bluuebunny/crossref_metadata_2025 huggingface dataset:
Nationwide multicenter study on adverse events associated with a patency capsule: Additional survey of appropriate use of patency capsule study
Authors: Omori Teppei , Ohmiya Naoki , Watanabe Kenji , Hirai Fumihito , Nakamura Masanao , Kitamura Kazuya , Ozeki Keiji , Oka Shiro , Kawano Seiji , Handa Osamu , Kawai Mikio , Ninomiya Kazeo , Sagawa Tamotsu , Wakamatsu Takahiro , Araki Akihiro , Koike Yuji , Kato Shingo , Hashimoto Shinichi , Mannami Tomohiko , Nakaji Konosuke , Tanaka Shinji , Matsui Toshiyuki ,   the J‐POP study group
Published: October 2023

Background and Aim

The PillCam patency capsule (PC) without a radio frequency identification tag was released to preclude retention of the small bowel capsule endoscope (CE) in Japan in 2012. We conducted a multicenter study to determine tag‐less PC‐related adverse events (AEs).

Methods

We first conducted a retrospective survey using a standardized data collection sheet for the clinical characteristics of PC‐related AEs among 1096 patients collected in a prospective survey conducted between January 2013 and May 2014 (Cohort 1). Next, we retrospectively investigated additional AEs that occurred before and after Cohort 1 within the period June 2012 and December 2014 among 1482 patients (Cohort 2).

Results

Of the 2578 patients who underwent PC examinations from both cohorts, 74 AEs occurred among 61 patients (2.37%). The main AEs were residual parylene coating in 25 events (0.97%), PC‐induced small bowel obstruction, suspicious of impaction, in 23 events (0.89%), and CE retention even after patency confirmation in 10 events (0.39%). Residual parylene coating was significantly associated with Crohn's disease (P < 0.01). Small bowel obstruction was significantly associated with physicians with less than 1 year of experience handling the PC and previous history of postprandial abdominal pain (P < 0.01 and P < 0.03, respectively). CE retention was ascribed to erroneous judgment of PC localization in all cases.

Conclusions

This large‐scale multicenter study provides evidence supporting the safety and efficiency of a PC to preclude CE retention. Accurate PC localization in patients without excretion and confirmation of previous history of postprandial abdominal pain before PC examinations is warranted (UMIN000010513).
The governance of policy integration and policy coordination through joined‐up government: How subnational levels counteract siloism and fragmentation within Swedish migration policy
Authors: Lidén Gustav , Nyhlén Jon
Published: October 2023

Modern welfare states struggle with fragmented policies and siloed governments, as well as with the need to deal with wicked problems. We argue that addressing such problems from the perspective of central government can be facilitated by notions of joined‐up government that, combined with vertical aspects of modern governance, provide a basis for analysis. To embark upon such challenges, we examine policy integration and policy coordination within the complex area of Swedish migration policies in light of the European migrant crisis. Through a content analysis of an extensive qualitative material (interviews and documents), we show that policy integration is weakly associated with joint objectives and decision‐making. As a contribution to prior knowledge in the field, we emphasize the unintuitive finding that counteracting siloism and fragmentation in Swedish migration policy is not achieved through coherent governance ranging across tiers, functions, and sectors but mainly at subnational levels through policy coordination relying on a bottom‐up approach.
GENETIC MARKERS AND GENOME-WIDE ASSOCIATION STUDY IN PLANTS
Authors: Tussipkan D. , Pan Zhaoe
Published: October 2023

Due to the advanced sequencing technologies, breeders and researchers can use DNA markers to characterize various plants' genetic diversity, kinship, and population structures. This review describes four kinds of genetic markers. Among them, DNA-based molecular markers were discussed in types, basic mechanisms, advantages, and disadvantages in detail. Secondly, we summarize the whole process of a genome-wide association study, and its advantages and disadvantages. We hope that this review provides fundamental information that will be useful for understanding different markers, especially, DNA-based molecular markers, and genome-wide association studies.
A novel protein encoded by circVPS13D attenuates antiviral innate immunity by targeting MAVS in teleost fish
Authors: Wang Linchao , Song Yanhong , Yan Xiaolong , Xu Tianjun
Published: October 2023

The signaling adaptor MAVS is a vital adaptor protein in retinoic acid-inducible gene I-like receptors (RLRs) signaling; thus, its expression and responses must be tightly regulated to avoid uncontrolled production of type I IFN by various mechanisms, including ubiquitination. The protein-coding ability of circRNAs has recently been a hot topic, but the roles of protein-coding circRNAs in antiviral innate immunity of teleost have rarely been reported. In this study, we identify that a novel circRNA derived from vacuolar protein sorting-associated protein 13D (
VPS13D
) gene, named circVPS13D, was a suppressor of RLR signaling pathways during poly(I:C) stimulation or
Siniperca chuatsi rhabdovirus
(SCRV) infection. Mechanistically, circVPS13D contains a 513-nucleotide (nt) open reading frame (ORF) and a sequence that is −174 nt as an internal ribosome entry site (IRES), which is required for translation initiation in 5’-cap-independent coding RNAs. SCRV infection promoted the expression of circVPS13D and circVPS13D encodes a novel peptide, termed VPS13D-170 amino acid (aa), which directly interacted with MAVS and inhibited IFN-I production. VPS13D-170aa targeted the K172 residue of MAVS through K48-linked polyubiquitination, leading to proteasomal degradation of MAVS.

IMPORTANCE

The expression of circVPS13D was upregulated with SCRV invasion, which proved that circVPS13D was involved in the regulation of the antiviral immune response. Our study revealed that the existence of circVPS13D promoted the replication of SCRV. Functionally, circVPS13D negatively regulates the antiviral responses of fish. Mechanistically, we confirmed that circVPS13D inhibited RLRs antiviral signaling pathway via the encoded protein VPS13D-170aa by targeting MAVS. Our study provided novel insights into the roles of protein-coding circRNAs and supported VPS13D-170aa as a negative regulator in the antiviral immune responses of teleost fish.
Characterization and biodistribution of under-employed gene therapy vector AAV7
Authors: Yost Samantha A. , Firlar Emre , Glenn Justin D. , Carroll Hayley B. , Foltz Steven , Giles April R. , Egley Jenny M. , Firnberg Elad , Cho Sungyeon , Nguyen Trang , Henry William M. , Janczura Karolina J. , Bruder Joseph , Liu Ye , Danos Olivier , Karumuthil-Melethil Subha , Pannem Sanjana , Yost Valerie , Engelson Yelena , Kaelber Jason T. , Dimant Hemi , Smith Jared B. , Mercer Andrew C.
Published: October 2023

AAV7 is a clade D adeno-associated virus (AAV) whose potential as a gene therapy vector has not been fully evaluated. We show here that high-titer AAV7 vectors can be produced in HEK293 cells and used to transduce cultured cells in an AAV receptor (AAVR)-dependent manner. In contrast with AAV9, AAV7 did not significantly interact with glycans when assayed on a panel of three hundred biologically relevant species. The structure of the AAV7 capsid was obtained by single particle cryo-electron microscopy at 2.7 Å, showing the expected AAV scaffold as well as unique features in variable surface loops. The biodistribution profiles of AAV7 and AAV9 vectors were compared in mice following intravenous administration and quantification of vector genomes and mRNA in tissues, as well as cryofluorescence tomography (CFT) and immunofluorescence (IF). AAV7 displayed a strong cardiac tropism and did not efficiently cross the blood-brain barrier. Surprisingly, strong transgene expression was observed throughout the head as shown by CFT, including regions of the cranial sinuses, teeth, and mandible for both AAV7 and AAV9, an attribute that has not been previously evaluated via traditional biodistribution methods.

IMPORTANCE

The use of adeno-associated viruses (AAVs) as gene delivery vectors has vast potential for the treatment of many severe human diseases. Over one hundred naturally existing AAV capsid variants have been described and classified into phylogenetic clades based on their sequences. AAV8, AAV9, AAVrh.10, and other intensively studied capsids have been propelled into pre-clinical and clinical use, and more recently, marketed products; however, less-studied capsids may also have desirable properties (e.g., potency differences, tissue tropism, reduced immunogenicity, etc.) that have yet to be thoroughly described. These data will help build a broader structure-function knowledge base in the field, present capsid engineering opportunities, and enable the use of novel capsids with unique properties.
Glycerophosphocholine provision rescues
Candida albicans
growth and signaling phenotypes associated with phosphate limitation
Authors: King William R. , Acosta-Zaldívar Maikel , Qi Wanjun , Cherico Nicholas , Cooke Lauren , Köhler Julia R. , Patton-Vogt Jana
Published: October 2023

The fungal pathogen
Candida albicans
must acquire phosphate to colonize, infect, and proliferate in the human host.
C. albicans
has four inorganic phosphate (P
i
) transporters, Pho84 being the major high-affinity transporter; its cells can also use glycerophosphocholine (GPC) as their sole phosphate source. GPC is a lipid metabolite derived from deacylation of the lipid phosphatidylcholine. GPC is found in multiple human tissues, including the renal medulla, where it acts as an osmolyte.
C. albicans
imports GPC into the cell via the Git3 and Git4 transporters. Internalized GPC can be hydrolyzed to release P
i
. To determine if GPC import and subsequent metabolism affect phosphate homeostasis upon P
i
limitation, we monitored growth and phenotypic outputs in cells provided with either P
i
or GPC. In
pho84
∆
/
∆ mutant cells that exhibit phenotypes associated with P
i
limitation, GPC provision rescued sensitivity to osmotic and cell wall stresses. The glycerophosphodiesterase Gde1 was required for phenotypic rescue of osmotic stress by GPC provision. GPC provision, like P
i
provision, resulted in repression of the PHO regulon and activation of TORC1 signaling. P
i
uptake was similar to GPC uptake when phosphate availability was low (200 µM). While available at lower concentrations than P
i
in the human host, GPC is an advantageous P
i
source for the fungus because it simultaneously serves as a choline source. In summary, we find GPC is capable of substituting for P
i
in
C. albicans
by many though not all criteria and may contribute to phosphate availability for the fungus in the human host.

IMPORTANCE

Candida albicans
is the most commonly isolated species from patients suffering from invasive fungal disease.
C. albicans
is most commonly a commensal organism colonizing a variety of niches in the human host. The fungus must compete for resources with the host flora to acquire essential nutrients such as phosphate. Phosphate acquisition and homeostasis have been shown to play a key role in
C. albicans
virulence, with several genes involved in these processes being required for normal virulence and several being upregulated during infection. In addition to inorganic phosphate (P
i
),
C. albicans
can utilize the lipid-derived metabolite glycerophosphocholine (GPC) as a phosphate source. As GPC is available within the human host, we examined the role of GPC in phosphate homeostasis in
C. albicans
. We find that GPC can substitute for P
i
by many though not all criteria and is likely a relevant physiological phosphate source for
C. albicans
.
The impact of global warming on the signature virulence gene, thermolabile hemolysin, of
Vibrio parahaemolyticus
Authors: Zhang Weishan , Chen Keyu , Zhang Lin , Zhang Ximeng , Zhu Baoli , Lv Na , Mi Kaixia
Published: October 2023

Global warming is increasing human exposure to pathogens and has already had an impact on human health.
Vibrio parahaemolyticus
, a major pathogen causing foodborne illness, accumulates in numerous aquatic organisms and can be affected by environmental stressors such as increased replication errors or DNA damage resulting in point mutations. This could lead to an elevation in the mutation rate, which influences the expansion of
Vibrio
spp. habitats and the spread of associated diseases. In this study, a total of 241 strains were isolated from aquatic products imported or exported through China Customs between 2005 and 2010. The whole genomes of those strains were sequenced, revealing a highly significant level of genetic diversity. Our analysis identified 27 new sequence types (STs) ranging from ST2950 to ST2976. The global temperature trend since 1950 affects the thermolabile hemolysin gene (
tlh
) found in all
Vibrio parahaemolyticus
leading to mutant sites exhibiting similar trends as temperatures rise; seven high-frequency mutation hotspots (A180G, T552G, G657T, T858C, C1062T, A1137G, and T1179C) were identified along with two clinically specific sites (T259C and A951T) that may indicate adaptation over time due to climate change, leading to increased virulence potential for this bacterial species. These results provide insight into the genetics of
Vibrio parahaemolyticus
and provide a reference for subsequent research, identification, and monitoring efforts related to its spread.

IMPORTANCE

In this study,
Vibrio parahaemolyticus
strains were collected from a large number of aquatic products globally and found that temperature has an impact on the virulence of these bacteria. As global temperatures rise, mutations in a gene marker called thermolabile hemolysin (
tlh
) also increase. This suggests that environmental isolates adapt to the warming environment and become more pathogenic. The findings can help in developing tools to analyze and monitor these bacteria as well as assess any link between climate change and vibrio-associated diseases, which could be used for forecasting outbreaks associated with them.
The Lithium Boom: Lithium Sources and Prospects for the Russian Lithium Industry
Authors: Tsivadze A. Yu. , Bezdomnikov A. A. , Kostikova G. V.
Published: October 2023

The explosive development of renewable energy in recent years is reshaping the geopolitical picture of the world. Solar panels and wind turbines have become the symbol of the new energy transition, while lithium-ion batteries have become its basis and the driver of development. It was lithium-ion batteries that made it possible to overcome the main problem of renewable energy – inconstancy and uncontrollability. The article highlights the lithium problem, the reasons for the volatility of lithium prices, the main sources of lithium and the difficulties of its production. In addition, the prospects of development of lithium industry in Russia and current domestic developments in lithium mining technology are considered.
C-reactive protein impairs immune response of CD8+T cells via FcγRIIb-p38MAPK-ROS axis in multiple myeloma
Authors: Jiang Jinxing , Peng Ziyi , Wang Junying , Chen Mengping , Wan Yike , Huang Honghui , Liu Zhiqiang , Wang Jingya , Hou Jian
Published: October 2023

Background

C-reactive protein (CRP) is a prototypical acute phase protein in humans with the function of regulating immune cells. Serum CRP levels are elevated in multiple myeloma (MM), associated with MM cell proliferation and bone destruction. However, its direct effects on T lymphocytes in MM have not been elucidated.

Methods

Public data sets were used to explore the correlation of CRP levels with immune cell infiltration and cytotoxicity score of CD8+T cells in MM. In vitro, repeated freeze-thaw myeloma cell lines were taken as tumor antigens to load dendritic cells (DCs) derived from HLA-A*0201-positive healthy donors. MM-specific cytotoxic T cells (MM-CTL) were obtained from T lymphocytes of the corresponding donors pulsed with these DCs. B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T cells were manipulated by transfecting with lentivirus encoding an anti-BCMA single-chain variable fragment. Then T cells from healthy controls, MM-CTLs and BCMA CAR-T cells were exposed to CRP and analyzed for cell proliferation, cytotoxicity, immunophenotypes. CRP binding capacity to T cells before and after Fc gamma receptors IIb (FcγRIIb) blockage, p38 mitogen-activated protein kinase (MAPK) pathway and the downstream molecules were also detected. In vivo, both normal C57BL/6J mice and the Vk*MYC myeloma mouse models were applied to confirm the impact of CRP on T cells.

Results

CRP levels were negatively correlated with cell-infiltration and cytotoxicity score of CD8+T cells in MM. In vitro experiments showed that CRP inhibited T-cell proliferation in a dose-dependent manner, impaired the cytotoxic activity and upregulated expression of senescent markers in CD8+T cells. In vivo results validated the suppressive role of CRP in CD8+T cells. CRP could bind to CD8+T cells, mainly to the naïve T subset, while the binding was dramatically decreased by FcγRIIb blockage. Furthermore, CRP resulted in increased phosphorylation of p38 MAPK, elevated levels of reactive oxygen species and oxidized glutathione in CD8+T cells.

Conclusions

We found that CRP impaired immune response of CD8+T cells via FcγRIIb-p38MAPK-ROS signaling pathway. The study casted new insights into the role of CRP in anti-myeloma immunity, providing implications for future immunotherapy in MM.
B cell polygenic risk scores associate with anti-dsDNA antibodies and nephritis in systemic lupus erythematosus
Authors: Hedenstedt Anna , Reid Sarah , Sayadi Ahmed , Eloranta Maija-Leena , Skoglund Elisabeth , Bolin Karin , Frodlund Martina , Lerang Karoline , Jönsen Andreas , Rantapää-Dahlqvist Solbritt , Bengtsson Anders A , Rudin Anna , Molberg Øyvind , Sjöwall Christopher , Sandling Johanna K , Leonard Dag
Published: October 2023

Objective

B cell function and autoantibodies are important in SLE pathogenesis. In this work, we aimed to investigate the impact of cumulative SLE B cell genetics on SLE subphenotype and autoantibody profile.

Methods

Female patients with SLE (n=1248) and healthy controls (n=400) were genotyped using Illumina’s Global Screening Array. Two polygenic risk scores (PRSs), one representing B cell genes and the other B cell activation genes, were calculated for each individual using risk loci for SLE in genes assigned to B cell-related pathways according to the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology and Reactome Databases.

Results

Double-stranded DNA (dsDNA) antibodies were more prevalent among patients with a high compared with a low SLE B cell PRS (OR 1.47 (1.07 to 2.01), p=0.018), and effect sizes were augmented in patients with human leucocyte antigen (HLA) risk haplotypes HLA-DRB1*03:01 and HLA-DRB1*15:01 (DRB1*03/15 −/− (OR 0.99 (0.56 to 1.77), p=0.98; DRB1*03/15 +/− or −/+ (OR 1.64 (1.06 to 2.54), p=0.028; and DRB1*03/15 +/+ (OR 4.47 (1.21 to 16.47), p=0.024). Further, a high compared with a low B cell PRS was associated with low complement levels in DRB1*03/15 +/+ patients (OR 3.92 (1.22 to 12.64), p=0.022). The prevalence of lupus nephritis (LN) was higher in patients with a B cell activation PRS above the third quartile compared with patients below (OR 1.32 (1.00 to 1.74), p=0.048).

Conclusions

High genetic burden related to B cell function is associated with dsDNA antibody development and LN. Assessing B cell PRSs may be important in order to determine immunological pathways influencing SLE and to predict clinical phenotype.
Evidence of summer thermal stratification in extreme northern lakes
Authors: Antoniades Dermot , Klanten Yohanna , Cameron Emma , Garcia-Oteyza Julia , Oliva Marc , Vincent Warwick F.
Published: October 2023

Rapid warming in the High Arctic has induced changes in terrestrial environments that have included major recent shifts in lakes and ponds. Numerous studies exist of spatial trends in water chemistry, bioindicator groups, and paleoenvironmental change from High Arctic lakes; however, little is known about lake thermal stratification regimes at high latitudes beyond assumptions based on generalized classification schemes. Here, we report on the presence in late July 2022 of positive thermal stratification during open-water conditions in two freshwater lakes near Clements Markham Inlet, on northern Ellesmere Island. These lakes are situated in the polar desert at 82.6°N, >1000 km north of the generally accepted northern limit of summer thermal stratification. Given their location approaching the northernmost land on Earth, the thermal profiles of these lakes suggest that the occurrence of summer stratification may no longer be discounted anywhere in the Northern Hemisphere.
Network-level evaluation method of the overall–intralayer–interlayer interface structural states of semi-rigid asphalt pavement
Authors: Fan Jianwei , Ma Tao , Zhu Yajing , Zhang Yiming
Published: October 2023

The pavement structure strength index (PSSI) indicator in the Chinese standard and the structural number (SN) indicator proposed by AASHTO are widely used to evaluate the structural states of semi-rigid asphalt pavement. However, PSSI and SN indicators do not involve the intra- and interlayer interface structural state, and the indicators are disconnected from the pavement design indicators. In this study, the intralayer remaining life and structural attenuation state were considered comprehensively to propose the indicators of the surface/base/subgrade structural state index (SSSI/BSSI/GSSI). The interlayer interface structural state index (ISSI) was proposed based on the friction coefficient between the surface and base layers. The pavement structural state index (PaSSI) was proposed by assigning the weightings to SSSI, BSSI, GSSI, and ISSI indicators. Compared with the PSSI or SN indicators, the proposed indicators realize the intralayer–interlayer–overall structural evaluation of the pavement, and the indicators were based on the pavement design indicators.
Constraints on primordial black holes in the mixed dark matter scenarios using the ratio $$\mathrm (^3{He}+D)/H$$
Authors: Yang Yupeng , Li Xiujuan , Li Gang
Published: October 2023

We derive the upper limit on the dark matter (DM) fraction in primordial black holes (PBHs) in the mixed DM scenarios. In this scenarios, a PBH can accrete weakly interacting massive particles (WIMPs) to form a ultracompact minihalo (UCMH) with a density profile of $$\rho _{\textrm{DM}}(r)\sim r^{-9/4}$$

ρ
DM

(
r
)

∼

r

-
9
/
4

. The energy released from UCMHs due to dark matter annihilation has influence on the photodissociation of $$^{4}{\textrm{He}}$$

4

He

, producing the $$^{3}{\textrm{He}}$$

3

He

and the D. By requiring that the ratio $$(^3\text {He}+\text {D})/\text {H}$$

(
3

He
+
D
)
/
H

caused by UCMHs does not exceed the measured value, we derive the upper limit on the dark matter fraction in PBHs. For the canonical value of DM thermally averaged annihilation cross section $$\left<\sigma v\right>=3\times 10^{-26}\text {cm}^{3}\,\text {s}^{-1}$$

σ
v

=
3
×

10

-
26

cm
3

s

-
1

, we find that the upper limit is $$f_{\textrm{PBH}} < 0.35(0.75)$$

f
PBH

<
0.35

(
0.75
)

for DM mass $$m_{\chi }=1(10)~ \text {GeV}$$

m
χ

=
1

(
10
)

GeV

. Compared with other limits obtained by different astronomical measurements, although our limit is not the strongest, we provide a different way of constraining the cosmological abundance of PBHs.
Demonstrating Spoofability of an Originating Number when Sending an SMS using SMPP
Authors: Tsunoda Akaki
Published: October 2023

The short message service (SMS), a service for exchanging texts via mobile networks, has become a universal means of communication. SMS is a mechanism for sending a text message to a specific mobile phone number. Its protocol enables the sender to specify the destination phone number but not the originating number. However, the short message peer-to-peer (SMPP) protocol, which forwards SMS messages, enables the sender to specify the originating number. If the SMPP protocol allows the sender to specify another person’s phone number as the originator, an attacker can use it to send a short message impersonating another person. In this study, short messages were sent from an SMPP gateway service with any phone number specified as the originator, and their delivery to the Japanese mobile network was verified. All the verified mobile network operators (MNOs) were able to spoof the origin to any international phone number, and one MNO was able to spoof it to any national phone number. The results of this study reveal that SMPP can potentially be exploited to spoof the originating number of an SMS. Furthermore, a threat scenario was devised using spoofing and mitigation measures.
Continuing WebAssembly with Effect Handlers
Authors: Phipps-Costin Luna , Rossberg Andreas , Guha Arjun , Leijen Daan , Hillerström Daniel , Sivaramakrishnan KC , Pretnar Matija , Lindley Sam
Published: October 2023

WebAssembly (Wasm) is a low-level portable code format offering near
native performance. It is intended as a compilation target for a wide
variety of source languages. However, Wasm provides no direct support
for non-local control flow features such as async/await,
generators/iterators, lightweight threads, first-class continuations,
etc. This means that compilers for source languages with such features
must ceremoniously transform whole source programs in order to target
Wasm.

We present WasmFX an extension to Wasm which provides a universal
target for non-local control features via effect handlers, enabling
compilers to translate such features directly into Wasm. Our
extension is minimal and only adds three main instructions for
creating, suspending, and resuming continuations. Moreover, our
primitive instructions are type-safe providing typed continuations
which are well-aligned with the design principles of Wasm whose stacks
are typed. We present a formal specification of WasmFX and show that
the extension is sound. We have implemented WasmFX as an extension to
the Wasm reference interpreter and also built a prototype WasmFX
extension for Wasmtime, a production-grade Wasm engine, piggybacking
on Wasmtime's existing fibers API. The preliminary performance
results for our prototype are encouraging, and we outline future plans
to realise a native implementation.
Adventure of a Lifetime: Extract Method Refactoring for Rust
Authors: Thy Sewen , Costea Andreea , Gopinathan Kiran , Sergey Ilya
Published: October 2023

We present a design and implementation of the automated "Extract Method" refactoring for Rust programs. Even though Extract Method is one of the most well-studied and widely used in practice automated refactorings, featured in all major IDEs for all popular programming languages, implementing it soundly for Rust is surprisingly non-trivial due to the restrictions of the Rust's ownership and lifetime-based type system.

In this work, we provide a systematic decomposition of the Extract Method refactoring for Rust programs into a series of program transformations, each concerned with satisfying a particular aspect of Rust type safety, eventually producing a well-typed Rust program. Our key discovery is the formulation of Extract Method as a composition of naive function hoisting and a series of automated program repair procedures that progressively make the resulting program "more well-typed" by relying on the corresponding repair oracles. Those oracles include a novel static intra-procedural ownership analysis that infers correct sharing annotations for the extracted function's parameters, and the lifetime checker of rustc, Rust's reference compiler.

We implemented our approach in a tool called REM---an automated Extract Method refactoring built on top of IntelliJ IDEA plugin for Rust. Our extensive evaluation on a corpus of changes in five popular Rust projects shows that REM (a) can extract a larger class of feature-rich code fragments into semantically correct functions than other existing refactoring tools, (b) can reproduce method extractions performed manually by human developers in the past, and (c) is efficient enough to be used in interactive development.
Interactive Debugging of Datalog Programs
Authors: Pacak André , Erdweg Sebastian
Published: October 2023

Datalog is used for complex programming tasks nowadays, consisting of numerous inter-dependent predicates. But Datalog lacks interactive debugging techniques that support the stepwise execution and inspection of the execution state. In this paper, we propose interactive debugging of Datalog programs following a top-down evaluation strategy called recursive query/subquery. While the recursive query/subquery approach is well-known in the literature, we are the first to provide a complete programming-language semantics based on it. Specifically, we develop the first small-step operational semantics for top-down Datalog, where subqueries occur as nested intermediate terms. The small-step semantics forms the basis of step-into interactions in the debugger. Moreover, we show how step-over interactions can be realized efficiently based on a hybrid Datalog semantics that adds a bottom-up database to our top-down operational semantics. We implemented a debugger for core Datalog following these semantics and explain how to adopt it for debugging the frontend languages of Soufflé and IncA. Our evaluation shows that our hybrid Datalog semantics can be used to debug real-world Datalog programs with realistic workloads.
From Capabilities to Regions: Enabling Efficient Compilation of Lexical Effect Handlers
Authors: Müller Marius , Schuster Philipp , Starup Jonathan Lindegaard , Ostermann Klaus , Brachthäuser Jonathan Immanuel
Published: October 2023

Effect handlers are a high-level abstraction that enables programmers to use effects in a structured
way. They have gained a lot of popularity within academia and subsequently also in industry. However,
the abstraction often comes with a significant runtime cost and there has been intensive research
recently on how to reduce this price.

A promising approach in this regard is to implement effect handlers using a CPS translation and
to provide sufficient information about the nesting of handlers. With this information the
CPS translation can decide how effects have to be lifted through handlers, i.e., which handlers
need to be skipped, in order to handle the effect at the correct place. A structured way to make
this information available is to use a calculus with a region system and explicit subregion
evidence. Such calculi, however, are quite verbose, which makes them impractical to use as a
source-level language.

We present a method to infer the lifting information for a calculus underlying a source-level language.
This calculus uses second-class capabilities for the safe use of effects. To do so, we define a typed translation
to a calculus with regions and evidence and we show that this lift-inference translation is typability-
and semantics-preserving. On the one hand, this exposes the precise relation between the second-class
property and the structure given by regions. On the other hand, it closes a gap in a compiler pipeline
enabling efficient compilation of the source-level language. We have implemented lift inference in this
compiler pipeline and conducted benchmarks which indicate that the approach is indeed working.
Reusing Just-in-Time Compiled Code
Authors: Mehta Meetesh Kalpesh , Krynski Sebastián , Gualandi Hugo Musso , Thakur Manas , Vitek Jan
Published: October 2023

Most code is executed more than once. If not entire programs then libraries remain unchanged from one run to the next. Just-in-time compilers expend considerable effort gathering insights about code they compiled many times, and often end up generating the same binary over and over again. We explore how to reuse compiled code across runs of different programs to reduce warm-up costs of dynamic languages. We propose to use
speculative contextual dispatch
to select versions of functions from an
off-line curated code repository
. That repository is a persistent database of previously compiled functions indexed by the context under which they were compiled. The repository is curated to remove redundant code and to optimize dispatch. We assess practicality by extending Ř, a compiler for the R language, and evaluating its performance. Our results suggest that the approach improves warmup times while preserving peak performance.
A Grounded Conceptual Model for Ownership Types in Rust
Authors: Crichton Will , Gray Gavin , Krishnamurthi Shriram
Published: October 2023

Programmers learning Rust struggle to understand ownership types, Rust’s core mechanism for ensuring memory safety without garbage collection. This paper describes our attempt to systematically design a pedagogy for ownership types. First, we studied Rust developers’ misconceptions of ownership to create the Ownership Inventory, a new instrument for measuring a person’s knowledge of ownership. We found that Rust learners could not connect Rust’s static and dynamic semantics, such as determining why an ill-typed program would (or would not) exhibit undefined behavior. Second, we created a conceptual model of Rust’s semantics that explains borrow checking in terms of flow-sensitive permissions on paths into memory. Third, we implemented a Rust compiler plugin that visualizes programs under the model. Fourth, we integrated the permissions model and visualizations into a broader pedagogy of ownership by writing a new ownership chapter for
The Rust Programming Language
, a popular Rust textbook. Fifth, we evaluated an initial deployment of our pedagogy against the original version, using reader responses to the Ownership Inventory as a point of comparison. Thus far, the new pedagogy has improved learner scores on the Ownership Inventory by an average of 9
Reference Capabilities for Flexible Memory Management
Authors: Arvidsson Ellen , Castegren Elias , Clebsch Sylvan , Drossopoulou Sophia , Noble James , Parkinson Matthew J. , Wrigstad Tobias
Published: October 2023

Verona is a concurrent object-oriented programming language that organises all the objects in a program into a forest of isolated regions. Memory is managed locally for each region, so programmers can control a program's memory use by adjusting objects' partition into regions, and by setting each region's memory management strategy. A thread can only mutate (allocate, deallocate) objects within one active region---its "window of mutability". Memory management costs are localised to the active region, ensuring overheads can be predicted and controlled. Moving the mutability window between regions is explicit, so code can be executed wherever it is required, yet programs remain in control of memory use. An ownership type system based on reference capabilities enforces region isolation, controlling aliasing within and between regions, yet supporting objects moving between regions and threads. Data accesses never need expensive atomic operations, and are always thread-safe.
Static Analysis of Memory Models for SMT Encodings
Authors: Haas Thomas , Maseli René , Meyer Roland , Ponce de León Hernán
Published: October 2023

The goal of this work is to improve the efficiency of bounded model checkers that are modular in the memory model.
Our first contribution is a static analysis for the given memory model that is performed as a preprocessing step and helps us significantly reduce the encoding size.
Memory model make use of relations to judge whether an execution is consistent. The analysis computes bounds on these relations: which pairs of events may or must be related.
What is new is that the bounds are relativized to the execution of events.
This makes it possible to derive, for the first time, not only upper but also meaningful lower bounds.
Another important feature is that the analysis can import information about the verification instance from external sources to improve its precision.
Our second contribution are new optimizations for the SMT encoding.
Notably, the lower bounds allow us to simplify the encoding of acyclicity constraints.
We implemented our analysis and optimizations within a bounded model checker and evaluated it on challenging benchmarks.
The evaluation shows up-to 40% reduction in verification time (including the analysis) over previous encodings.
Our optimizations allow us to efficiently check safety, liveness, and data race freedom in Linux kernel code.
Saggitarius: A DSL for Specifying Grammatical Domains
Authors: Miltner Anders , Loehr Devon , Mong Arnold , Fisher Kathleen , Walker David
Published: October 2023

Common data types like dates, addresses, phone numbers and tables can have multiple textual representations, and many heavily-used languages, such as SQL, come in several dialects. These variations can cause data to be misinterpreted, leading to silent data corruption, failure of data processing systems, or even security vulnerabilities. Saggitarius is a new language and system designed to help programmers reason about the format of data, by describing grammatical domains---that is, sets of context-free grammars that describe the many possible representations of a datatype. We describe the design of Saggitarius via example and provide a relational semantics. We show how Saggitarius may be used to analyze a data set: given example data, it uses an algorithm based on semi-ring parsing and MaxSAT to infer which grammar in a given domain best matches that data. We evaluate the effectiveness of the algorithm on a benchmark suite of 110 example problems, and we demonstrate that our system typically returns a satisfying grammar within a few seconds with only a small number of examples. We also delve deeper into a more extensive case study on using Saggitarius for CSV dialect detection. Despite being general-purpose, we find that Saggitarius offers comparable results to hand-tuned, specialized tools; in the case of CSV, it infers grammars for 84% of benchmarks within 60 seconds, and has comparable accuracy to custom-built dialect detection tools.
Mechanisms of Regeneration and Fibrosis in the Endometrium
Authors: Ang Claire J. , Skokan Taylor D. , McKinley Kara L.
Published: October 2023

The uterine lining (endometrium) regenerates repeatedly over the life span as part of its normal physiology. Substantial portions of the endometrium are shed during childbirth (parturition) and, in some species, menstruation, but the tissue is rapidly rebuilt without scarring, rendering it a powerful model of regeneration in mammals. Nonetheless, following some assaults, including medical procedures and infections, the endometrium fails to regenerate and instead forms scars that may interfere with normal endometrial function and contribute to infertility. Thus, the endometrium provides an exceptional platform to answer a central question of regenerative medicine: Why do some systems regenerate while others scar? Here, we review our current understanding of diverse endometrial disruption events in humans, nonhuman primates, and rodents, and the associated mechanisms of regenerative success and failure. Elucidating the determinants of these disparate repair processes promises insights into fundamental mechanisms of mammalian regeneration with substantial implications for reproductive health.
The Unreasonable Effectiveness of Reaction Diffusion in Vertebrate Skin Color Patterning
Authors: Milinkovitch Michel C. , Jahanbakhsh Ebrahim , Zakany Szabolcs
Published: October 2023

In 1952, Alan Turing published the reaction-diffusion (RD) mathematical framework, laying the foundations of morphogenesis as a self-organized process emerging from physicochemical first principles. Regrettably, this approach has been widely doubted in the field of developmental biology. First, we summarize Turing's line of thoughts to alleviate the misconception that RD is an artificial mathematical construct. Second, we discuss why phenomenological RD models are particularly effective for understanding skin color patterning at the meso/macroscopic scales, without the need to parameterize the profusion of variables at lower scales. More specifically, we discuss how RD models ( a) recapitulate the diversity of actual skin patterns, ( b) capture the underlying dynamics of cellular interactions, ( c) interact with tissue size and shape, ( d) can lead to ordered sequential patterning, ( e) generate cellular automaton dynamics in lizards and snakes, ( f) predict actual patterns beyond their statistical features, and ( g) are robust to model variations. Third, we discuss the utility of linear stability analysis and perform numerical simulations to demonstrate how deterministic RD emerges from the underlying chaotic microscopic agents.
Neofunctionalization of Toll Signaling in Insects: From Immunity to Dorsoventral Patterning
Authors: Roth Siegfried
Published: October 2023

Toll signaling plays a crucial role in pathogen defense throughout the animal kingdom. It was discovered, however, for its function in dorsoventral (DV) axis formation in Drosophila. In all other insects studied so far, but not outside the insects, Toll is also required for DV patterning. However, in insects more distantly related to Drosophila, Toll's patterning role is frequently reduced and substituted by an expanded influence of BMP signaling, the pathway implicated in DV axis formation in all major metazoan lineages. This suggests that Toll was integrated into an ancestral BMP-based patterning system at the base of the insects or during insect evolution. The observation that Toll signaling has an immune function in the extraembryonic serosa, an early differentiating tissue of most insect embryos, suggests a scenario of how Toll was co-opted from an ancestral immune function for its new role in axis formation.
Single Buried Intramedullary K-Wire Fixation in Nonthumb Metacarpal Shaft Fractures with Immediate Postoperative Mobilization without Any Immobilization
Authors: Siriwittayakorn Wuttipong , Adulkasem Nath , Sangthongsil Pichet , Pitiguagool Wasapol , Atthakorn Wattanai , Watatham Kraisong , Siritattamrong Wichit
Published: October 2023

Objective. This study aims to evaluate the outcomes of single intramedullary K-wire fixation in nonthumb, metacarpal shaft fractures with immediate postoperative hand mobilization without any immobilization. Method. This is a retrospective case series conducted from January 2019 to December 2022. We included patients with closed, simple transverse, or short oblique metacarpal shaft fracture treated with single, 1.4 mm, intramedullary K-wire fixation. Gentle postoperative range of motion exercise was encouraged in every patient without any hand, finger, or wrist motion restriction material. Clinical outcomes were evaluated with total active flexion; grip strength; disability of arm, shoulder, and hand (DASH) score; and the American Society for Surgery of the Hand Total Active Flexion (ASSH TAF) score. Results. This study included 34 patients, 25 males and 9 females with a mean age of 33.14 years (ranging 18–59). A total of 43 metacarpal shafts were treated. The mean DASH score at two and 6 weeks postoperative was 41.5 (ranging 19.16–60.34) and 9.58 (ranging 0.83–23.27). The mean final DASH score at last follow-up was 3.48 (ranging 0–8.33). Mean TAF at 2 weeks postoperative, 6 weeks postoperative, and at final follow-up was 203.8 (ranging 185–240), 238.2 (ranging 220–270), and 259.25 (ranging 240–270) degrees, respectively. The mean grip strength of the injured hand was 66.14 and 86.1% of the uninjured hand at 6 weeks and 3 months postoperative. There was no nonunion, malrotation, or infection. In conclusion, single intramedullary K-wire fixation gives excellent outcomes in the treatment of single or multiple, simple, metacarpal shaft fractures without the need of postoperative immobilization.
Characteristic of Elite Male 800-m Runner’s Race Performance Based on Hybrid Computing Methods
Authors: Chen Chao , Ma Jie , Song Jinzhuang , He Shengbao , Tan Mengchao
Published: October 2023

The purpose of the study was to analyze the characteristics of elite men’s 800-m race performance, which help coaches to obtained the winning experience of 800-m race and prepare for athletes’ training more efficiently. Hybrid computing methods were applied to analyze athletes’ race performance. The study found that the competitive capability of elite athletes mainly include maximal speed running, speed endurance, and even pacing running. The maximal speed advance from 700–800 to 100–200-m sector, the velocity is also increase at the same time. The first peak speed (100–200 m) is higher than the second (500–600 m). Reduce the 0–400 m split times could be contributing to achieve personal best. 200–400 m is the even pacing phase which have the function of adjust physiological condition and preserve energy. The speed endurance was the most important factor to won the 800-m race. Place in permanent ranking and adopt the follow-running tactic can increase the odds to be medalist.
Peculiarities of the Formation of Students’ Business Communication Skills within the Distance Learning
Authors: Nagay Irina , Khalabuzar Oksana , Alieksieieva Hanna , Antonenko Oleksandr , Ovsyannikov Oleksandr
Published: October 2023

The article deals with the problems of the formation of students’ business communications skills at higher educational institutions. The authors ground the hypothesis that the implementation of nonstandard ways and forms of teaching foreign language provides the increasing of effectiveness of formation of students’ business communicative skills. The goal of research work deals with the theoretical justification and presentation of nonstandard interactive means and forms of educational activity oriented on the formation of business communication skills (BCS) of students within distance learning. Due to the applied qualitative and quantitative methods of research (conducted surveys, experimental research work, data analysis, etc.), it was proved the necessity of implementation of the interactive technologies into the educational process. The authors found out that modern society requires the new generation of specialists who must be educated, professional in their fields, and able to compete within the rapidly changing paradigms of the business systems. For the further implementation by teachers, they are given samples of nonstandard forms of educational activity, certain interactive technologies, instructions, and advice on ways of increasing the effectiveness of BCS. There are described prospects of the further research activity, which will be devoted to the problem of strengthening of BCS.