and microdialysate was obtained from a cerebral intraparenchymal probe.

Results

The median fAUC0–24 was 57.6 (24.9–365) mg·h/L in plasma, 64.1 (43.5–306.1) mg·h/L in CSF, and 27.0 (10.7–217.6) mg·h/L in cerebral ISF. The median penetration ratio (fAUCbrain_or_CSF/fAUCplasma) was 0.5 (0.25–0.81) for cerebral ISF and 0.92 (0.79–1) for CSF. Cerebral ISF concentrations correlated well with plasma (R = 0.93, P < 0.001) and CSF levels (R = 0.93, P < 0.001).

The median fAUC0–24/MIC ratio was ≥100 in plasma and CSF for MICs of ≤0.5 mg/L, and in cerebral ISF for MICs of ≤0.25 mg/L. The median fT>MIC was ≥80% of the dosing interval in CSF for MICs of ≤0.5 mg/L, and in plasma and cerebral ISF for MICs of ≤0.25 mg/L.

Conclusions

Linezolid demonstrates a high degree of cerebral penetration, and brain concentrations correlate well with plasma and CSF levels. However, substantial variability in plasma levels, and thus cerebral concentrations, may result in subtherapeutic tissue concentrations in critically ill patients with standard dosing, necessitating therapeutic drug monitoring.
Carbohydrate-binding ability of a recombinant protein containing the DM9 motif from Drosophila melanogaster
Authors: Hatakeyama Tomomitsu , Kojima Fuki , Ohkawachi Issei , Sawai Hitomi , Unno Hideaki
Published: February 2024

Proteins containing DM9 motifs, which were originally identified in the Drosophila melanogaster genome, are widely distributed in various organisms and are assumed to be involved in their innate immune response. In this study, we produced a recombinant protein of CG13321 (rCG13321) from D. melanogaster, which consists of four DM9 motifs, in Escherichia coli cells. In affinity chromatography using a mannose-immobilized column, rCG13321 exhibited mannose-binding ability and was separated into high-affinity and low-affinity fractions, named HA and LA, respectively, based on its binding ability to the column. In addition to having a higher affinity for the column, HA exhibited self-oligomerization ability, suggesting slight differences in tertiary structure. Both LA and HA showed hemagglutinating activity and were able to agglutinate an oligomannose-containing dendrimer, indicating that they have multiple carbohydrate-binding sites. Glycan array analysis suggested that rCG13321 primarily recognizes d-mannose and d-rhamnose through hydrogen bonding with the 2-, 3- and 4-hydroxy groups. Isothermal titration calorimetry demonstrated that rCG13321 has a comparable affinity to typical lectins. These findings suggest that CG13321 functions as a carbohydrate-binding protein or lectin that recognizes mannose and related carbohydrate-containing molecules on the surface of foreign organisms as a pattern recognition molecule.
The Religious Dimensions of Epidemic Disease: Cholera, the Ghost Rite, and Missionary Medicine in Nineteenth-Century Korea
Authors: Kim Shin Kwon
Published: February 2024

One of the most catastrophic pandemics in human history was the repeated spread of cholera in the nineteenth century. In spite of its historical significance, few scholars have studied cholera’s influence in East Asia. This paper illustrates how cholera was considered, conceptualized, and treated by Korean people prior to contact with North American medical missionaries in 1885. In particular, the article compares the government-ordered public health measures during the Joseon dynasty, focusing on the “ghost rite” performed during outbreaks of epidemic disease with the work of medical missionaries in the late nineteenth century. This study finds that even after the introduction of Western biomedicine, the Korean people persisted with a religious-based etiology of cholera and other infectious diseases until the twentieth century.
Racial and ethnic disparities in genomic testing among lung cancer patients: a systematic review
Authors: Meernik Clare , Raveendran Yadurshini , Kolarova Michaela , Rahman Fariha , Olunuga Ebunoluwa , Hammond Emmery , Shivaramakrishnan Akhilesh , Hendren Steph , Bosworth Hayden B , Check Devon K , Green Michelle , Strickler John H , Akinyemiju Tomi
Published: February 2024

Background

Racial and ethnic disparities in genomic testing could exacerbate disparities in access to precision cancer therapies and survival—particularly in the context of lung cancer where genomic testing has been recommended for the past decade. However, prior studies assessing disparities in genomic testing have yielded mixed results.

Methods

We conducted a systemic review to examine racial and ethnic disparities in the use of genomic testing among lung cancer patients in the United States. Two comprehensive searches in PubMed, Embase, and Scopus were conducted (September 2022, May 2023). Original studies that assessed rates of genomic testing by race or ethnicity were included. Findings were narratively synthesized by outcome.

Results

The search yielded 2739 unique records, resulting in 18 included studies. All but 1 study were limited to patients diagnosed with non–small cell lung cancer. Diagnosis years ranged from 2007 to 2022. Of the 18 studies, 11 found statistically significant differences in the likelihood of genomic testing by race or ethnicity; in 7 of these studies, testing was lower among Black patients compared with White or Asian patients. However, many studies lacked adjustment for key covariates and included patients with unclear eligibility for testing.

Conclusions

A majority of studies, though not all, observed racial and ethnic disparities in the use of genomic testing among patients with lung cancer. Heterogeneity of study results throughout a period of changing clinical guidelines suggests that minoritized populations—Black patients in particular—have faced additional barriers to genomic testing, even if not universally observed at all institutions.
Long noncoding RNA KCNQ1OT1 aggravates cerebral infarction by regulating PTBT1/SIRT1 via miR-16-5p
Authors: Jiang Yuanming , Ma Chi , Guan Yuxiu , Yang Wenqi , Yu Jiaqi , Shi Hanfei , Ding Zihang , Zhang Zhuobo
Published: February 2024

Cerebral infarction (CI) is one of the leading causes of disability and death. LncRNAs are key factors in CI progression. Herein, we studied the function of long noncoding RNA KCNQ1OT1 in CI patient plasma samples and in CI models. Quantitative real-time PCR and Western blotting tested gene and protein expressions. The interactions of KCNQ1OT1/PTBP1 and miR-16-5p were analyzed using dual-luciferase reporter and RNA immunoprecipitation assays; MTT assays measured cell viability. Cell migration and angiogenesis were tested by wound healing and tube formation assays. Pathological changes were analyzed by triphenyltetrazolium chloride and routine staining. We found that KCNQ1OT1 and PTBP1 were overexpressed and miR-16-5p was downregulated in CI patient plasma and in oxygen-glucose deprived (OGD) induced mouse brain microvascular endothelial (bEnd.3) cells. KCNQ1OT1 knockdown suppressed pro-inflammatory cytokine production and stimulated angiogenic responses in OGD-bEnd.3 cells. KCNQ1OT1 upregulated PTBP1 by sponging miR-16-5p. PTBP1 overexpression or miR-16-5p inhibition attenuated the effects of KCNQ1OT1 knockdown. PTBP1 silencing protected against OGD-bEnd.3 cell injury by enhancing SIRT1. KCNQ1OT1 silencing or miR-16-5p overexpression also alleviated ischemic injury in a mice middle cerebral artery occlusion model. Thus, KCNQ1OT1 silencing alleviates CI by regulating the miR-16-5p/PTBP1/SIRT1 pathway, providing a theoretical basis for novel therapeutic strategies targeting CI.
Symptomatic appendiceal intussusception—rare pitfall of the historical inversion technique
Authors: Nan Xinyi , Pyle Braden , Kwik Charlotte , Nolan Greg J
Published: February 2024

Appendiceal intussusception is a rare condition with an unknown incidence of clinical presentation, and an estimated incidence of 0.01% is based on a histological study only. It presents a diagnostic challenge with lack of standardized management strategies, and its description in literature is limited to case reports and series. Clinical presentation is often variable and nonspecific; it is uncommon to have a definitive preoperative diagnosis. Iatrogenic appendiceal intussusception can occur as a result of the historical simple inversion or inversion-ligation appendicectomy technique, but it is seldom reported to cause symptoms. We present a case of symptomatic appendiceal intussusception diagnosed preoperatively on both computed tomography and colonoscopy prior to proceeding with elective definitive surgery in a patient with no reported prior history of appendicectomy.
An alternative definition of tense operators on residuated lattices
Authors: Calomino Ismael , Pelaitay Gustavo , Zuluaga Botero William
Published: February 2024

In this paper, we introduce and study an alternative definition of tense operators on residuated lattices. We give a categorical equivalence for the class of tense ICRDL-algebras, which is motivated by an old construction by J. Kalman. The paper concludes with some applications regarding descriptions of congruences and a 2-contextual translation.
Low-Temperature X-ray Microanalysis Sheds New Light on Mineral Nutrition Aspects of Insect Leaf Galling
Authors: Fernando Denise R , Green Peter T , Marshall Alan T
Published: February 2024

Manipulation of host plant physiology by leaf-galling insects is a multifaceted process. Among fundamental knowledge gaps surrounding this scientifically intriguing phenomenon is the appropriation of plant mineral nutrients and moisture for galling advantage. Small, soluble mineral ions and watery cell contents in dense gall tissues risk disruption during routine sample preparations. In this study, an X-ray microanalysis was applied to investigate gall mineral nutrition. Morphologically diverse leaf galls were sampled from three Australian rainforest tree species. Using cryo-analytical scanning electron microscopy, real-time X-ray analytical maps of cellular mineral nutrients and water were integrated with anatomical images of gall and leaf cross-sectional surfaces. A comparison of host-leaf and gall anatomies bore direct evidence of drastic changes to leaf cells through the galling process. Distinct “wet” and “dry” regions within galls were anatomically and/or chemically differentiated, suggesting specific functionality. “Wet” regions comprising hydrated cells including soft gall-cavity linings where larvae are known to feed contained soluble plant mineral nutrients, while C-rich “dry” tissues largely devoid of mineral nutrients likely contribute structural support. Mapping immobile nutrients such as Mn may provide a means of “matching” specific gall cell types to those in ungalled host-leaf tissues. The findings here provided otherwise inaccessible insights into leaf-gall mineral nutrition.
Association Analysis Provides Insights into Plant Mitonuclear Interactions
Authors: Lian Qun , Li Shuai , Kan Shenglong , Liao Xuezhu , Huang Sanwen , Sloan Daniel B , Wu Zhiqiang
Published: February 2024

Cytonuclear interaction refers to the complex and ongoing process of coevolution between nuclear and organelle genomes, which are responsible for cellular respiration, photosynthesis, lipid metabolism, etc. and play a significant role in adaptation and speciation. There have been a large number of studies to detect signatures of cytonuclear interactions. However, identification of the specific nuclear and organelle genetic polymorphisms that are involved in these interactions within a species remains relatively rare. The recent surge in whole genome sequencing has provided us an opportunity to explore cytonuclear interaction from a population perspective. In this study, we analyzed a total of 3,439 genomes from 7 species to identify signals of cytonuclear interactions by association (linkage disequilibrium) analysis of variants in both the mitochondrial and nuclear genomes across flowering plants. We also investigated examples of nuclear loci identified based on these association signals using subcellular localization assays, gene editing, and transcriptome sequencing. Our study provides a novel perspective on the investigation of cytonuclear coevolution, thereby enriching our understanding of plant fitness and offspring sterility.
The levels of p53 govern the hierarchy of DNA damage tolerance pathway usage
Authors: Castaño Bryan A , Schorer Sabrina , Guo Yitian , Calzetta Nicolás L , Gottifredi Vanesa , Wiesmüller Lisa , Biber Stephanie
Published: February 2024

It is well-established that, through canonical functions in transcription and DNA repair, the tumor suppressor p53 plays a central role in safeguarding cells from the consequences of DNA damage. Recent data retrieved in tumor and stem cells demonstrated that p53 also carries out non-canonical functions when interacting with the translesion synthesis (TLS) polymerase iota (POLι) at DNA replication forks. This protein complex triggers a DNA damage tolerance (DDT) mechanism controlling the DNA replication rate. Given that the levels of p53 trigger non-binary rheostat-like functions in response to stress or during differentiation, we explore the relevance of the p53 levels for its DDT functions at the fork. We show that subtle changes in p53 levels modulate the contribution of some DDT factors including POLι, POLη, POLζ, REV1, PCNA, PRIMPOL, HLTF and ZRANB3 to the DNA replication rate. Our results suggest that the levels of p53 are central to coordinate the balance between DDT pathways including (i) fork-deceleration by the ZRANB3-mediated fork reversal factor, (ii) POLι-p53-mediated fork-slowing, (iii) POLι- and POLη-mediated TLS and (iv) PRIMPOL-mediated fork-acceleration. Collectively, our study reveals the relevance of p53 protein levels for the DDT pathway choice in replicating cells.
All exons are not created equal—exon vulnerability determines the effect of exonic mutations on splicing
Authors: Holm Lise L , Doktor Thomas K , Flugt Katharina K , Petersen Ulrika S S , Petersen Rikke , Andresen Brage S
Published: February 2024

It is now widely accepted that aberrant splicing of constitutive exons is often caused by mutations affecting cis-acting splicing regulatory elements (SREs), but there is a misconception that all exons have an equal dependency on SREs and thus a similar vulnerability to aberrant splicing. We demonstrate that some exons are more likely to be affected by exonic splicing mutations (ESMs) due to an inherent vulnerability, which is context dependent and influenced by the strength of exon definition. We have developed VulExMap, a tool which is based on empirical data that can designate whether a constitutive exon is vulnerable. Using VulExMap, we find that only 25% of all exons can be categorized as vulnerable, whereas two-thirds of 359 previously reported ESMs in 75 disease genes are located in vulnerable exons. Because VulExMap analysis is based on empirical data on splicing of exons in their endogenous context, it includes all features important in determining the vulnerability. We believe that VulExMap will be an important tool when assessing the effect of exonic mutations by pinpointing whether they are located in exons vulnerable to ESMs.
Performing highly parallelized and reproducible GWAS analysis on biobank-scale data
Authors: Schönherr Sebastian , Schachtl-Riess Johanna F , Di Maio Silvia , Filosi Michele , Mark Marvin , Lamina Claudia , Fuchsberger Christian , Kronenberg Florian , Forer Lukas
Published: February 2024

Genome-wide association studies (GWAS) are transforming genetic research and enable the detection of novel genotype-phenotype relationships. In the last two decades, over 60 000 genetic associations across thousands of traits have been discovered using a GWAS approach. Due to increasing sample sizes, researchers are increasingly faced with computational challenges. A reproducible, modular and extensible pipeline with a focus on parallelization is essential to simplify data analysis and to allow researchers to devote their time to other essential tasks. Here we present nf-gwas, a Nextflow pipeline to run biobank-scale GWAS analysis. The pipeline automatically performs numerous pre- and post-processing steps, integrates regression modeling from the REGENIE package and supports single-variant, gene-based and interaction testing. It includes an extensive reporting functionality that allows to inspect thousands of phenotypes and navigate interactive Manhattan plots directly in the web browser. The pipeline is tested using the unit-style testing framework nf-test, a crucial requirement in clinical and pharmaceutical settings. Furthermore, we validated the pipeline against published GWAS datasets and benchmarked the pipeline on high-performance computing and cloud infrastructures to provide cost estimations to end users. nf-gwas is a highly parallelized, scalable and well-tested Nextflow pipeline to perform GWAS analysis in a reproducible manner.
Covert cortical processing: a diagnosis in search of a definition
Authors: Young Michael J , Fecchio Matteo , Bodien Yelena G , Edlow Brian L
Published: February 2024

Historically, clinical evaluation of unresponsive patients following brain injury has relied principally on serial behavioral examination to search for emerging signs of consciousness and track recovery. Advances in neuroimaging and electrophysiologic techniques now enable clinicians to peer into residual brain functions even in the absence of overt behavioral signs. These advances have expanded clinicians’ ability to sub-stratify behaviorally unresponsive and seemingly unaware patients following brain injury by querying and classifying covert brain activity made evident through active or passive neuroimaging or electrophysiologic techniques, including functional MRI, electroencephalography (EEG), transcranial magnetic stimulation-EEG, and positron emission tomography. Clinical research has thus reciprocally influenced clinical practice, giving rise to new diagnostic categories including cognitive-motor dissociation (i.e. ‘covert consciousness’) and covert cortical processing (CCP). While covert consciousness has received extensive attention and study, CCP is relatively less understood. We describe that CCP is an emerging and clinically relevant state of consciousness marked by the presence of intact association cortex responses to environmental stimuli in the absence of behavioral evidence of stimulus processing. CCP is not a monotonic state but rather encapsulates a spectrum of possible association cortex responses from rudimentary to complex and to a range of possible stimuli. In constructing a roadmap for this evolving field, we emphasize that efforts to inform clinicians, philosophers, and researchers of this condition are crucial. Along with strategies to sensitize diagnostic criteria and disorders of consciousness nosology to these vital discoveries, democratizing access to the resources necessary for clinical identification of CCP is an emerging clinical and ethical imperative.
Longitudinal Analysis of Mpox Virus DNA Detectability From Multiple Specimen Types During Acute Illness: A Cohort Study
Authors: Tan Darrell H S , Pico Espinosa Oscar , Matelski John , Khera Shreya S , Qamar Attia , Persaud Reva , Hurst Jacklyn R , Ly Angel , Lam Jessica , Naghibosadat Maedeh , Christie Natasha , Hasso Maan , Gough Kevin , Taggart Linda R , Tan Charlie , Ostrowski Mario , Ma Huiting , Gray-Owen Scott D , Kozak Robert , Mishra Sharmistha
Published: February 2024

Background

Longitudinal data on the detectability of monkeypox virus (MPXV) genetic material in different specimen types are scarce.

Methods

We describe MPXV-specific polymerase chain reaction (PCR) results from adults with confirmed mpox infection from Toronto, Canada, including a cohort undergoing weekly collection of specimens from multiple anatomic sites until 1 week after skin lesions had fully healed. We quantified the time from symptom onset to resolution of detectable viral DNA (computed tomography [Ct] ≥ 35) by modeling exponential decay in Ct value as a function of illness day for each site, censoring at the time of tecovirimat initiation.

Results

Among 64 men who have sex with men, the median (interquartile range [IQR]) age was 39 (32.75–45.25) years, and 49% had HIV. Twenty received tecovirimat. Viral DNA was detectable (Ct < 35) at baseline in 74% of genital/buttock/perianal skin swabs, 56% of other skin swabs, 44% of rectal swabs, 37% of throat swabs, 27% of urine, 26% of nasopharyngeal swabs, and 8% of semen samples. The median time to resolution of detectable DNA (IQR) was longest for genital/buttock/perianal skin and other skin swabs at 30.0 (23.0–47.9) and 22.4 (16.6–29.4) days, respectively, and shortest for nasopharyngeal swabs and semen at 0 (0–12.1) and 0 (0–0) days, respectively. We did not observe an effect of tecovirimat on the rate of decay in viral DNA detectability in any specimen type (all P > .05).

Conclusions

MPXV DNA detectability varies by specimen type and persists for over 3–4 weeks in skin specimens. The rate of decay did not differ by tecovirimat use in this nonrandomized study.
A Pilot Study of Pembrolizumab in Combination With Y90 Radioembolization in Subjects With Poor Prognosis Hepatocellular Carcinoma
Authors: Yu Shawn , Yu Menggang , Keane Barry , Mauro David M , Helft Paul R , Harris William P , Sanoff Hanna K , Johnson Matthew S , O’Neil Bert , McRee Autumn Jackson , Somasundaram Ashwin
Published: February 2024

Background

Combination checkpoint inhibition therapy with yttrium-90 (Y90) radioembolization represents an emerging area of interest in the treatment of advanced hepatocellular carcinoma (HCC). HCRN GI15-225 is an open-label, single-arm multicenter, pilot study (NCT03099564).

Methods

Eligible patients had poor prognosis, localized HCC defined as having portal vein thrombus, multifocal disease, and/or diffuse disease that were not eligible for liver transplant or surgical resection. Patients received pembrolizumab 200 mg intravenously every 3 weeks in conjunction with glass yttrium-90 (Y90) radioembolization TheraSphere. Primary endpoint was 6-month progression-free survival (PFS6) per RECIST 1.1. Secondary endpoints included time to progression (TTP), objective response rate (ORR), overall survival (OS), and safety/tolerability.

Results

Between October 23, 2017 and November 24, 2020, 29 patients were enrolled: 2 were excluded per protocol. Fifteen of the remaining 27 patients were free of progression at 6 months (55.6%; 95% CI, 35.3-74.5) with median PFS 9.95 months (95% CI, 4.14-15.24) and OS 27.30 months (95% CI, 10.15-39.52). One patient was not evaluable for response due to death; among the remaining 26 patients, ORR was 30.8% (95% CI, 14.3-51.8) and DCR was 84.6% (95% CI, 65.1-95.6).

Conclusion

In patients with localized, poor prognosis HCC, pembrolizumab in addition to glass Y90 radioembolization demonstrated promising efficacy and safety consistent with prior observations (ClinicalTrials.gov Identifier: NCT03099564; IRB Approved: 16-3255 approved July 12, 2016).
p17/C18-ceramide–mediated mitophagy is an endogenous neuroprotective response in preclinical and clinical brain injury
Authors: Karakaya Eda , Oleinik Natalia , Edwards Jazlyn , Tomberlin Jensen , Barker Randy Bent , Berber Burak , Ericsson Maria , Alsudani Habeeb , Ergul Adviye , Beyaz Semir , Lemasters John J , Ogretmen Besim , Albayram Onder
Published: February 2024

Repeat concussions (or repetitive mild traumatic brain injury [rmTBI]) are complex pathological processes consisting of a primary insult and long-term secondary complications and are also a prerequisite for chronic traumatic encephalopathy (CTE). Recent evidence implies a significant role of autophagy-mediated dysfunctional mitochondrial clearance, mitophagy, in the cascade of secondary deleterious events resulting from TBI. C18-ceramide, a bioactive sphingolipid produced in response to cell stress and damage, and its synthesizing enzyme (CerS1) are precursors to selective stress-mediated mitophagy. A transporter, p17, mediates the trafficking of CerS1, induces C18-ceramide synthesis in the mitochondrial membrane, and acts as an elimination signal in cell survival. Whether p17-mediated mitophagy occurs in the brain and plays a causal role in mitochondrial quality control in secondary disease development after rmTBI are unknown. Using a novel repetitive less-than-mild TBI (rlmTBI) injury paradigm, ablation of mitochondrial p17/C18-ceramide trafficking in p17 knockout (KO) mice results in a loss of C18-ceramide–induced mitophagy, which contributes to susceptibility and recovery from long-term secondary complications associated with rlmTBI. Using a ceramide analog with lipid-selenium conjugate drug, LCL768 restored mitophagy and reduced long-term secondary complications, improving cognitive deficits in rlmTBI-induced p17KO mice. We obtained a significant reduction of p17 expression and a considerable decrease of CerS1 and C18-ceramide levels in cortical mitochondria of CTE human brains compared with age-matched control brains. These data demonstrated that p17/C18-ceramide trafficking is an endogenous neuroprotective mitochondrial stress response following rlmTBI, thus suggesting a novel prospective strategy to interrupt the CTE consequences of concussive TBI.
Smelling things
Authors: Martina Giulia , Nudds Matthew
Published: February 2024

In this paper, we outline and defend a view on which in olfactory experience we can, and often do, smell ordinary things of various kinds—for instance, cookies, coffee, and cake burnings—and the olfactory properties they have. A challenge to this view are cases of smelling in the absence of the source of a smell, such as when a fishy smell lingers after the fish is gone. Such cases, many philosophers argue, show that what we perceive in olfactory experience are odour objects, and not ordinary things. On behalf of our opponent, we articulate a screening-off argument based on cases of lingering smells for the thesis that we do not smell ordinary things. We then develop an alternative account of these cases that is consistent with our view. In doing so, we call into question two claims that are typically built into the notion of an odour object.