bluuebunny/crossref_metadata_2025 huggingface dataset:
Calcium silicate biocomposites: effects of selenium oxide on the physico-mechanical features and their in-vitro biological assessments
Authors: S Sakthi @ Muthulakshmi , S Shailajha , B Shanmugapriya , K Chidhambara Priya Dharshini
Published: November 2023

Bone tissue regenerative material serves as a prospective recovery candidate with self-adaptable biological properties of bio-activation, degradability, compatibility, and antimicrobial efficacy instead of metallic implants. Such materials are highly expensive due to chemical reagents and complex synthesis procedures, making them unaffordable for patients with financial constraints. This research produced an efficient bone tissue regenerative material using inexpensive naturally occurring source materials, including silica sand and limestone. The extracted SiO2 and CaO particles (75:25 wt%) were subjected to hydrothermal synthesis (water treatment instead of chemical solvents) to produce the CaSiO3 biomaterial (code: S). Selenium oxide was doped with calcium silicate at 3, 5, and 10 wt.% to enhance its properties, yielding biocomposite materials (i.e. S3, S5, and S10). The physico-mechanical properties of these materials were investigated with x-ray diffraction, Fourier transform infrared, FESEM-EDS, and micro-universal testing machine. The results revealed that the synthesized biocomposites have a crystalline wollastonite phase with a porously fused rough surface. From structural parametric calculations, we found that the biocomposites have reduced particle size and enhanced surface area due to the influence of selenium oxide. The biocomposite S10, having high SeO2 content, attained the maximum compressive strength of 75.2 MPa. In-vitro studies of bioactivity, biodegradability, biocompatibility, and antibacterial activity were performed. At 7 and 14 d of bioactivity, the synthesized biocomposites are capable of dissolving their ions into simulated body fluid (SBF) solution to precipitate hydroxyapatite and a required Ca/P ratio of 1.69 was achieved by S3. A comparative analysis has been performed on the degradation activity in Tris-HCl and the consequent pH changes during SBF treatment. The bio-analysis revealed that the biocomposite S3 shows enhanced bioactivity through a controlled degradation rate and secured cell viability of 88% at a concentration of 100 μg ml−1. It also offers significant bacterial inhibition potency against E.coli and S.aureus bacteria.
Drivers of domestic wells vulnerability during droughts in California’s Central Valley
Authors: Rodríguez-Flores José M , Fernandez-Bou Angel Santiago , Ortiz-Partida J Pablo , Medellín-Azuara Josué
Published: November 2023

Over the past decade, California has experienced two multiyear droughts, resulting in water insecurity for communities and significant economic losses for the agricultural sector. Despite the recognition of water as a human right in the state since 2012, droughts consistently lead to the failure of thousands of domestic wells due to intensified groundwater pumping for irrigation purposes. In the Central Valley alone, groundwater sustains the livelihoods of thousands of individuals (and millions across the state) serving as their sole water source, rendering them vulnerable due to inadequate groundwater management. In this study, we present a spatial statistical model to identify critical localized factors within the food-water-human system that contribute to the vulnerability of domestic wells during droughts. Our results indicate that the depth of domestic wells, density of domestic and agricultural wells, socioeconomic conditions, and the extent of perennial crops play significant roles in predicting well failures during droughts. We show the implications of addressing these factors within the context of ongoing groundwater sustainability initiatives, and we propose strategies to safeguard the water source for thousands of individuals necessary to protect domestic wells.
Effects of weaving parameters on the properties of completely biological tissue-engineered vascular grafts
Authors: Roudier Gaëtan , Hourques Marie , Da Silva Nicolas , Gluais Maude , Binyet Emmanuel , Olive Jean-Marc , L’Heureux Nicolas
Published: November 2023

Tissue-engineered vascular grafts (TEVGs) made of human textiles have been recently introduced and offer remarkable biocompatibility as well as tunable mechanical properties. The approach combines the use of cell-assembled extracellular matrix (CAM) threads, produced by cultured cellsin vitro, with weaving, a versatile assembly method that gives fine control over graft properties. Herein, we investigated how production parameters can modify the geometrical and mechanical properties of TEVGs to better match that of native blood vessels in order to provide long-term patency. Our goals were to decrease the mechanical strength and the luminal surface profile of our first generation of woven TEVGs, while maintaining low transmural permeability and good suture retention strength. Different TEVGs were produced by varying CAM sheet strength as well as weaving parameters such as warp count, weft ribbons width, and weft tension. An optimized design reduced the burst pressure by 35%, wall thickness by 38% and increased compliance by 269%. The improved TEVG had properties closer to that of native blood vessels, with a burst pressure of 3492 mmHg, a wall thickness of 0.69 mm, and a compliance of 4.8%/100 mmHg, while keeping excellent suture retention strength (4.7 N) and low transmural permeability (24 ml·min−1·cm−2). Moreover, the new design reduced the luminal surface profile by 48% and utilized 47% less CAM. With a comparable design, the use of decellularized CAM threads, instead of devitalized ones, led to TEVGs with much more permeable walls and higher burst pressure. The next step is to implant this optimized graft in an allogeneic sheep model of arteriovenous shunt to assess itsin vivoremodeling and performance.
Blend of polyvinylpyrrolidone/thermally reduced graphene for adsorption of heavy metal ions in water
Authors: Le Diep Ngoc , Nguyen Linh Duy , Tran Dong Duy , Le Hoang Doan Tan , Dang Chien Mau , Doan Tin Chanh Duc
Published: November 2023

This paper presents the preparation of a modified polyvinylpyrrolidone (PVP)/graphene mixture and evaluates its adsorption capacity for heavy metal ions in water. Graphene with a high specific surface area of about 362 m2 g−1 was obtained through the thermal separation of graphite oxide (GO), which had been synthesised from graphite by the Hummer method. The graphene-PVP blend was prepared by dispersing the graphene into a PVP solution and then crosslinking it to prevent washout by water. This crosslinking ensured a well-dispersed and stable graphene-PVP blend. The maximum adsorption capacity of graphene-PVP for Cu2+ and Cd2+ ions was found to be 158 mg g−1 and 134 mg g−1, respectively, at pH 3 and a contact time of 30 min. The experimental results were found to be consistent with Langmuir and pseudo-second-order kinetic models. The study further reveals that the adsorption mechanism of Cu2+ and Cd2+ ions on graphene-PVP follows an ion exchange mechanism, driven by strong interactions between PVP and metal ions. The study provides an easy, low-cost, and eco-friendly method to produce highly adsorptive graphene-PVP materials.
Fucoidan and dendrimer-based nanocapsule exhibiting effectiveness in methotrexate controlled delivery towards rheumatoid arthritis treatment
Authors: Nguyen Dinh Trung , Doan Hai Phuong , Tran Thi Kim Ngan , Huynh Chan Khon , Tran Ngoc Quyen , Dang Le Hang
Published: November 2023

In recent years, nanomaterials have been intensively studied and applied in various fields, including pharmaceutical applications. This platform can act as a carrier for anticancer drugs or for insoluble bioactive compounds. To increase the stability and prolong the effect of anticancer drugs, we have incorporated a sulfated polysaccharide fucoidan (Fu) into PAMAM dendrimer G3.0 to form a G3.0-Fu complex. Then, a nano-sized encapsulated anticancer drug, methotrexate (MTX), was successfully embedded in the synthesised dendrimer complex namely G3.0-Fu/MTX. Newly synthesised G3.0-Fu/MTX was characterised by transmission electron microscopy (TEM), dynamic light scattering (DLS), and zeta potential measurement.

Additionally, the loading efficiency of MTX was assessed via UV spectroscopy. Our findings revealed that upon combining with Fu, the G3.0 nanoparticle size increased from 4.3 ± 1.1 nm to 56 ± 6 nm. The changes in zeta potential aligned with drug entrapment efficiency and the results from TEM and DLS. The drug release activity of G3.0-Fu/MTX was increased compared to free MTX after 24 h. G3.0-Fu also showed high cytocompatibility in fibroblast cells. Taken together, the G3.0-Fu could be used to increase the encapsulation of several kinds of hydrophobic drugs and G3.0-Fu/MTX could be further studied in rheumatoid arthritis treatment.
Phase field model for electric-thermal coupled discharge breakdown of polyimide nanocomposites under high frequency electrical stress
Authors: HAN 韩 Zhiyun 智云 , LI 李 Qingmin 庆民 , LI 李 Junke 俊科 , WANG 王 Mengxi 梦溪 , REN 任 Hanwen 瀚文 , ZOU 邹 Liang 亮
Published: November 2023

In contrast to conventional transformers, power electronic transformers, as an integral component of new energy power system, are often subjected to high-frequency and transient electrical stresses, leading to heightened concerns regarding insulation failures. Meanwhile, the underlying mechanism behind discharge breakdown failure and nanofiller enhancement under high-frequency electrical stress remains unclear. An electric-thermal coupled discharge breakdown phase field model was constructed to study the evolution of the breakdown path in polyimide nanocomposite insulation subjected to high-frequency stress. The investigation focused on analyzing the effect of various factors, including frequency, temperature, and nanofiller shape, on the breakdown path of Polyimide (PI) composites. Additionally, it elucidated the enhancement mechanism of nano-modified composite insulation at the mesoscopic scale. The results indicated that with increasing frequency and temperature, the discharge breakdown path demonstrates accelerated development, accompanied by a gradual dominance of Joule heat energy. This enhancement is attributed to the dispersed electric field distribution and the hindering effect of the nanosheets. The research findings offer a theoretical foundation and methodological framework to inform the optimal design and performance management of new insulating materials utilized in high-frequency power equipment.
General Law of iterated logarithm for Markov processes: Liminf laws
Authors: Cho Soobin , Kim Panki , Lee Jaehun
Published: November 2023

Continuing from Cho, Kim, and Lee [General Law of iterated logarithm for Markov processes: Limsup law, arXiv:2102,01917v3], in this paper, we discuss general criteria and forms of liminf laws of iterated logarithm (LIL) for continuous-time Markov processes. Under some minimal assumptions, which are weaker than those in Cho et al., we establish liminf LIL at zero (at infinity, respectively) in general metric measure spaces. In particular, our assumptions for liminf law of LIL at zero and the form of liminf LIL are truly local so that we can cover highly space-inhomogenous cases. Our results cover all examples in Cho et al. including random conductance models with long range jumps. Moreover, we show that the general form of liminf law of LIL at zero holds for a large class of jump processes whose jumping measures have logarithmic tails and Feller processes with symbols of varying order which are not covered before.
WFA-GPU: gap-affine pairwise read-alignment using GPUs
Authors: Aguado-Puig Quim , Doblas Max , Matzoros Christos , Espinosa Antonio , Moure Juan Carlos , Marco-Sola Santiago , Moreto Miquel
Published: November 2023

Motivation

Advances in genomics and sequencing technologies demand faster and more scalable analysis methods that can process longer sequences with higher accuracy. However, classical pairwise alignment methods, based on dynamic programming (DP), impose impractical computational requirements to align long and noisy sequences like those produced by PacBio and Nanopore technologies. The recently proposed wavefront alignment (WFA) algorithm paves the way for more efficient alignment tools, improving time and memory complexity over previous methods. However, high-performance computing (HPC) platforms require efficient parallel algorithms and tools to exploit the computing resources available on modern accelerator-based architectures.

Results

This paper presents WFA-GPU, a GPU (graphics processing unit)-accelerated tool to compute exact gap-affine alignments based on the WFA algorithm. We present the algorithmic adaptations and performance optimizations that allow exploiting the massively parallel capabilities of modern GPU devices to accelerate the alignment computations. In particular, we propose a CPU–GPU co-design capable of performing inter-sequence and intra-sequence parallel sequence alignment, combining a succinct WFA-data representation with an efficient GPU implementation. As a result, we demonstrate that our implementation outperforms the original multi-threaded WFA implementation by up to 4.3× and up to 18.2× when using heuristic methods on long and noisy sequences. Compared to other state-of-the-art tools and libraries, the WFA-GPU is up to 29× faster than other GPU implementations and up to four orders of magnitude faster than other CPU implementations. Furthermore, WFA-GPU is the only GPU solution capable of correctly aligning long reads using a commodity GPU.

Availability and implementation

WFA-GPU code and documentation are publicly available at https://github.com/quim0/WFA-GPU.
Maternal preconception stress produces sex-specific effects at the maternal:fetal interface to impact offspring development and phenotypic outcomes
Authors: Cissé Yasmine M , Montgomery Kristen R , Zierden Hannah C , Hill Elizabeth M , Kane Patrick J , Huang Weiliang , Kane Maureen A , Bale Tracy L
Published: November 2023

Entering pregnancy with a history of adversity, including adverse childhood experiences and racial discrimination stress, is a predictor of negative maternal and fetal health outcomes. Little is known about the biological mechanisms by which preconception adverse experiences are stored and impact future offspring health outcomes. In our maternal preconception stress (MPS) model, female mice underwent chronic stress from postnatal days 28–70 and were mated 2 weeks post-stress. Maternal preconception stress dams blunted the pregnancy-induced shift in the circulating extracellular vesicle proteome and reduced glucose tolerance at mid-gestation, suggesting a shift in pregnancy adaptation. To investigate MPS effects at the maternal:fetal interface, we probed the mid-gestation placental, uterine, and fetal brain tissue transcriptome. Male and female placentas differentially regulated expression of genes involved in growth and metabolic signaling in response to gestation in an MPS dam. We also report novel offspring sex- and MPS-specific responses in the uterine tissue apposing these placentas. In the fetal compartment, MPS female offspring reduced expression of neurodevelopmental genes. Using a ribosome-tagging transgenic approach we detected a dramatic increase in genes involved in chromatin regulation in a PVN-enriched neuronal population in females at PN21. While MPS had an additive effect on high-fat-diet (HFD)-induced weight gain in male offspring, both MPS and HFD were necessary to induce significant weight gain in female offspring. These data highlight the preconception period as a determinant of maternal health in pregnancy and provides novel insights into mechanisms by which maternal stress history impacts offspring developmental programming.
Distinct involvement of the cranial and spinal nerves in progressive supranuclear palsy
Authors: Tanaka Hidetomo , Martinez-Valbuena Ivan , Forrest Shelley L , Couto Blas , Reyes Nikolai Gil , Morales-Rivero Alonso , Lee Seojin , Li Jun , Karakani Ali M , Tang-Wai David F , Tator Charles , Khadadadi Mozhgan , Sadia Nusrat , Tartaglia Maria Carmela , Lang Anthony E , Kovacs Gabor G
Published: November 2023

The most frequent neurodegenerative proteinopathies include diseases with deposition of misfolded tau or α-synuclein in the brain. Pathological protein aggregates in the PNS are well-recognized in α-synucleinopathies and have recently attracted attention as a diagnostic biomarker. However, there is a paucity of observations in tauopathies. To characterize the involvement of the PNS in tauopathies, we investigated tau pathology in cranial and spinal nerves (PNS-tau) in 54 tauopathy cases [progressive supranuclear palsy (PSP), n = 15; Alzheimer’s disease (AD), n = 18; chronic traumatic encephalopathy (CTE), n = 5; and corticobasal degeneration (CBD), n = 6; Pick’s disease, n = 9; limbic-predominant neuronal inclusion body 4-repeat tauopathy (LNT), n = 1] using immunohistochemistry, Gallyas silver staining, biochemistry, and seeding assays. Most PSP cases revealed phosphorylated and 4-repeat tau immunoreactive tau deposits in the PNS as follows: (number of tau-positive cases/available cases) cranial nerves III: 7/8 (88%); IX/X: 10/11 (91%); and XII: 6/6 (100%); anterior spinal roots: 10/10 (100%). The tau-positive inclusions in PSP often showed structures with fibrillary (neurofibrillary tangle-like) morphology in the axon that were also recognized with Gallyas silver staining. CBD cases rarely showed fine granular non-argyrophilic tau deposits. In contrast, tau pathology in the PNS was not evident in AD, CTE and Pick’s disease cases. The single LNT case also showed tau pathology in the PNS. In PSP, the severity of PNS-tau involvement correlated with that of the corresponding nuclei, although, occasionally, p-tau deposits were present in the cranial nerves but not in the related brainstem nuclei. Not surprisingly, most of the PSP cases presented with eye movement disorder and bulbar symptoms, and some cases also showed lower-motor neuron signs. Using tau biosensor cells, for the first time we demonstrated seeding capacity of tau in the PNS. In conclusion, prominent PNS-tau distinguishes PSP from other tauopathies. The morphological differences of PNS-tau between PSP and CBD suggest that the tau pathology in PNS could reflect that in the central nervous system. The high frequency and early presence of tau lesions in PSP suggest that PNS-tau may have clinical and biomarker relevance.
Vaccine Effectiveness Against Pediatric Influenza-A–Associated Urgent Care, Emergency Department, and Hospital Encounters During the 2022–2023 Season: VISION Network
Authors: Adams Katherine , Weber Zachary A , Yang Duck-Hye , Klein Nicola P , DeSilva Malini B , Dascomb Kristin , Irving Stephanie A , Naleway Allison L , Rao Suchitra , Gaglani Manjusha , Flannery Brendan , Garg Shikha , Kharbanda Anupam B , Grannis Shaun J , Ong Toan C , Embi Peter J , Natarajan Karthik , Fireman Bruce , Zerbo Ousseny , Goddard Kristin , Timbol Julius , Hansen John R , Grisel Nancy , Arndorfer Julie , Ball Sarah W , Dunne Margaret M , Kirshner Lindsey , Chung Jessie R , Tenforde Mark W
Published: November 2023

Background

During the 2022–2023 influenza season, the United States experienced the highest influenza-associated pediatric hospitalization rate since 2010–2011. Influenza A/H3N2 infections were predominant.

Methods

We analyzed acute respiratory illness (ARI)–associated emergency department or urgent care (ED/UC) encounters or hospitalizations at 3 health systems among children and adolescents aged 6 months–17 years who had influenza molecular testing during October 2022–March 2023. We estimated influenza A vaccine effectiveness (VE) using a test-negative approach. The odds of vaccination among influenza-A–positive cases and influenza-negative controls were compared after adjusting for confounders and applying inverse-propensity-to-be-vaccinated weights. We developed overall and age-stratified VE models.

Results

Overall, 13 547 of 44 787 (30.2%) eligible ED/UC encounters and 263 of 1862 (14.1%) hospitalizations were influenza-A–positive cases. Among ED/UC patients, 15.2% of influenza-positive versus 27.1% of influenza-negative patients were vaccinated; VE was 48% (95% confidence interval [CI], 44–52%) overall, 53% (95% CI, 47–58%) among children aged 6 months–4 years, and 38% (95% CI, 30–45%) among those aged 9–17 years. Among hospitalizations, 17.5% of influenza-positive versus 33.4% of influenza-negative patients were vaccinated; VE was 40% (95% CI, 6–61%) overall, 56% (95% CI, 23–75%) among children ages 6 months–4 years, and 46% (95% CI, 2–70%) among those 5–17 years.

Conclusions

During the 2022–2023 influenza season, vaccination reduced the risk of influenza-associated ED/UC encounters and hospitalizations by almost half (overall VE, 40–48%). Influenza vaccination is a critical tool to prevent moderate-to-severe influenza illness in children and adolescents.
Bartonella quintana Endocarditis: A Systematic Review of Individual Cases
Authors: Boodman Carl , Gupta Nitin , Nelson Christina A , van Griensven Johan
Published: November 2023

Background

Bartonella quintana is a louse-borne bacterium that remains a neglected cause of endocarditis in low-resource settings. Our understanding of risk factors, clinical manifestations, and treatment of B. quintana endocarditis are biased by older studies from high-income countries.

Methods

We searched Pubmed Central, Medline, Scopus, Embase, EBSCO (CABI) Global Health, Web of Science and international trial registers for articles published before March 2023 with terms related to Bartonella quintana endocarditis. We included articles containing case-level information on B. quintana endocarditis and extracted data related to patient demographics, clinical features, diagnostic testing, treatment, and outcome.

Results

A total of 975 records were identified, of which 569 duplicates were removed prior to screening. In total, 84 articles were eligible for inclusion, describing a total of 167 cases. Infections were acquired in 40 different countries; 62 cases (37.1%) were acquired in low- and middle-income countries (LMICs). Disproportionately more female and pediatric patients were from LMICs. More patients presented with heart failure (n = 70/167 [41.9%]) than fever (n = 65/167 [38.9%]). Mean time from symptom onset to presentation was 5.1 months. Also, 25.7% of cases (n = 43/167) were associated with embolization, most commonly to the spleen and brain; 65.5% of antimicrobial regimens included doxycycline. The vast majority of cases underwent valve replacement surgery (n = 154/167, [98.0%]). Overall case fatality rate was 9.6% (n = 16/167).

Conclusions

B. quintana endocarditis has a global distribution, and long delays between symptom onset and presentation frequently occur. Improved clinician education and diagnostic capacity are needed to screen at-risk populations and identify infection before endocarditis develops.
Clinical Predictors of Early and Late Endoscopic Recurrence Following Ileocolonic Resection in Crohn’s Disease
Authors: Hernández-Rocha Cristian , Walshe Margaret , Birch Sondra , Sabic Ksenija , Korie Ujunwa , Chasteau Colleen , Miladinova Vessela M , Sabol William B , Mengesha Emebet , Hanna Mary , Pozdnyakova Valeriya , Datta Lisa , Kohen Rita , Milgrom Raquel , Stempak Joanne M , Bitton Alain , Brant Steven R , Rioux John D , McGovern Dermot P B , Duerr Richard H , Cho Judy H , Schumm Phil L , Silverberg Mark S , Lazarev Mark
Published: November 2023

Background and Aims

Multiple factors are suggested to place Crohn’s disease patients at risk of recurrence after ileocolic resection with conflicting associations. We aimed to identify clinical predictors of recurrence at first [early] and further [late] postoperative colonoscopy.

Methods

Crohn’s disease patients undergoing ileocolic resection were prospectively recruited at six North American centres. Clinical data were collected and endoscopic recurrence was defined as Rutgeerts score ≥i2. A multivariable model was fitted to analyse variables independently associated with recurrence.

Results

A total of 365 patients undergoing 674 postoperative colonoscopies were included with a median age of 32 years, 189 [51.8%] were male, and 37 [10.1%] were non-Whites. Postoperatively, 133 [36.4%] used anti-tumour necrosis factor [anti-TNF] and 30 [8.2%] were smokers. At first colonoscopy, 109 [29.9%] had recurrence. Male gender (odds ratio [OR] = 1.95, 95% confidence interval [CI] 1.12–3.40), non-White ethnicity [OR = 2.48, 95% CI 1.09–5.63], longer interval between surgery and colonoscopy [OR = 1.09, 95% CI 1.002–1.18], and postoperative smoking [OR = 2.78, 95% CI 1.16–6.67] were associated with recurrence, while prophylactic anti-TNF reduced the risk [OR = 0.28, 95% CI 0.14–0.55]. Postoperative anti-TNF prophylaxis had a protective effect on anti-TNF experienced patients but not on anti-TNF naïve patients. Among patients without recurrence at first colonoscopy, Rutgeerts score i1 was associated with subsequent recurrence [OR = 4.43, 95% CI 1.73–11.35].

Conclusions

We identified independent clinical predictors of early and late Crohn’s disease postoperative endoscopic recurrence. Clinical factors traditionally used for risk stratification failed to predict recurrence and need to be revised.
The impact of Fisher's reproductive compensation on raising equilibrium frequencies of semidominant, nonlethal mutations under mutation/selection balance
Authors: Hastings Ian M
Published: November 2023

Fisher's reproductive compensation (fRC) occurs when a species’ demography means the death of an individual results in increased survival probability of his/her relatives, usually assumed to be full sibs. This likely occurs in many species, including humans. Several important recessive human genetic diseases cause early foetal/infant death allowing fRC to act on these mutations. The impact of fRC on these genetic conditions has been previously calculated and shown to be substantial as quantified by ω, the fold increase in equilibrium frequencies of the mutation under fRC compared with its absence, i.e. ω = 1.22 and ω = 1.33 for autosomal and sex-linked loci, respectively. However, the impact of fRC on the frequency of the much larger class of semidominant, nonlethal mutations is unknown. This is calculated here as ω = 2 − h*s for autosomal loci and ω up to 2 for sex-linked loci where h is dominance (varied between 0.05 and 0.95) and s is selection coefficient (varied between 0.05 and 0.9). These results show that the actions of fRC can almost double the equilibrium frequency of deleterious mutations with low values of h and/or s (noting that “low” is s∼0.05 to 0.1). It is noted that fRC may act differentially across the genome with genes expressed early in life being fully exposed to fRC while those expressed later in life may be unaffected; this could lead to systematic differences in deleterious allele frequency across the genome.
Examining multiple funding flows to public healthcare providers in low- and middle-income countries — results from case studies in Burkina Faso, Kenya, Morocco, Nigeria, Tunisia and Vietnam
Authors: Dkhimi Fahdi , Honda Ayako , Hanson Kara , Mbau Rahab , Onwujekwe Obinna , Phuong Hoang Thi , Mathauer Inke , Akhnif El Houcine , Jaouadi Imen , Kiendrébéogo Joël Arthur , Ezumah Nkoli , Kabia Evelyn , Barasa Edwine
Published: November 2023

Provider payment methods are traditionally examined by appraising the incentive signals inherent in individual payment mechanisms. However, mixed payment arrangements, which result in multiple funding flows from purchasers to providers, could be better understood by applying a systems approach that assesses the combined effects of multiple payment streams on healthcare providers. Guided by the framework developed by Barasa et al. (2021) (Barasa E, Mathauer I, Kabia E et al. 2021. How do healthcare providers respond to multiple funding flows? A conceptual framework and options to align them. Health Policy and Planning  36: 861–8.), this paper synthesizes the findings from six country case studies that examined multiple funding flows and describes the potential effect of multiple payment streams on healthcare provider behaviour in low- and middle-income countries. The qualitative findings from this study reveal the extent of undesirable provider behaviour occurring due to the receipt of multiple funding flows and explain how certain characteristics of funding flows can drive the occurrence of undesirable behaviours. Service and resource shifting occurred in most of the study countries; however, the occurrence of cost shifting was less evident. The perceived adequacy of payment rates was found to be the strongest driver of provider behaviour in the countries examined. The study results indicate that undesirable provider behaviours can have negative impacts on efficiency, equity and quality in healthcare service provision. Further empirical studies are required to add to the evidence on this link. In addition, future research could explore how governance arrangements can be used to coordinate multiple funding flows, mitigate unfavourable consequences and identify issues associated with the implementation of relevant governance measures.
Antibody-Mediated Suppression Regulates the Humoral Immune Response to Influenza Vaccination in Humans
Authors: Lu Xiuhua , Liu Feng , Tzeng Wen-Ping , York Ian A , Tumpey Terrence M , Levine Min Z
Published: November 2023

Background

Preexisting immunity, including memory B cells and preexisting antibodies, can modulate antibody responses to influenza in vivo to antigenically related antigens. We investigated whether preexisting hemagglutination inhibition (HAI) antibodies targeting the K163 epitope on the hemagglutinin (K163 antibodies) could affect antibody responses following vaccination with A/California/07/2009-like A(H1N1)pdm09 influenza viruses in humans.

Methods

Pre- and postvaccination sera collected from 300 adults (birth years, 1961–1998) in 6 seasons (2010–2016) were analyzed by HAI assays with 2 reverse genetics viruses and A(H1N1) viruses circulated from 1977 to 2018. Antibody adsorption assays were used to verify the preexisting K163 antibody–mediated suppression effect.

Results

Preexisting K163 antibody titers ≥80 affected HAI antibody responses following influenza vaccination containing A/California/07/2009-like antigens. At high K163 antibody concentrations (HAI antibody titers ≥160), all HAI antibody responses were suppressed. However, at moderate K163 antibody concentrations (HAI antibody titer, 80), only K163 epitope–specific antibody responses were suppressed, and novel HAI antibody responses targeting the non-K163 epitopes were induced by vaccination. Novel antibodies targeting non-K163 epitopes cross-reacted with newly emerging A(H1N1)pdm09 strains with a K163Q mutation rather than historic 1977–2007 A(H1N1) viruses.

Conclusions

K163 antibody–mediated suppression shapes antibody responses to A(H1N1)pdm09 vaccination. Understanding how preexisting antibodies suppress and redirect vaccine-induced antibody responses is of great importance to improve vaccine effectiveness.
3D hydrodynamics simulations of a 3 M⊙ core helium burning star
Authors: Blouin Simon , Herwig Falk , Mao Huaqing , Denissenkov Pavel , Woodward Paul R
Published: November 2023

The inner structure of core helium burning (CHeB) stars remains uncertain due to the yet unknown nature of mixing at the boundary of their cores. Large convective cores beyond a bare Schwarzschild model are favoured both from theoretical arguments and from asteroseismological constraints. However, the exact nature of this extra mixing, and in particular the possible presence of semiconvective layers, is still debated. In this work, we approach this problem through a new avenue by performing the first full-sphere 3D hydrodynamics simulations of the interiors of CHeB stars. We use the ppmstar explicit gas dynamics code to simulate the inner 0.45$\, {\rm M}_{\odot }$ of a 3 M⊙ CHeB star. Simulations are performed using different Cartesian grid resolutions (7683, 11523, and 17283) and heating rates. We use two different initial states, one based on mesas's predictive mixing scheme (which significantly extends the core beyond the Schwarzschild boundary) and one based on the convective premixing approach (which exhibits a semiconvective interface). The general behaviour of the flow in the convective core and in the stable envelope (where internal gravity waves are observed) is consistent with our recent simulations of core convection in massive main-sequence stars, and so are the various luminosity scaling relations. The semiconvective layers are dominated by strong internal gravity waves that do not produce measurable species mixing, but overshooting motions from the convective core gradually homogenize the semiconvective interface. This process can possibly completely erase the semiconvective layers, which would imply that CHeB stars do not harbour a semiconvection zone.
Synthesis of peptide–siRNA conjugates via internal sulfonylphosphoramidate modifications and evaluation of their in vitro activity
Authors: Smidt Jakob Melgaard , Lykke Lennart , Stidsen Carsten Enggaard , Pristovšek Nuša , Gothelf Kurt V
Published: November 2023

Conjugates of therapeutic oligonucleotides (ONs) including peptide conjugates, provide a potential solution to the major challenge of specific tissue delivery faced by this class of drugs. Conjugations are often positioned terminal at the ONs, although internal placement of other chemical modifications are known to be of critical importance. The introduction of internal conjugation handles in chemically modified ONs require highly specialized and expensive nucleoside phosphoramidites. Here, we present a method for synthesizing a library of peptide–siRNA conjugates by conjugation at internal phosphorous positions via sulfonylphosphoramidate modifications incorporated into the sense strand. The sulfonylphosphoramidate modification offers benefits as it can be directly incorporated into chemically modified ONs by simply changing the oxidation step during synthesis, and furthermore holds the potential to create multifunctionalized therapeutic ONs. We have developed a workflow using a novel pH-controlled amine-to-amine linker that yields peptide–siRNA conjugates linked via amide bonds, and we have synthesized conjugates between GLP1 peptides and a HPRT1 siRNA as a model system. The in vitro activity of the conjugates was tested by GLP1R activity and knockdown of the HPRT1 gene. We found that conjugation near the 3′-end is more favorable than certain central internal positions and different internal conjugation strategies were compared.
Cistrome Data Browser: integrated search, analysis and visualization of chromatin data
Authors: Taing Len , Dandawate Ariaki , L’Yi Sehi , Gehlenborg Nils , Brown Myles , Meyer Clifford A
Published: November 2023

The Cistrome Data Browser is a resource of ChIP-seq, ATAC-seq and DNase-seq data from humans and mice. It provides maps of the genome-wide locations of transcription factors, cofactors, chromatin remodelers, histone post-translational modifications and regions of chromatin accessible to endonuclease activity. Cistrome DB v3.0 contains approximately 45 000 human and 44 000 mouse samples with about 32 000 newly collected datasets compared to the previous release. The Cistrome DB v3.0 user interface is implemented as a single page application that unifies menu driven and data driven search functions and provides an embedded genome browser, which allows users to find and visualize data more effectively. Users can find informative chromatin profiles through keyword, menu, and data-driven search tools. Browser search functions can predict the regulators of query genes as well as the cell type and factor dependent functionality of potential cis-regulatory elements. Cistrome DB v3.0 expands the display of quality control statistics, incorporates sequence logos into motif enrichment displays and includes more expansive sample metadata. Cistrome DB v3.0 is available at http://db3.cistrome.org/browser.
Genome-wide transformation reveals extensive exchange across closely related Bacillus species
Authors: Förster Mona , Rathmann Isabel , Yüksel Melih , Power Jeffrey J , Maier Berenike
Published: November 2023

Bacterial transformation is an important mode of horizontal gene transfer that helps spread genetic material across species boundaries. Yet, the factors that pose barriers to genome-wide cross-species gene transfer are poorly characterized. Here, we develop a replacement accumulation assay to study the effects of genomic distance on transfer dynamics. Using Bacillus subtilis as recipient and various species of the genus Bacillus as donors, we find that the rate of orthologous replacement decreases exponentially with the divergence of their core genomes. We reveal that at least 96% of the B. subtilis core genes are accessible to replacement by alleles from Bacillus spizizenii. For the more distantly related Bacillus atrophaeus, gene replacement events cluster at genomic locations with high sequence identity and preferentially replace ribosomal genes. Orthologous replacement also creates mosaic patterns between donor and recipient genomes, rearranges the genome architecture, and governs gain and loss of accessory genes. We conclude that cross-species gene transfer is dominated by orthologous replacement of core genes which occurs nearly unrestricted between closely related species. At a lower rate, the exchange of accessory genes gives rise to more complex genome dynamics.
HOCOMOCO in 2024: a rebuild of the curated collection of binding models for human and mouse transcription factors
Authors: Vorontsov Ilya E , Eliseeva Irina A , Zinkevich Arsenii , Nikonov Mikhail , Abramov Sergey , Boytsov Alexandr , Kamenets Vasily , Kasianova Alexandra , Kolmykov Semyon , Yevshin Ivan S , Favorov Alexander , Medvedeva Yulia A , Jolma Arttu , Kolpakov Fedor , Makeev Vsevolod J , Kulakovskiy Ivan V
Published: November 2023

We present a major update of the HOCOMOCO collection that provides DNA binding specificity patterns of 949 human transcription factors and 720 mouse orthologs. To make this release, we performed motif discovery in peak sets that originated from 14 183 ChIP-Seq experiments and reads from 2554 HT-SELEX experiments yielding more than 400 thousand candidate motifs. The candidate motifs were annotated according to their similarity to known motifs and the hierarchy of DNA-binding domains of the respective transcription factors. Next, the motifs underwent human expert curation to stratify distinct motif subtypes and remove non-informative patterns and common artifacts. Finally, the curated subset of 100 thousand motifs was supplied to the automated benchmarking to select the best-performing motifs for each transcription factor. The resulting HOCOMOCO v12 core collection contains 1443 verified position weight matrices, including distinct subtypes of DNA binding motifs for particular transcription factors. In addition to the core collection, HOCOMOCO v12 provides motif sets optimized for the recognition of binding sites in vivo and in vitro, and for annotation of regulatory sequence variants. HOCOMOCO is available at https://hocomoco12.autosome.org and https://hocomoco.autosome.org.
m6A epitranscriptome analysis reveals differentially methylated transcripts that drive early chemoresistance in bladder cancer
Authors: Hodara Emmanuelle , Mades Aubree , Swartz Lisa , Iqbal Maheen , Xu Tong , Bsteh Daniel , Farnham Peggy J , Rhie Suhn K , Goldkorn Amir
Published: November 2023

N 6-Methyladenosine (m6A) RNA modifications dynamically regulate messenger RNA processing, differentiation and cell fate. Given these functions, we hypothesized that m6A modifications play a role in the transition to chemoresistance. To test this, we took an agnostic discovery approach anchored directly to chemoresistance rather than to any particular m6A effector protein. Specifically, we used methyl-RNA immunoprecipitation followed by sequencing (MeRIP-seq) in parallel with RNA sequencing to identify gene transcripts that were both differentially methylated and differentially expressed between cisplatin-sensitive and cisplatin-resistant bladder cancer (BC) cells. We filtered and prioritized these genes using clinical and functional database tools, and then validated several of the top candidates via targeted quantitative polymerase chain reaction (qPCR) and MeRIP-PCR. In cisplatin-resistant cells, SLC7A11 transcripts had decreased methylation associated with decreased m6A reader YTHDF3 binding, prolonged RNA stability, and increased RNA and protein levels, leading to reduced ferroptosis and increased survival. Consistent with this, cisplatin-sensitive BC cell lines and patient-derived organoids exposed to cisplatin for as little as 48 h exhibited similar mechanisms of SLC7A11 upregulation and chemoresistance, trends that were also reflected in public cancer survival databases. Collectively, these findings highlight epitranscriptomic plasticity as a mechanism of rapid chemoresistance and a potential therapeutic target.
Clinical Predictors of Survival in Patients With BRAFV600-Mutated Metastatic Melanoma Treated With Combined BRAF and MEK Inhibitors After Immune Checkpoint Inhibitors
Authors: Kahn Adriana M , Perry Curtis J , Etts Katrina , Kluger Harriet , Sznol Mario
Published: November 2023

Prospective and between trial comparisons indicate that first-line treatment with immune checkpoint inhibitors improves survival outcomes compared to first-line therapy with combined BRAF and MEK inhibitors in metastatic melanoma containing BRAFV600E/K mutations. Long-term outcomes for BRAF/MEK inhibition after progression on immunotherapy have not been reported. Moreover, clinical variables associated with outcome from treatment with combined BRAF/MEK inhibition were previously identified in the first-line setting but have not been investigated when targeted therapies are administered after progression on immune therapy. We performed a retrospective single institution analysis of 40 metastatic melanoma patients receiving combined BRAF/MEK inhibitors after progression on an anti-PD-1 or ipilimumab plus nivolumab to assess response rate by RECIST 1.1, progression-free and overall survival (PFS and OS). Pretreatment clinical variables were analyzed for association with OS. Ipilimumab/nivolumab was the first-line immunotherapy regimen in 39 patients (97.5%), and BRAFV600E/K mutations were present in 33 (83%) and 7 (17%) patients, respectively. The median OS from start of BRAF/MEK inhibitors was 20.3 months (1.73-106.4+, 95% CI of median 13.3-30.7). Clinical characteristics associated with worse survival prior to starting BRAF/MEK inhibitors included age > 60 years (median OS 14 vs. 28 months; HR 2.5; 95% CI 0.91-6.87, P = .023), ECOG-PS > 2 (median OS 7 vs. 33 months; HR 2.89; 95% CI 0.78-10.76, P = .018), and presence of bone metastases (median OS 9 vs. 52 months; HR 3.17; 95% CI 1.33-7.54, P = .002). These associations with shorter survival maintained their significance on multivariate analysis. If confirmed in larger cohorts, the identified prognostic variables can be used for stratification of patients in future randomized trials.
Type II metacaspase mediates light-dependent programmed cell death in Chlamydomonas reinhardtii
Authors: Lambert Lou , de Carpentier Félix , André Phuc , Marchand Christophe H , Danon Antoine
Published: November 2023

Among the crucial processes that preside over the destiny of cells from any type of organism are those involving their self-destruction. This process is well characterized and conceptually logical to understand in multicellular organisms; however, the levels of knowledge and comprehension of its existence are still quite enigmatic in unicellular organisms. We use Chlamydomonas (Chlamydomonas reinhardtii) to lay the foundation for understanding the mechanisms of programmed cell death (PCD) in a unicellular photosynthetic organism. In this paper, we show that while PCD induces the death of a proportion of cells, it allows the survival of the remaining population. A quantitative proteomic analysis aiming at unveiling the proteome of PCD in Chlamydomonas allowed us to identify key proteins that led to the discovery of essential mechanisms. We show that in Chlamydomonas, PCD relies on the light dependence of a photosynthetic organism to generate reactive oxygen species and induce cell death. Finally, we obtained and characterized mutants for the 2 metacaspase genes in Chlamydomonas and showed that a type II metacaspase is essential for PCD execution.
Characteristics of Japanese physician influencers on Twitter during the COVID-19 pandemic and fact-checking their tweets on COVID-19-related drugs
Authors: Suzuki Tomoya , Tanimoto Tetsuya , Kamamoto Sae , Ozaki Akihiko , Torii Hiroyuki A , Hase Daisuke , Murayama Anju , Yoshimura Hiroki , Uno Kazuko
Published: November 2023

Background

During the coronavirus disease-2019 (COVID-19) pandemic, segments of the public relied on social media platforms such as Twitter for medical information shared by medical personnel. Although physicians are likely to disseminate more accurate information on Twitter than non-medical individuals, it cannot be taken for granted. As such, tweets written by physicians in Japan should also be scrutinized for accuracy.

Purpose

The purpose of this study was to create a profile of the most popular physician influencers on Twitter in Japan, and to do a fact-check of their tweets regarding COVID-19-related drugs.

Design

This is a retrospective observational study.

Methods

We purchased Twitter data for Japan for the initial 9 months of the COVID-19 pandemic (from January 2020 to September 2020), and extracted tweets with keywords related to COVID-19 at a sampling rate of 3%. The most popular physicians were identified and selected consecutively by searching for the top 1000 accounts using Twitter’s search function. These top accounts were considered influencers and their tweets and retweets concerning COVID-19-related drugs were fact-checked against scientific literature.

Results

We identified 21 physician influencers with real names: most were male in their 40s and 50s working at private medical facilities. The contents of their tweets were mainly sourced from scientific publications that were current at that time. The fact-check revealed that only one of 50 tweets was not correct while the others had no identifiable inaccuracies.

Conclusions

Except for one tweet, tweets written and retweeted by Japanese physician influencers concerning the COVID-19-related drugs contained predominantly accurate information.
Repayment Flexibility and Risk Taking: Experimental Evidence from Credit Contracts
Authors: Battaglia Marianna , Gulesci Selim , Madestam Andreas
Published: November 2023

A widely held view is that small firms in developing countries are prevented from making profitable investments by lack of access to credit and insurance markets. One solution is to provide repayment flexibility in credit contracts. Repayment flexibility eases both the credit constraint, as it allows for increased spending during the start-up phase, and offers insurance, in case of fluctuations in income. In a field experiment among traditional microfinance clients and larger collateralized borrowers in Bangladesh, we randomly assign the option to delay up to 2 monthly repayments at any point during a 12-month loan cycle. The flexible contract leads to substantial improvements in the traditional microfinance clients’ business outcomes, driven by borrowers in the upper tail of the distribution. In addition, we find a significant impact on socio-economic status, combined with lower default rates. We show theoretically and empirically that these effects are induced by an increase in entrepreneurial risk taking, implying that the primary mechanism is insurance provision. Repayment flexibility also attracts less risk-averse borrowers interested in business expansion. At the same time, the effects for the larger loan are much more modest. Our findings suggest that lack of insurance is an important constraint for small firms but that a simple financial product that increases repayment flexibility can be an effective tool for enabling enterprise growth.