bluuebunny/crossref_metadata_2025_split huggingface dataset:
Badly approximable grids and k$k$‐divergent lattices
Authors: Moshchevitin Nikolay , Rao Anurag , Shapira Uri 
Published: June 2024

AbstractLet be a matrix. In this paper, we investigate the set of badly approximable targets for , where is the ‐torus. It is well known that is a winning set for Schmidt's game and hence is a dense subset of full Hausdorff dimension. We investigate the relationship between the measure of and Diophantine properties of . On the one hand, we give the first examples of a nonsingular such that has full measure with respect to some nontrivial algebraic measure on the torus. For this, we use transference theorems due to Jarnik and Khintchine, and the parametric geometry of numbers in the sense of Roy. On the other hand, we give a novel Diophantine condition on that slightly strengthens nonsingularity, and show that under the assumption that satisfies this condition, is a null‐set with respect to any nontrivial algebraic measure on the torus. For this, we use naive homogeneous dynamics, harmonic analysis, and a novel concept that we refer to as mixing convergence of measures.
Live-cell analysis of IMPDH protein levels during yeast colony growth provides insights into the regulation of GTP synthesis
Authors: Shand Erica L. , Sweeney Kieran , Sundling Kaitlin E. , McClean Megan N. , Brow David A. 
Published: June 2024

ABSTRACT

The purine nucleotides ATP and GTP are made from the common precursor inosine monophosphate (IMP). Maintaining the correct balance of these nucleotides for optimal cell growth is controlled in part by the enzyme IMP dehydrogenase (IMPDH), which catalyzes the first dedicated step of GTP biosynthesis. The regulation of IMPDH mRNA and protein levels in the yeast
S. cerevisiae
grown in liquid culture has been studied in some detail, but regulation of IMPDH protein under conditions of cellular crowding on a solid substrate has not been examined. Here, we report real-time, live-cell analysis of the accumulation of the Imd2 isoform of IMPDH in yeast cells forming a monolayer colony in a microfluidic device over a 50-hour time course. We observe two distinct phases of increased Imd2 accumulation: a guanine-insensitive phase early in outgrowth and a guanine-sensitive phase later, when cells become crowded. We show that the IMPDH inhibitor mycophenolic acid enhances both phases of increase. Deletion of a transcription attenuator upstream of the mRNA start site that decreases Imd2 mRNA synthesis in the presence of high GTP increases the baseline level of Imd2 protein 10-fold and abolishes guanine-sensitive but not guanine-insensitive induction. Our results suggest that at least two mechanisms of yeast Imd2 regulation exist, the known GTP-dependent attenuation of RNA polymerase II elongation and a GTP concentration-independent pathway that may be controlled by cell growth state. Live-cell analysis of IMPDH protein levels in a growing yeast colony confirms a known mechanism of regulation and provides evidence for an additional mode of regulation.

IMPORTANCE
This study used live-cell microscopy to track changes in the level of a key enzyme in GTP nucleotide biosynthesis, inosine monophosphate dehydrogenase (IMPDH), during growth of a brewers yeast colony over 2 days in a microfluidic device. The results show that feedback regulation via transcription attenuation allows cells to adapt to nutrient limitation in the crowded environs of a yeast colony. They also identify a novel mode of regulation of IMPDH level that is not driven by guanine nucleotide availability.
Activities and genetic interactions of fission yeast Aps1, a Nudix-type inositol pyrophosphatase and inorganic polyphosphatase
Authors: Ghosh Shreya , Sanchez Ana M. , Schwer Beate , Prucker Isabel , Jork Nikolaus , Jessen Henning J. , Shuman Stewart 
Published: June 2024

ABSTRACT

Inositol pyrophosphate 1,5-IP
8
regulates expression of a fission yeast phosphate homeostasis regulon, comprising phosphate acquisition genes
pho1
,
pho84
, and
tgp1
, via its action as an agonist of precocious termination of transcription of the upstream lncRNAs that repress
PHO
mRNA synthesis. 1,5-IP
8
levels are dictated by a balance between the Asp1 N-terminal kinase domain that converts 5-IP
7
to 1,5-IP
8
and three inositol pyrophosphatases—the Asp1 C-terminal domain (a histidine acid phosphatase), Siw14 (a cysteinyl-phosphatase), and Aps1 (a Nudix enzyme). In this study, we report the biochemical and genetic characterization of Aps1 and an analysis of the effects of Asp1, Siw14, and Aps1 mutations on cellular inositol pyrophosphate levels. We find that Aps1’s substrate repertoire embraces inorganic polyphosphates, 5-IP
7
, 1-IP
7
, and 1,5-IP
8
. Aps1 displays a ~twofold preference for hydrolysis of 1-IP
7
versus 5-IP
7
and
aps1
∆ cells have twofold higher levels of 1-IP
7
vis-à-vis wild-type cells. While neither Aps1 nor Siw14 is essential for growth, an
aps1
∆
siw14
∆ double mutation is lethal on YES medium. This lethality is a manifestation of IP
8
toxicosis, whereby excessive 1,5-IP
8
drives derepression of
tgp1,
leading to Tgp1-mediated uptake of glycerophosphocholine. We were able to recover an
aps1
∆
siw14
∆ mutant on ePMGT medium lacking glycerophosphocholine and to suppress the severe growth defect of
aps1
∆
siw14
∆ on YES by deleting
tgp1
. However, the severe growth defect of an
aps1
∆
asp1-H397A
strain could not be alleviated by deleting
tgp1
, suggesting that 1,5-IP
8
levels in this double-pyrophosphatase mutant exceed a threshold beyond which overzealous termination affects other genes, which results in cytotoxicity.

IMPORTANCE

Repression of the fission yeast
PHO
genes
tgp1
,
pho1
, and
pho84
by lncRNA-mediated interference is sensitive to changes in the metabolism of 1,5-IP
8
, a signaling molecule that acts as an agonist of precocious lncRNA termination. 1,5-IP
8
is formed by phosphorylation of 5-IP
7
and catabolized by inositol pyrophosphatases from three distinct enzyme families: Asp1 (a histidine acid phosphatase), Siw14 (a cysteinyl phosphatase), and Aps1 (a Nudix hydrolase). This study entails a biochemical characterization of Aps1 and an analysis of how Asp1, Siw14, and Aps1 mutations impact growth and inositol pyrophosphate pools
in vivo
. Aps1 catalyzes hydrolysis of inorganic polyphosphates, 5-IP
7
, 1-IP
7
, and 1,5-IP
8
in vitro
, with a ~twofold preference for 1-IP
7
over 5-IP
7
.
aps1
∆ cells have twofold higher levels of 1-IP
7
than wild-type cells. An
aps1
∆
siw14
∆ double mutation is lethal because excessive 1,5-IP
8
triggers derepression of
tgp1
, leading to toxic uptake of glycerophosphocholine.
Whole-genome sequencing of
Klebsiella pneumoniae
isolated from clinical specimens in Chattogram, Bangladesh
Authors: Tanni Afroza Akter , Sharmen Farjana , Chakma Kallyan , Yasmin Farhana , Akash Al-Shahriar , Akash Md. Ashikur Alim , Riana Sumaiya Hafiz , Afrin Sajia , Ferdous Jannatul , Sultana Nahid , Biswas Sanjoy Kanti , Islam S. M. Rafiqul , Mannan Adnan 
Published: June 2024

ABSTRACT

The emergence of multidrug-resistant
Klebsiella pneumoniae
(Kpn) is a global concern due to the increasing rate of mortality and hospital cost burden in the affected population. This study reports the whole-genome sequences of nine multidrug-resistant Kpn from a hospital in Chattogram city of Bangladesh.
Unveiling contrasts in microbiota response: A1c control improves dysbiosis in low-A1c T2DM, but fails in high-A1c cases—a key to metabolic memory?
Authors: Napoli Thiago Fraga , Cortez Ramon V , Sparvoli Luiz Gustavo , Taddei Carla R , Salles Joao Eduardo Nunes 
Published: June 2024

IntroductionType 2 diabetes mellitus (T2DM) is associated with dysbiosis in the gut microbiota (MB). Individually, each medication appears to partially correct this. However, there are no studies on the response of the MB to changes in A1c. Therefore, we investigated the MB’s response to intensive glycemic control.Research design and methodsWe studied two groups of patients with uncontrolled T2DM, one group with an A1c <9% (18 patients—G1) and another group with an A1c >9% (13 patients—G2), aiming for at least a 1% reduction in A1c. We collected A1c and fecal samples at baseline, 6, and 12 months. G1 achieved an average A1c reduction of 1.1%, while G2 a reduction of 3.13%.ResultsG1’s microbiota saw a decrease in Erysipelotrichaceae_UCG_003 and in Mollicutes order (both linked to metabolic syndrome and associated comorbidities). G2, despite having a more significant reduction in A1c, experienced an increase in the proinflammatory bacteriaMegasphaeraandAcidaminococcus, and only one beneficial genus,Phascolarctobacterium, increased, producer of butyrate.ConclusionDespite a notable A1c outcome, G2 could not restore its MB. This seeming resistance to change, leading to a persistent inflammation component found in G2, might be part of the “metabolic memory” in T2DM.
Decreasing incidence of admission neonatal hypothermia in Gandhi Memorial Hospital, Addis Ababa, Ethiopia: quality improvement project
Authors: Wotango Biniam Yohannes , Workineh Wubet Mihretu , Abdana Tariku Deressa , Kidane Hailegebriel , Aragaw Aynekulu , Bekele Bisrat Tamene 
Published: June 2024

BackgroundWHO reported that neonatal hypothermia accounts for about 27% of newborn deaths worldwide. It is a serious concern in Ethiopia and other parts of sub-Saharan Africa; it poses a serious threat to global health, increasing morbidity and mortality. Hypothermic neonates are more likely to experience respiratory distress, infections and other issues that could result in longer hospital stays and delayed development. The objective of this quality improvement project was to minimise intensive medical treatments, maximise resource usage and enhance overall health outcomes for newborns at Gandhi Memorial Hospital by reducing neonatal hypothermia.MethodsOver 10 months (from 1 March 2021 to 30 January 2022), neonatal hypothermia incidence was assessed using Quality Supervision Mentoring Team and Health Management Information System data. Root cause analysis and literature review led to evidence-based interventions in a change bundle. After team training and neonatal intensive care unit (NICU) relocation, Plan-Do-Study-Act cycles tested the bundle. Close temperature monitoring and data collection occurred. Run charts evaluated intervention success against baseline data, informing conclusions about effectiveness.ResultThe quality improvement project reduced neonatal hypothermia in NICU admissions from a baseline median of 80.6% to a performance median of 30%.Conclusion and recommendationThe quality improvement project at Gandhi Memorial Hospital effectively reduced neonatal hypothermia through interventions such as the temperature management bundle and NICU relocation, leading to improved patient care, fewer hypothermic neonates and enhanced body temperature management. Continuous monitoring, adherence to best practices, sharing success and outcome assessment are crucial for enhancing the project’s effectiveness and sustaining positive impacts on neonatal hypothermia reduction and patient outcomes.
Improving influenza vaccine uptake in clinical risk groups: patient, provider and commissioner perspectives on the acceptability and feasibility of expanding delivery pathways in England
Authors: Kasstan Ben , Lazarus Rajeka , Ali Ifra , Mounier-Jack Sandra 
Published: June 2024

BackgroundPeople under the age of 65 in clinical risk groups are at increased risk of severe complications and death from influenza. In England, influenza vaccine coverage rates in this cohort remain profoundly low. This qualitative study aimed to explore (1) the reasons that underly suboptimal influenza vaccine uptake among different clinical risk groups in England and (2) how healthcare providers and commissioners perceive the feasibility and acceptability of integrating the influenza vaccine programme in non-primary care settings.MethodsThe study consisted of two phases. Phase I involved 32 semi-structured interviews conducted with individuals from three clinical risk groups: diabetes, chronic liver disease or chronic respiratory disease (or comorbidities). Phase II consisted of semi-structured interviews with 50 healthcare providers based in National Health Service primary and secondary care settings, and influenza vaccine commissioners and programme managers. Data were analysed thematically.ResultsAccess was not the primary issue underlying suboptimal vaccine uptake among participants in clinical risk groups, who instead cited low-risk perceptions of influenza infection and deficits of information about the relevance of vaccination for their condition management. Healthcare providers in non-primary care settings rarely discussed or recommended influenza vaccination across patient pathways, despite being able to address the concerns raised by participants in clinical risk groups. Healthcare providers were positive about the potential to offer vaccine recommendations and delivery, but questions remain around feasibility.ConclusionPatient pathways are punctuated with varying opportunities to discuss or deliver influenza vaccines during the winter season, though the commissioning and organisation of chronic disease management shapes how clinical risk groups interface with primary/secondary tiers of healthcare services. Embedding vaccine delivery in non-primary care settings may help to reduce inequalities and offer patients at risk the information and consent pathways they desire but is not a cost-neutral innovation and requires resource allocation.
Large language model-driven sentiment analysis for facilitating fibromyalgia diagnosis
Authors: Venerito Vincenzo , Iannone Florenzo 
Published: June 2024

BackgroundFibromyalgia (FM) is a complex disorder with widespread pain and emotional distress, posing diagnostic challenges. FM patients show altered cognitive and emotional processing, with a preferential allocation of attention to pain-related information. This attentional bias towards pain cues can impair cognitive functions such as inhibitory control, affecting patients’ ability to manage and express emotions. Sentiment analysis using large language models (LLMs) can provide insights by detecting nuances in pain expression. This study investigated whether open-source LLM-driven sentiment analysis could aid FM diagnosis.Methods40 patients with FM, according to the 2016 American College of Rheumatology Criteria and 40 non-FM chronic pain controls referred to rheumatology clinics, were enrolled. Transcribed responses to questions on pain and sleep were machine translated to English and analysed by the LLM Mistral-7B-Instruct-v0.2 using prompt engineering targeting FM-associated language nuances for pain expression (‘prompt-engineered’) or an approach without this targeting (‘ablated’). Accuracy, precision, recall, specificity and area under the receiver operating characteristic curve (AUROC) were calculated using rheumatologist diagnosis as ground truth.ResultsThe prompt-engineered approach demonstrated accuracy of 0.87, precision of 0.92, recall of 0.84, specificity of 0.82 and AUROC of 0.86 for distinguishing FM. In comparison, the ablated approach had an accuracy of 0.76, precision of 0.75, recall of 0.77, specificity of 0.75 and AUROC of 0.76. The accuracy was superior to the ablated approach (McNemar’s test p<0.001).ConclusionThis proof-of-concept study suggests LLM-driven sentiment analysis, especially with prompt engineering, may facilitate FM diagnosis by detecting subtle differences in pain expression. Further validation is warranted, particularly the inclusion of secondary FM patients.
Antiarrhythmic Mechanisms of Epidural Blockade After Myocardial Infarction
Authors: Hoang Jonathan D. , van Weperen Valerie Y.H. , Kang Ki-Woon , Jani Neil R. , Swid Mohammed A. , Chan Christopher A. , Lokhandwala Zulfiqar Ali , Lux Robert L. , Vaseghi Marmar 
Published: June 2024

BACKGROUND:
Thoracic epidural anesthesia (TEA) has been shown to reduce the burden of ventricular tachycardia in small case series of patients with refractory ventricular tachyarrhythmias and cardiomyopathy. However, its electrophysiological and autonomic effects in diseased hearts remain unclear, and its use after myocardial infarction is limited by concerns for potential right ventricular dysfunction.

METHODS:

Myocardial infarction was created in Yorkshire pigs (N=22) by left anterior descending coronary artery occlusion. Approximately, six weeks after myocardial infarction, an epidural catheter was placed at the C7-T1 vertebral level for injection of 2% lidocaine. Right and left ventricular hemodynamics were recorded using Millar pressure–conductance catheters, and ventricular activation recovery intervals (ARIs), a surrogate of action potential durations, by a 56-electrode sock and 64-electrode basket catheter. Hemodynamics and ARIs, baroreflex sensitivity and intrinsic cardiac neural activity, and ventricular effective refractory periods and slope of restitution (S
max
) were assessed before and after TEA. Ventricular tachyarrhythmia inducibility was assessed by programmed electrical stimulation.

RESULTS:

TEA reduced inducibility of ventricular tachyarrhythmias by 70%. TEA did not affect right ventricular–systolic pressure or contractility, although left ventricular–systolic pressure and contractility decreased modestly. Global and regional ventricular ARIs increased, including in scar and border zone regions post-TEA. TEA reduced ARI dispersion specifically in border zone regions. Ventricular effective refractory periods prolonged significantly at critical sites of arrhythmogenesis, and S
max
was reduced. Interestingly, TEA significantly improved cardiac vagal function, as measured by both baroreflex sensitivity and intrinsic cardiac neural activity.

CONCLUSIONS:

TEA does not compromise right ventricular function in infarcted hearts. Its antiarrhythmic mechanisms are mediated by increases in ventricular effective refractory period and ARIs, decreases in S
max
, and reductions in border zone electrophysiological heterogeneities. TEA improves parasympathetic function, which may independently underlie some of its observed antiarrhythmic mechanisms. This study provides novel insights into the antiarrhythmic mechanisms of TEA while highlighting its applicability to the clinical setting.
Therapeutic Efficacy of Mexiletine for Long QT Syndrome Type 2: Evidence From Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes, Transgenic Rabbits, and Patients
Authors: Crotti Lia , Neves Raquel , Dagradi Federica , Musu Giulia , Giannetti Federica , Bos J. Martijn , Barbieri Miriam , Cerea Paolo , Giovenzana Fulvio L.F. , Torchio Margherita , Mura Manuela , Gnecchi Massimiliano , Conte Giulio , Auricchio Angelo , Sala Luca , Odening Katja E. , Ackerman Michael J. , Schwartz Peter J. 
Published: June 2024

BACKGROUND:
Despite major advances in the clinical management of long QT syndrome, some patients are not fully protected by beta-blocker therapy. Mexiletine is a well-known sodium channel blocker, with proven efficacy in patients with sodium channel–mediated long QT syndrome type 3. Our aim was to evaluate the efficacy of mexiletine in long QT syndrome type 2 (LQT2) using cardiomyocytes derived from patient-specific human induced pluripotent stem cells, a transgenic LQT2 rabbit model, and patients with LQT2.

METHODS:

Heart rate–corrected field potential duration, a surrogate for QTc, was measured in human induced pluripotent stem cells from 2 patients with LQT2 (KCNH2-p.A561V, KCNH2-p.R366X) before and after mexiletine using a multiwell multi-electrode array system. Action potential duration at 90% repolarization (APD
90
) was evaluated in cardiomyocytes isolated from transgenic LQT2 rabbits (KCNH2-p.G628S) at baseline and after mexiletine application. Mexiletine was given to 96 patients with LQT2. Patients were defined as responders in the presence of a QTc shortening ≥40 ms. Antiarrhythmic efficacy of mexiletine was evaluated by a Poisson regression model.

RESULTS:

After acute treatment with mexiletine, human induced pluripotent stem cells from both patients with LQT2 showed a significant shortening of heart rate–corrected field potential duration compared with dimethyl sulfoxide control. In cardiomyocytes isolated from LQT2 rabbits, acute mexiletine significantly shortened APD
90
by 113 ms, indicating a strong mexiletine-mediated shortening across different LQT2 model systems. Mexiletine was given to 96 patients with LQT2 either chronically (n=60) or after the acute oral drug test (n=36): 65% of the patients taking mexiletine only chronically and 75% of the patients who performed the acute oral test were responders. There was a significant correlation between basal QTc and ∆QTc during the test (
r
= −0.8;
P
<0.001). The oral drug test correctly predicted long-term effect in 93% of the patients. Mexiletine reduced the mean yearly event rate from 0.10 (95% CI, 0.07–0.14) to 0.04 (95% CI, 0.02–0.08), with an incidence rate ratio of 0.40 (95% CI, 0.16–0.84), reflecting a 60% reduction in the event rate (
P
=0.01).

CONCLUSIONS:
Mexiletine significantly shortens cardiac repolarization in LQT2 human induced pluripotent stem cells, in the LQT2 rabbit model, and in the majority of patients with LQT2. Furthermore, mexiletine showed antiarrhythmic efficacy. Mexiletine should therefore be considered a valid therapeutic option to be added to conventional therapies in higher-risk patients with LQT2.
The Central Eurasian Dawn of Everything
Authors: Atwood Christopher P. 
Published: June 2024

Abstract
The Scythian Empire is Beckwith’s latest effort to redefine the European civilizational legacy as Central Eurasian, from its feudal origins to the development of philosophy, science, politics, and religion. Beckwith proposes that a Scythian Empire, spanning from the Mediterranean to the Ganges to the Yellow River, played a central role in shaping ancient civilizations, challenging conventional views of history. The Scythian religion is interpreted, based on Herodotus’ accounts, as fundamentally monotheistic. Although it offers insightful points on the importance of Central Eurasia in shaping ancient civilizations, the book and its claims of a unified Scythian Empire and monotheistic Aryan religion remain controversial.
Anatomical Connectivity Constrains Dynamic Functional Connectivity among Neural Systems: Implications for Cognition and Behavior
Authors: Courtney Susan M. , Hinault Thomas 
Published: June 2024

Abstract
Leslie Ungerleider had a tremendous impact across many different areas of cognitive neuroscience. Her ideas and her approach, as well as her findings, will continue to impact the field for generations to come. One of the most impactful aspects of her approach was her focus on the ways that anatomical connections constrain functional communications among brain regions. Furthermore, she emphasized that changes in these functional communications, whether from lesions to the anatomical connections or temporary modulations of the efficacy of information transmission resulting from selective attention, have consequences for cognition and behavior. By necessity, this short review cannot cover the vast amount of research that contributed to or benefited from Leslie's work. Rather, we focus on one line of research that grew directly from some of Leslie's early work and her mentoring on these important concepts. This research and the many other lines of research that arose from these same origins has helped develop our understanding of the visual system, and cognitive systems more generally, as collections of highly organized, specialized, dynamic, and interacting subsystems.