bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA methylation remodeled amino acids biosynthesis regulates flower senescence in carnation (Dianthus caryophyllus)
Authors: Feng Shan , Jiang Xinyu , Huang Zhiheng , Li Fan , Wang Ruiming , Yuan Xinyi , Sun Zheng , Tan Hualiang , Zhong Linlin , Li Shenchong , Cheng Yunjiang , Bao Manzhu , Qiao Hong , Song Qingxin , Wang Jihua , Zhang Fan 
Published: January 2024

Summary
Dynamic DNA methylation regulatory networks are involved in many biological processes. However, how DNA methylation patterns change during flower senescence and their relevance with gene expression and related molecular mechanism remain largely unknown.
Here, we used whole genome bisulfite sequencing to reveal a significant increase of DNA methylation in the promoter region of genes during natural and ethylene‐induced flower senescence in carnation (Dianthus caryophyllus L.), which was correlated with decreased expression of DNA demethylase gene DcROS1. Silencing of DcROS1 accelerated while overexpression of DcROS1 delayed carnation flower senescence.
Moreover, among the hypermethylated differentially expressed genes during flower senescence, we identified two amino acid biosynthesis genes, DcCARA and DcDHAD, with increased DNA methylation and reduced expression in DcROS1 silenced petals, and decreased DNA methylation and increased expression in DcROS1 overexpression petals, accompanied by decreased or increased amino acids content. Silencing of DcCARA and DcDHAD accelerates carnation flower senescence. We further showed that adding corresponding amino acids could largely rescue the senescence phenotype of DcROS1, DcCARA and DcDHAD silenced plants.
Our study not only demonstrates an essential role of DcROS1‐mediated remodeling of DNA methylation in flower senescence but also unravels a novel epigenetic regulatory mechanism underlying DNA methylation and amino acid biosynthesis during flower senescence.
The age and primary reason for the first dental visit in children with special health care needs
Authors: Collie Amanda Dickerson , Jayaraman Jayakumar , Carrico Caroline , Upshur Conway , Bortell Elizabeth 
Published: January 2024

AbstractAimTo evaluate the average age and primary reason for the first dental visit among patients with special health care needs (SHCN) as well as to examine barriers related to accessing care for children with special health care needs.MethodsThis is a cross‐sectional survey that was distributed to caregivers of children with special health care needs (CSHCN). Study data was collected through REDCap, a secure web‐based survey application.ResultsA total of 75 caregivers participated in the survey. Only 13% of caregivers reported that their child was less than 1 by the time of their first dental visit. Nearly all reported seeing a pediatric dentist for their first visit (89%) and that it was for a routine exam and cleaning (83%). About one‐third of guardians reported an experience where a dentist was unable to care for their child due to their SHCN (36%).DiscussionIt appears that caregivers of CSHCN that participated in this survey have established routine care with a pediatric dentist at an early age. It is important to continue to educate caregivers on the importance of routine care as well as support general dentists in their role of caring for patients with SHCN.
Therapeutic efficacy and safety of pathogen‐reduced platelet components: Results of a meta‐analysis of randomized controlled trials
Authors: Cid Joan , Charry Paola , Lozano Miquel 
Published: January 2024

AbstractBackground and ObjectivesClinical efficacy and safety of pathogen‐reduced platelet concentrates (PR‐PCs) concerning bleeding prevention are still debated despite conclusive real‐world data from multiple countries where PR‐PCs are transfused routinely. We performed a meta‐analysis of randomized controlled trials (RCTs) comparing the clinical efficacy and safety of conventional platelet components (PCs) and PR‐PCs prepared with the amotosalen/ultraviolet A light (INTERCEPT platelet concentrate [I‐PC]) or riboflavin/ultraviolet light (Mirasol platelet concentrate [M‐PC]) technologies, transfused in thrombocytopenic adult patients.Materials and MethodsA literature search was conducted, and 10 RCTs met the criteria for inclusion in this meta‐analysis. Summary odds ratios (ORs) of clinically significant bleeding (World Health Organization [WHO] bleeding grade ≥2), severe bleeding (WHO bleeding score ≥3) and all‐cause mortality were calculated.ResultsThe use of I‐PC was not associated with an increase in the OR of clinically significant bleeding when compared to non‐treated PCs (OR, 1.12; 95% CI: 0.89–1.41; p = 0.33), whereas transfusions with M‐PC showed an increase in clinically significant bleeding (OR, 1.34; 95% CI: 1.03–1.75; p = 0.03). The OR of severe bleeding did not increase with either I‐PC or M‐PC (OR 0.88; 95% CI: 0.59–1.31; p = 0.52 for I‐PC; OR 1.25; 95% CI: 0.66–2.37; p = 0.49 for M‐PC). In the case of all‐cause mortality, compared to non‐treated PC, I‐PC showed an OR of 0.61 (95% CI: 0.36–1.04; p = 0.07), and M‐PC showed an OR of 3.04 (95% CI: 0.81–11.47; p = 0.1).ConclusionNo differences were observed concerning the clinical efficacy and safety of overall PR‐PCs when compared to non‐treated PCs. However, differences are evident when analysing platelets prepared with the two PR technologies independently.
Differential splenic responses to hyperoxic breathing at high altitude in Sherpa and lowlanders
Authors: Holmström Pontus K. , Harman Taylor S. , Kalker Anne , Steiner Bethany , Hawkins Ella , Jorgensen Kelsey C. , Zhu Kimberly T. , Kunwar Ajaya J. , Thakur Nilam , Dhungel Sunil , Sherpa Nima , Day Trevor A. , Schagatay Erika K. , Bigham Abigail W. , Brutsaert Tom D. 
Published: January 2024

AbstractThe human spleen contracts in response to stress‐induced catecholamine secretion, resulting in a temporary rise in haemoglobin concentration ([Hb]). Recent findings highlighted enhanced splenic response to exercise at high altitude in Sherpa, possibly due to a blunted splenic response to hypoxia. To explore the potential blunted splenic contraction in Sherpas at high altitude, we examined changes in spleen volume during hyperoxic breathing, comparing acclimatized Sherpa with acclimatized individuals of lowland ancestry. Our study included 14 non‐Sherpa (7 female) residing at altitude for a mean continuous duration of 3 months and 46 Sherpa (24 female) with an average of 4 years altitude exposure. Participants underwent a hyperoxic breathing test at altitude (4300 m; barrometric pressure = ∼430 torr; = ∼90 torr). Throughout the test, we measured spleen volume using ultrasonography and monitored oxygen saturation (). During rest, Sherpa exhibited larger spleens (226 ± 70 mL) compared to non‐Sherpa (165 ± 34 mL;P < 0.001; effect size (ES) = 0.95, 95% CI: 0.3–1.6). In response to hyperoxia, non‐Sherpa demonstrated 22 ± 12% increase in spleen size (35 ± 17 mL, 95% CI: 20.7–48.9;P < 0.001; ES = 1.8, 95% CI: 0.93–2.66), while spleen size remained unchanged in Sherpa (−2 ± 13 mL, 95% CI: −2.4 to 7.3;P = 0.640; ES = 0.18, 95% CI: −0.10 to 0.47). Our findings suggest that Sherpa and non‐Sherpas of lowland ancestry exhibit distinct variations in spleen volume during hyperoxia at high altitude, potentially indicating two distinct splenic functions. In Sherpa, this phenomenon may signify a diminished splenic response to altitude‐related hypoxia at rest, potentially contributing to enhanced splenic contractions during physical stress. Conversely, non‐Sherpa experienced a transient increase in spleen size during hyperoxia, indicating an active tonic contraction, which may influence early altitude acclimatization in lowlanders by raising [Hb].
Evolution and separation of actinobacterial pyranose and
C
-glycoside-3-oxidases
Authors: Kostelac Anja , Taborda André , Martins Lígia O. , Haltrich Dietmar 
Published: January 2024

ABSTRACT

FAD-dependent pyranose oxidase (POx) and
C
-glycoside-3-oxidase (CGOx) are both members of the glucose-methanol-choline superfamily of oxidoreductases and belong to the same sequence space. Pyranose oxidases had been studied for their oxidation of monosaccharides such as D-glucose, but recently, a bacterial
C
-glycoside-3-oxidase that is phylogenetically related to POx and that reacts with
C
-glycosides such as carminic acid, mangiferin or puerarin has been described. Since these actinobacterial CGOx enzymes belong to the same sequence space as bacterial POx, they must have evolved from the same ancestor. Here, we performed a phylogenetic analysis of actinobacterial sequences and resurrected seven ancestral enzymes of the POx/CGOx sequence space to study the evolutionary trajectory of substrate preferences for monosaccharides and
C
-glycosides. Clade I, with its dimeric member POx from
Kitasatospora aureofaciens
, shows strict preference for monosaccharides (D-glucose and D-xylose) and does not react with any of the glycosides tested. No extant member of clade II has been studied to date. The two extant members of clades III and IV, monomeric POx/CGOx from
Pseudoarthrobacter siccitolerans
and
Streptomyces canus
, oxidized both monosaccharides as well as various
C
-glycosides (homoorientin, isovitexin, mangiferin, and puerarin). Steady-state kinetic parameters of several clades III and IV ancestral enzymes indicate that the generalist ancestor N35 slowly evolved to present-day enzymes with a much higher preference for
C
-glycosides than monosaccharides. Based on structural predictions of ancestors, we hypothesize that the strict specificity of bacterial clade I POx (and also fungal POx) is the result of oligomerization, which in turn results from the evolution of protein segments that were shown to be important for oligomerization, the arm, and the head domain.

IMPORTANCE

C
-Glycosides often form active compounds in various plants. Breakage of the C-C bond in these glycosides to release the aglycone is challenging and proceeds via a two-step reaction, the oxidation of the sugar and subsequent cleavage of the C-C bond. Recently, an enzyme from a soil bacterium, FAD-dependent
C
-glycoside-3-oxidase (CGOx), was shown to catalyze the initial oxidation reaction. Here, we show that CGOx belongs to the same sequence space as pyranose oxidase (POx), and that an actinobacterial ancestor of the POx/CGOx family evolved into four clades, two of which show a high preference for
C
-glycosides.
Extension of the Schwarzschild black hole solution in f(R) gravitational theory and its physical properties
Authors: Nashed G. G. L. 
Published: January 2024

AbstractThe successes of f(R) gravitational theory as a logical extension of Einstein’s theory of general relativity (GR) encourage us to delve deep into this theory and continue our study to attempt to derive an extension of the Schwarzschild black hole (BH) solution. In this study, in order to solve the output nonlinear differential equation, we closed the form of the system by assuming the derivative of f(R) with respect to the scalar curvature R to have the form $$F(r)=\frac{\textrm{d}f(R(r))}{\textrm{d}R(r)}=1- \frac{\alpha }{r^4}$$

F

(
r
)

=

d
f
(
R
(
r
)
)

d
R
(
r
)

=
1
-

α

r
4

, where $$\alpha $$
α
is a dimensional constant. Our study shows that when $$\alpha \rightarrow 0$$

α
→
0

, we obtain the Schwarzschild BH solution of GR assuming some constraints on the constant of integration, and if these constraints are bounded, we obtain the anti-de Sitter (AdS)/de Sitter (dS) spacetime. For the general case, i.e., when $$\alpha \ne 0$$

α
≠
0

, we obtain a BH solution that tends asymptotically to AdS/dS spacetime. Moreover, we derive the timelike and null particle geodesics of the BH solution studied in this article. The equation of motion and effective potential of test particles are calculated to study the stability of radial orbits (trajectories). The energy and angular momentum are calculated to study the circular motion and stability of circular orbits. We also derive the stability condition using the geodesic deviation. Moreover, we discuss the physics of the output BH solutions through calculation of the thermodynamic quantities including entropy, the Hawking temperature, and Gibbs free energy. Finally, we check the validity of the first law of thermodynamics applied to the BH of this study. Although we can derive a Schwarzschild black hole solution in the lower order of f(R), specifically when $$f(R)=R$$

f
(
R
)
=
R

, where the gravitational mass is generated from the source of gravity, we demonstrate that in the higher orders of f(R), when $$f(R)\ne R$$

f
(
R
)
≠
R

, the source of gravity is attributed primarily to higher-order corrections, and the source of gravity that was originally derived from the Schwarzschild black hole has ceased to be dominant.
An Axiomatic Basis for Computer Programming on the Relaxed Arm-A Architecture: The AxSL Logic
Authors: Hammond Angus , Liu Zongyuan , Pérami Thibaut , Sewell Peter , Birkedal Lars , Pichon-Pharabod Jean 
Published: January 2024

Very relaxed concurrency memory models, like those of the Arm-A, RISC-V, and IBM Power hardware architectures, underpin much of computing but break a fundamental intuition about programs, namely that syntactic program order and the reads-from relation always both induce order in the execution. Instead, out-of-order execution is allowed except where prevented by certain pairwise dependencies, barriers, or other synchronisation. This means that there is no notion of the 'current' state of the program, making it challenging to design (and prove sound) syntax-directed, modular reasoning methods like Hoare logics, as usable resources cannot implicitly flow from one program point to the next.
We present AxSL, a separation logic for the relaxed memory model of Arm-A, that captures the fine-grained reasoning underpinning the low-overhead synchronisation mechanisms used by high-performance systems code. In particular, AxSL allows transferring arbitrary resources using relaxed reads and writes when they induce inter-thread ordering. We mechanise AxSL in the Iris separation logic framework, illustrate it on key examples, and prove it sound with respect to the axiomatic memory model of Arm-A. Our approach is largely generic in the axiomatic model and in the instruction-set semantics, offering a potential way forward for compositional reasoning for other similar models, and for the combination of production concurrency models and full-scale ISAs.
Unboxed Data Constructors: Or, How cpp Decides a Halting Problem
Authors: Chataing Nicolas , Dolan Stephen , Scherer Gabriel , Yallop Jeremy 
Published: January 2024

We propose a new language feature for ML-family languages, the ability to selectively
unbox
certain data constructors, so that their runtime representation gets compiled away to just the identity on their argument. Unboxing must be statically rejected when it could introduce confusion, that is, distinct values with the same representation.

We discuss the use-case of big numbers, where unboxing allows to write code that is both efficient and safe, replacing either a safe but slow version or a fast but unsafe version. We explain the static analysis necessary to reject incorrect unboxing requests. We present our prototype implementation of this feature for the OCaml programming language, discuss several design choices and the interaction with advanced features such as Guarded Algebraic Datatypes.
Our static analysis requires expanding type definitions in type expressions, which is not necessarily normalizing in presence of recursive type definitions. In other words, we must decide normalization of terms in the first-order λ-calculus with recursion. We provide an algorithm to detect non-termination on-the-fly during reduction, with proofs of correctness and completeness. Our algorithm turns out to be closely related to the normalization strategy for macro expansion in the cpp preprocessor.
Soundly Handling Linearity
Authors: Tang Wenhao , Hillerström Daniel , Lindley Sam , Morris J. Garrett 
Published: January 2024

We propose a novel approach to soundly combining linear types with multi-shot effect handlers. circear type systems statically ensure that resources such as file handles and communication channels are used exactly once. Effect handlers provide a rich modular programming abstraction for implementing features ranging from exceptions to concurrency to backtracking. Whereas conventional linear type systems bake in the assumption that continuations are invoked exactly once, effect handlers allow continuations to be discarded (e.g. for exceptions) or invoked more than once (e.g. for backtracking). This mismatch leads to soundness bugs in existing systems such as the programming language Links, which combines linearity (for session types) with effect handlers. We introduce control-flow linearity as a means to ensure that continuations are used in accordance with the linearity of any resources they capture, ruling out such soundness bugs.We formalise the notion of control-flow linearity in a System F-style core calculusFeff∘equipped with linear types, an effect type system, and effect handlers. We define a linearity-aware semantics in order to formally prove thatFeff∘preserves the integrity of linear values in the sense that no linear value is discarded or duplicated. In order to show that control-flow linearity can be made practical, we adapt circks based on the design ofFeff∘, in doing so fixing a long-standing soundness bug.Finally, to better expose the potential of control-flow linearity, we define an ML-style core calculusQeff∘, based on qualified types, which requires no programmer provided annotations, and instead relies entirely on type inference to infer control-flow linearity. Both linearity and effects are captured by qualified types.Qeff∘overcomes a number of practical limitations ofFeff∘, supporting abstraction over linearity, linearity dependencies between type variables, and a much more fine-grained notion of control-flow linearity.
Parikh’s Theorem Made Symbolic
Authors: Hague Matthew , Jeż Artur , Lin Anthony W. 
Published: January 2024

Parikh’s Theorem is a fundamental result in automata theory with numerous applications in computer science. These include software verification (e.g. infinite-state verification, string constraints, and theory of arrays), verification of cryptographic protocols (e.g. using Horn clauses modulo equational theories) and database querying (e.g. evaluating path-queries in graph databases), among others. Parikh’s Theorem states that the letter-counting abstraction of a language recognized by finite automata or context-free grammars is definable in Linear Integer Arithmetic (a.k.a. Presburger Arithmetic). In fact, there is a linear-time algorithm computing existential Presburger formulas capturing such abstractions, which enables an efficient analysis via SMT-solvers. Unfortunately, real-world applications typically require large alphabets (e.g. Unicode, containing a ‍million of characters) — which are well-known to be not amenable to explicit treatment of the alphabets — or even worse infinite alphabets.
Symbolic automata have proven in the last decade to be an effective algorithmic framework for handling large finite or even infinite alphabets. A symbolic automaton employs an effective boolean algebra, which offers a symbolic representation of character sets (i.e. in terms of predicates) and often lends itself to an exponentially more succinct representation of a language. Instead of letter-counting, Parikh’s Theorem for symbolic automata amounts to counting the number of times different predicates are satisfied by an input sequence. Unfortunately, naively applying Parikh’s Theorem from classical automata theory to symbolic automata yields existential Presburger formulas of exponential size. In this paper, we provide a new construction for Parikh’s Theorem for symbolic automata and grammars, which avoids this exponential blowup: our algorithm computes an existential formula in polynomial-time over (quantifier-free) Presburger and the base theory. In fact, our algorithm extends to the model of parametric symbolic grammars, which are one of the most expressive models of languages over infinite alphabets. We have implemented our algorithm and show it can be used to solve string constraints that are difficult to solve by existing solvers.
Phase II Study of the Liposomal Formulation of Eribulin (E7389-LF) in Combination with Nivolumab: Results from the Small Cell Lung Cancer Cohort
Authors: Nishio Makoto , Murakami Shuji , Kawakami Hisato , Okishio Kyoichi , Tamiya Motohiro , Kobayashi Haruki , Fujimoto Daichi , Sugawara Shunichi , Kozuki Toshiyuki , Oya Yuko , Izumi Hiroki , Shiroyama Takayuki , Satouchi Miyako , Yamamoto Noboru , Kaname Shota , Matsuoka Daiko , Otake Yohei , Takase Takao , Semba Taro , Azuma Koichi 
Published: January 2024

Abstract

Purpose:
E7389-LF is a liposomal formulation of eribulin that contributes to tumor vascular remodeling. The phase II part of this phase Ib/II study assessed the efficacy/safety of E7389-LF in combination with nivolumab in several disease cohorts; herein, we report results from the small cell lung cancer (SCLC) cohort.

Experimental Design:
Patients with unresectable/measurable SCLC and disease progression with first-line platinum-based chemotherapy with/without an immune checkpoint inhibitor (ICI) were enrolled to receive E7389-LF 2.1 mg/m2 plus nivolumab 360 mg intravenously every 3 weeks. The primary objective of this part was to assess the objective response rate (ORR). Secondary objectives included assessments of safety and progression-free survival (PFS); exploratory assessments included overall survival (OS) and biomarkers.

Results:
Thirty-four patients were enrolled. By the data cut-off date (May 31, 2022), 29 (85.3%) had discontinued. Efficacy/biomarker analyses included 33 patients (1 had their diagnosis changed postenrollment); the ORR of E7389-LF plus nivolumab was 24.2% [95% confidence interval (CI): 11.1–42.3], the median PFS was 3.98 months (95% CI: 2.63–4.40), and, at a median follow-up of 10.6 months, the median OS was not reached (95% CI: not estimable). Notably, 27 of 33 patients (81.8%) had received an ICI as their prior first-line therapy. Treatment-related, treatment-emergent adverse events occurred in 97.1% (any grade) and 82.4% (grade ≥3) of enrolled patients; the most common event was neutropenia. Changes in vascular and immune-related plasma markers were observed.

Conclusions:
E7389-LF 2.1 mg/m2 in combination with nivolumab 360 mg every 3 weeks showed notable antitumor activity as second-line therapy for SCLC; no new safety signals were observed compared with either agent as monotherapy.

Significance:
This phase II part of a phase Ib/II study assessed liposomal eribulin (E7389-LF) plus nivolumab in 34 patients with pretreated SCLC; 8 of 33 evaluable patients (including 6/27 pretreated with ICIs) had objective responses. The combination was tolerable; increases in vasculature-related biomarkers tended to correlate with responses.