bluuebunny/crossref_metadata_2025 huggingface dataset:
Epitopes in the HA and NA of H5 and H7 avian influenza viruses that are important for antigenic drift
Authors: Luczo Jasmina M , Spackman Erica
Published: May 2024

Avian influenza viruses evolve antigenically to evade host immunity. Two influenza A virus surface glycoproteins, the haemagglutinin and neuraminidase, are the major targets of host immunity and undergo antigenic drift in response to host pre-existing humoral and cellular immune responses. Specific sites have been identified as important epitopes in prominent subtypes such as H5 and H7, which are of animal and public health significance due to their panzootic and pandemic potential. The haemagglutinin is the immunodominant immunogen, it has been extensively studied, and the antigenic reactivity is closely monitored to ensure candidate vaccine viruses are protective. More recently, the neuraminidase has received increasing attention for its role as a protective immunogen. The neuraminidase is expressed at a lower abundance than the haemagglutinin on the virus surface but does elicit a robust antibody response. This review aims to compile the current information on haemagglutinin and neuraminidase epitopes and immune escape mutants of H5 and H7 highly pathogenic avian influenza viruses. Understanding the evolution of immune escape mutants and the location of epitopes is critical for identification of vaccine strains and development of broadly reactive vaccines that can be utilized in humans and animals.
Comprehensive Characterization of the Integrin Family Across 32 Cancer Types
Authors: Zou Cheng , Zhu Jinwei , Xiong Jiangling , Tian Yu , Peng Yousong , Cheung Edwin , Zhang Dingxiao
Published: May 2024

Integrin genes are widely involved in tumorigenesis. Yet, a comprehensive characterization of integrin family members and their interactome at the pan-cancer level is lacking. Here, we systematically analyzed integrin family in approximately 10,000 tumors across 32 cancer types. Globally, integrins represent a frequently altered and misexpressed pathway, with alteration and dysregulation overall being protumorigenic. Expression dysregulation, better than mutational landscape, of integrin family successfully identifies a subgroup of aggressive tumors with a high level of proliferation and stemness. The results reveal that several molecular mechanisms collectively regulate integrin expression in a context-dependent manner. For potential clinical usage, we constructed a weighted scoring system, integrinScore, to measure integrin signaling patterns in individual tumors. Remarkably, integrinScore was consistently correlated with predefined molecular subtypes in multiple cancers, with integrinScore-high tumors being more aggressive. Importantly, integrinScore was cancer-dependent and closely associated with proliferation, stemness, tumor microenvironment, metastasis, and immune signatures. IntegrinScore also predicted patients’ response to immunotherapy. By mining drug databases, we unraveled an array of compounds that may modulate integrin signaling. Finally, we built a user-friendly database, Pan-cancer Integrin Explorer (PIExplorer; http://computationalbiology.cn/PIExplorer), to facilitate researchers to explore integrin-related knowledge. Collectively, we provide a comprehensive characterization of integrins across cancers and offer gene-specific and cancer-specific rationales for developing integrin-targeted therapy.
Barriers and facilitators to health professionals’ engagement in quality improvement initiatives: a mixed-methods systematic review
Authors: Elizalde Joanna , Lumibao Jommel , Lizarondo Lucylynn
Published: May 2024

Quality improvement (QI) initiatives in healthcare are crucial for enhancing service quality and healthcare outcomes. The success of these initiatives depends on the active engagement of healthcare professionals, which can be influenced by several factors within the healthcare system. This systematic review synthesized the factors influencing healthcare professionals’ engagement in QI projects, focusing on identifying both barriers and facilitators. A mixed methods systematic review (MMSR) was conducted using the JBI methodology for MMSR. Databases such as MEDLINE, CINAHL, Scopus, and Embase were searched for studies that explored barriers and facilitators to QI engagement of health professionals in the clinical setting. Methodological quality was assessed using the Mixed-Methods Appraisal Tool (MMAT). The extracted data were synthesized using the JBI convergent integrated approach to MMSR. Eighteen studies (seven qualitative, nine quantitative, and two mixed-methods) published between 2007 and 2023 were included in the review. The analysis revealed barriers and facilitators to engagement in QI initiatives at different levels of the health system. At the QI program level, the engagement of health professionals to QI was influenced by the approach to QI, evidence underpinning the QI initiative, QI knowledge and training, and access to QI specialists. At the health professional level, barriers and facilitators were related to their organizational role, motivation, perceptions about QI, and collaborations with individuals and groups. At the organizational level, factors related to culture and climate, leadership, available resources (including human resource and workload, infrastructure, and incentives), and institutional priorities influenced health professionals’ participation in QI. This review highlights the complex interplay of organizational, individual, and QI program level factors that influence the engagement of healthcare professionals in QI. Overcoming these complex barriers and leveraging facilitators is crucial for enhancing participation in QI efforts. The findings underscore the need for a multi-level strategy that focuses on creating a conducive organizational culture, providing robust leadership, and ensuring adequate resources and training for healthcare professionals. Such strategies hold the potential to enhance the effectiveness and sustainability of QI initiatives in healthcare settings.
Making It Work—Experiences of Women Who Engage in Technological Making at Home
Authors: Regal Georg , Smit Dorothé , França Nathalia Campreguer , Fuchsberger Verena , Tscheligi Manfred
Published: May 2024

This paper presents the results of a 5-month diary study into the practices and routines that develop around technological making in the home, particularly focused on the experiences of women, as they continue to be an underrepresented group in the maker community. In this study, we provided participants with an entry-level electronics making kit. Over the course of twenty weeks, the participants documented their making activities via photos, videos, text messages and taking part in interviews. By means of interpretative phenomenological analysis, we identified six core themes related to women’s experiences with technological making in the home. These experiences ranged from positive—feeling challenged, proud of accomplishments, inspired; to negative—feeling frustrated, guilty due to lack of progress or confused and overwhelmed. These experiences are discussed and contextualized by aspects related to hurdles experienced by the participants, and success factors that contribute to proactive engagement with making in the home.

Research Highlights Twenty-week photo diary study and interpretative phenomenological analysis. Identification of six core themes based on empirical data on experiences with technological making in the home context. Discourse around thresholds to engage women in technological making and the maker community. Design and research directions to reduce barriers in technological making.
Implementation of the EUCAST rapid antimicrobial susceptibility test (RAST) for carbapenemase/ESBL-producing Escherichia coli and Klebsiella pneumoniae isolates, and its effect on mortality
Authors: Tayşi Muhammet Rıdvan , Öcal Duygu , Çiçek Şentürk Gönül , Çalişkan Elif , Çelik Bahar , Şencan İrfan
Published: May 2024

Objectives

With the rise in antimicrobial resistance, there is a growing demand for rapid antimicrobial susceptibility testing (RAST). In this study, we applied the EUCAST RAST method to ESBL/carbapenemase-producing Escherichia coli and Klebsiella pneumoniae isolates without using advanced identification systems and analysed the effect of this method on mortality rates Also the clinical impact of this method on patients infected with these bacteria and its effect on mortality rates were investigated.

Methods

RAST was used for clinical blood cultures containing carbapenemase/ESBL-producing E. coli and K. pneumoniae without advanced identification systems (e.g. MALDI TOF), with preliminary identification by simple diagnostic tests (predicted RAST, or p-RAST), and its categorical agreement was investigated. The impact of the method on mortality was analysed by comparing the clinical data of patients whose blood cultures were subject to p-RAST (p-RAST group, n = 49) and those who were not subject to p-RAST (non-RAST group, n = 145).

Results

p-RAST results were analysed based on 539 antibiotic-bacteria combinations. Total error rates at 4, 6 and 8 h of incubation were 2.9%, 3.9% and 3.8%, respectively. In the p-RAST group, patients who did not receive appropriate antibiotics (29/45, 59.1%) were switched to appropriate treatment within 8 h at the latest. In contrast, in the non-RAST group, treatment of patients who received inappropriate antibiotics (79/145, 54.5%) could be changed after at least 24 h. Mortality rates were lower in the p-RAST group than in the non-RAST group (28.6% versus 51.7%, P = 0.005).

Conclusions

p-RAST can be used safely in hospital laboratories with high rates of antimicrobial resistance and can reduce mortality rates by shortening the transition time to appropriate treatment.
Biomedical blockchain with practical implementations and quantitative evaluations: a systematic review
Authors: Lacson Roger , Yu Yufei , Kuo Tsung-Ting , Ohno-Machado Lucila
Published: May 2024

Objective

Blockchain has emerged as a potential data-sharing structure in healthcare because of its decentralization, immutability, and traceability. However, its use in the biomedical domain is yet to be investigated comprehensively, especially from the aspects of implementation and evaluation, by existing blockchain literature reviews. To address this, our review assesses blockchain applications implemented in practice and evaluated with quantitative metrics.

Materials and Methods

This systematic review adapts the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework to review biomedical blockchain papers published by August 2023 from 3 databases. Blockchain application, implementation, and evaluation metrics were collected and summarized.

Results

Following screening, 11 articles were included in this review. Articles spanned a range of biomedical applications including COVID-19 medical data sharing, decentralized internet of things (IoT) data storage, clinical trial management, biomedical certificate storage, electronic health record (EHR) data sharing, and distributed predictive model generation. Only one article demonstrated blockchain deployment at a medical facility.

Discussion

Ethereum was the most common blockchain platform. All but one implementation was developed with private network permissions. Also, 8 articles contained storage speed metrics and 6 contained query speed metrics. However, inconsistencies in presented metrics and the small number of articles included limit technological comparisons with each other.

Conclusion

While blockchain demonstrates feasibility for adoption in healthcare, it is not as popular as currently existing technologies for biomedical data management. Addressing implementation and evaluation factors will better showcase blockchain’s practical benefits, enabling blockchain to have a significant impact on the health sector.
Functional completeness and primitive positive decomposition of relations on finite domains
Authors: Koshkin Sergiy
Published: May 2024

We give a new and elementary construction of primitive positive decomposition of higher arity relations into binary relations on finite domains. Such decompositions come up in applications to constraint satisfaction problems, clone theory and relational databases. The construction exploits functional completeness of 2-input functions in many-valued logic by interpreting relations as graphs of partially defined multivalued ‘functions’. The ‘functions’ are then composed from ordinary functions in the usual sense. The construction is computationally effective and relies on well-developed methods of functional decomposition, but reduces relations only to ternary relations. An additional construction then decomposes ternary into binary relations, also effectively, by converting certain disjunctions into existential quantifications. The result gives a uniform proof of Peirce’s reduction thesis on finite domains, and shows that the graph of any Sheffer function composes all relations there.
PrP is cleaved from the surface of mast cells by ADAM10 and proteases released during degranulation
Authors: Willows Steven D , Vliagoftis Harissios , Sim Valerie L , Kulka Marianna
Published: May 2024

While several functions of the endogenous prion protein have been studied, the homeostatic function of prion protein is still debated. Notably, prion protein is highly expressed on mast cells, granular immune cells that regulate inflammation. When activated, mast cells shed prion protein, although the mechanism and consequences of this are not yet understood. First, we tested several mast cell lines and found that, while prion protein was almost always present, the total amount differed greatly. Activation of mast cells induced a cleavage of the N-terminal region of prion protein, and this was reduced by protease inhibitors. Exogenous mast cell proteases caused a similar loss of the prion protein N-terminus. Additionally, mast cells shed prion protein in an ADAM10-dependent fashion, even in the absence of activation. Our results suggest that prion protein is cleaved from resting mast cells by ADAM10 and from activated mast cells by mast cell proteases. Prion protein also appears to affect mast cell function, as Prnp−/− bone marrow–derived mast cells showed lower levels of degranulation and cytokine release, as well as lower levels of both FcεRI and CD117. Finally, we sought to provide clinical relevance by measuring the levels of prion protein in bodily fluids of asthmatic patients, a disease that involves the activation of mast cells. We found an N-terminal fragment of prion protein could be detected in human sputum and serum, and the amount of this prion protein fragment was decreased in the serum of patients with asthma.
Genipin improves obesity through promoting bile secretion and changing bile acids composition in diet-induced obese rats
Authors: Guan Lili , Zhang Lei , Gong Dezheng , Li Pengcheng , Zhu Shengnan , Tang Jiulan , Du Man , Zhang Maokun , Zou Yuan
Published: May 2024

Objectives

Bile acids (BAs), as signaling molecules to regulate metabolism, have received considerable attention. Genipin is an iridoid compound extracted from Fructus Gradeniae, which has been shown to relieve adiposity and metabolic syndrome. Here, we investigated the mechanism of genipin counteracting obesity and its relationship with BAs signals in diet-induced obese (DIO) rats.

Methods

The DIO rats were received intraperitoneal injections of genipin for 10 days. The body weight, visceral fat, lipid metabolism in the liver, thermogenic genes expressions in brown fat, BAs metabolism and signals, and key enzymes for BAs synthesis were determined.

Key findings

Genipin inhibited fat synthesis and promoted lipolysis in the liver, and upregulated thermogenic gene expressions in brown adipose tissue of DIO rats. Genipin increased bile flow rate and upregulated the expressions of aquaporin 8 and the transporters of BAs in liver. Furthermore, genipin changed BAs composition by promoting alternative pathways and inhibiting classical pathways for BAs synthesis and upregulated the expressions of bile acid receptors synchronously.

Conclusions

These results suggest that genipin ameliorate obesity through BAs-mediated signaling pathways.
A dual regulatory role for the arbuscular mycorrhizal master regulator RAM1 in tomato
Authors: Ho-Plágaro Tania , Tamayo-Navarrete María Isabel , Ćavar Zeljković Sanja , Tarkowski Petr , García-Garrido José Manuel
Published: May 2024

The REQUIRED FOR ARBUSCULAR MYCORRHIZATION1 (RAM1) transcription factor from the GRAS family is well known for its role as a master regulator of the arbuscular mycorrhizal (AM) symbiosis in dicotyledonous and monocotyledonous species, being essential in transcriptional reprogramming for the development and functionality of the arbuscules. In tomato, SlGRAS27 is the putative orthologue of RAM1 (here named SlRAM1), but has not yet been characterized. A reduced colonization of the root and impaired arbuscule formation were observed in SlRAM1-silenced plants, confirming the functional conservation of the RAM1 orthologue in tomato. However, unexpectedly, SlRAM1-overexpressing (UBIL:SlRAM1) plants also showed decreased mycorrhizal colonization. Analysis of non-mycorrhizal UBIL:SlRAM1 roots revealed an overall regulation of AM-related genes and a reduction of strigolactone biosynthesis. Moreover, external application of the strigolactone analogue GR244DO almost completely reversed the negative effects of SlRAM1 overexpression on the frequency of mycorrhization. However, it only partially recovered the pattern of arbuscule distribution observed in control plants. Our results strongly suggest that SlRAM1 has a dual regulatory role during mycorrhization and, in addition to its recognized action as a positive regulator of arbuscule development, it is also involved in different mechanisms for the negative regulation of mycorrhization, including the repression of strigolactone biosynthesis.
High-accuracy emulators for observables in ΛCDM, Neff, Σmν, and w cosmologies
Authors: Bolliet Boris , Spurio Mancini Alessio , Hill J Colin , Madhavacheril Mathew , Jense Hidde T , Calabrese Erminia , Dunkley Jo
Published: May 2024

We use the emulation framework CosmoPower to construct and publicly release neural network emulators of cosmological observables, including the cosmic microwave background (CMB) temperature and polarization power spectra, matter power spectrum, distance-redshift relation, baryon acoustic oscillation (BAO) and redshift-space distortion (RSD) observables, and derived parameters. We train our emulators on Einstein–Boltzmann calculations obtained with high-precision numerical convergence settings, for a wide range of cosmological models including ΛCDM, wCDM, ΛCDM + Neff, and ΛCDM + Σmν. Our CMB emulators are accurate to better than 0.5 per cent out to ℓ = 104, which is sufficient for Stage-IV data analysis, and our P(k) emulators reach the same accuracy level out to $k=50 \, \, \mathrm{Mpc}^{-1}$, which is sufficient for Stage-III data analysis. We release the emulators via an online repository (CosmoPower Organisation), which will be continually updated with additional extended cosmological models. Our emulators accelerate cosmological data analysis by orders of magnitude, enabling cosmological parameter extraction analyses, using current survey data, to be performed on a laptop. We validate our emulators by comparing them to class and camb and by reproducing cosmological parameter constraints derived from Planck TT, TE, EE, and CMB lensing data, as well as from the Atacama Cosmology Telescope Data Release 4 CMB data, Dark Energy Survey Year-1 galaxy lensing and clustering data, and Baryon Oscillation Spectroscopic Survey Data Release 12 BAO and RSD data.
An analytic description of electron thermalization in kilonovae ejecta
Authors: Shenhar Ben , Guttman Or , Waxman Eli
Published: May 2024

A simple analytic description is provided of the rate of energy deposition by β-decay electrons in the homologously expanding radioactive plasma ejected in neutron star mergers, valid for a wide range of ejecta parameters – initial entropy, electron fraction {s0, Ye}, and scaled (time-independent) density ρt3. The formulae are derived using detailed numerical calculations following the time-dependent composition and β-decay emission spectra (including the effect of delayed deposition). The deposition efficiency depends mainly on ρt3 and only weakly on {s0, Ye}. The time te at which the ratio between the rates of electron energy deposition and energy production drops to 1 − e−1, is given by $t_e=t_{0e}\Big (\frac{\rho t^3}{0.5(\rho t^3)_0}\Big)^a$, where $(\rho t^3)_0=\frac{0.05\, {\rm M}_{\odot }}{4\pi (0.2c)^3}$, t0e(s0, Ye) ≈ 17 d, and 0.4 ≤ a(s0, Ye) ≤ 0.5. The fractional uncertainty in te due to nuclear physics uncertainties is $\approx 10~{{\ \rm per\ cent}}$. The result a ≤ 0.5 reflects the fact that the characteristic β-decay electron energies do not decrease with time (largely due to ‘inverted decay chains’ in which a slowly decaying isotope decays to a rapidly decaying isotope with higher end-point energy). We provide an analytic approximation for the time-dependent electron energy deposition rate, reproducing the numerical results to better than 50 per cent (typically $\lt 30~{{\ \rm per\ cent}}$, well within the energy production rate uncertainty due to nuclear physics uncertainties) over a 3–4 orders-of-magnitude deposition rate decrease with time. Our results may be easily incorporated in calculations of kilonovae light curves (with general density and composition structures), eliminating the need to numerically follow the time-dependent electron spectra. Identifying te, e.g. in the bolometric light curve, will constrain the ejecta density distribution.
Factors associated with discrepancies in disease activity as assessed by SDAI and RAPID3 in patients with rheumatoid arthritis: Data from a multicentre observational study (T-FLAG)
Authors: Suzuki Mochihito , Asai Shuji , Ohashi Yoshifumi , Sobue Yasumori , Ishikawa Hisato , Takahashi Nobunori , Terabe Kenya , Sato Ryo , Kosugiyama Hironobu , Hasegawa Junya , Ohno Yusuke , Sugiura Takaya , Imagama Shiro
Published: May 2024

Objectives

The present study aimed to examine discrepancies between assessments based on Routine Assessment of Patient Index Data 3 (RAPID3) and Simple Disease Activity Index (SDAI) in rheumatoid arthritis (RA) patients with controlled disease activity.

Methods

Data from 464 RA patients in SDAI remission or low disease activity (REM/LDA) were analysed. Patient-reported outcome (PRO) measures, including Health Assessment Questionnaire Disability Index (HAQ-DI), 25-question Geriatric Locomotive Function Scale (GLFS-25), and Kihon checklist (KCL), were assessed. Logistic regression models were used to identify factors associated with RAPID3 moderate or high disease activity (MDA/HDA). Cutoff values of RAPID3 MDA/HDA for each PRO evaluation item were determined using receiver operating characteristic curve analysis.

Results

Among RA patients in SDAI REM/LDA, 84.9% were in RAPID3 REM/LDA. Multivariable analysis revealed that HAQ-DI, GLFS-25, and KCL were independently associated with RAPID3 MDA/HDA. Subdomain analysis of KCL revealed that activities of daily living, physical function, cognitive function, and depressive mood were significantly associated with RAPID3 MDA/HDA. Cutoff values for HAQ-DI and KCL were 0.38 and 8, respectively.

Conclusions

In RA patients with controlled disease activity, discrepancies between RAPID3 and SDAI assessments were observed, with factors such as HAQ-DI, GLFS-25, and KCL being independently associated with RAPID3 MDA/HDA.
Factors associated with drug retention of mepolizumab in patients with eosinophilic granulomatosis with polyangiitis: A multicentre REVEAL cohort study
Authors: Shiomi Mayu , Watanabe Ryu , Matsuda Shogo , Kotani Takuya , Okazaki Ayana , Masuda Yuichi , Yoshida Tsuneyasu , Shoji Mikihito , Tsuge Ryosuke , Kadoba Keiichiro , Hiwa Ryosuke , Yamamoto Wataru , Takeda Akitoshi , Itoh Yoshiaki , Hashimoto Motomu
Published: May 2024

Objectives

To determine the current retention rate of mepolizumab (MPZ) and identify factors associated with drug retention in patients with eosinophilic granulomatosis with polyangiitis (EGPA) in the Kansai multicentre cohort (REVEAL cohort).

Methods

Sixty patients diagnosed with EGPA and treated with MPZ between December 2016 and June 2023 were enrolled. The clinical characteristics, including laboratory data, treatments administered, and disease course outcomes, were collected retrospectively. The patients were stratified into MPZ continuation (n = 53) and discontinuation (n = 7) groups, and drug retention was statistically compared using the log-rank test.

Results

The median age of patients was 54.5 years, with 55% females, and 33% antineutrophil cytoplasmic antibody-positive at disease onset. MPZ exhibited a retention rate of 78.7% after 5 years. The reasons for discontinuation included treatment of coexisting diseases, inadequate response, and remission. Patient characteristics at disease onset were comparable between the groups. Patients receiving immunosuppressants (IS) before MPZ introduction demonstrated significantly higher retention rates (P = 0.038). During the final observation, the MPZ continuation group had a lower vasculitis damage index score (P = 0.027).

Conclusions

MPZ exhibited a high 5-year retention rate, particularly in patients requiring IS. This study implies that long-term use of MPZ may mitigate irreversible organ damage.
Drawing human pedigree charts with DrawPed
Authors: Schönberger Janina , Steinhaus Robin , Seelow Dominik
Published: May 2024

Creating pedigree charts is a recurring task in biomedical research, but there are few online tools for drawing complex human pedigrees available and even fewer are free. With DrawPed we aim to close this gap. DrawPed automatically draws pedigree charts from standard PED format pedigree files. Users can also create pedigrees from scratch and interactively edit existing pedigrees. The application can display conditions not captured in a PED file such as deceased persons or suspected consanguinity of parents. Pedigree charts are displayed as SVGs, which are scalable and hence publication-ready. Pedigrees can be exported as PED files for storage, exchange, or use in other applications. DrawPed is open source and freely available at https://www.genecascade.org/DrawPed/.
Constraints on the emergence of RNA through non-templated primer extension with mixtures of potentially prebiotic nucleotides
Authors: Jia Xiwen , Zhang Stephanie J , Zhou Lijun , Szostak Jack W
Published: May 2024

The emergence of RNA on the early Earth is likely to have been influenced by chemical and physical processes that acted to filter out various alternative nucleic acids. For example, UV photostability is thought to have favored the survival of the canonical nucleotides. In a recent proposal for the prebiotic synthesis of the building blocks of RNA, ribonucleotides share a common pathway with arabino- and threo-nucleotides. We have therefore investigated non-templated primer extension with 2-aminoimidazole-activated forms of these alternative nucleotides to see if the synthesis of the first oligonucleotides might have been biased in favor of RNA. We show that non-templated primer extension occurs predominantly through 5′-5′ imidazolium-bridged dinucleotides, echoing the mechanism of template-directed primer extension. Ribo- and arabino-nucleotides exhibited comparable rates and yields of non-templated primer extension, whereas threo-nucleotides showed lower reactivity. Competition experiments confirmed the bias against the incorporation of threo-nucleotides. The incorporation of an arabino-nucleotide at the end of the primer acts as a chain terminator and blocks subsequent extension. These biases, coupled with potentially selective prebiotic synthesis, and the templated copying that is known to favour the incorporation of ribonucleotides, provide a plausible model for the effective exclusion of arabino- and threo-nucleotides from primordial oligonucleotides.
A programmable dual-targeting siRNA scaffold supports potent two-gene modulation in the central nervous system
Authors: Belgrad Jillian , Tang Qi , Hildebrand Sam , Summers Ashley , Sapp Ellen , Echeverria Dimas , O’Reilly Dan , Luu Eric , Bramato Brianna , Allen Sarah , Cooper David , Alterman Julia , Yamada Ken , Aronin Neil , DiFiglia Marian , Khvorova Anastasia
Published: May 2024

Divalent short-interfering RNA (siRNA) holds promise as a therapeutic approach allowing for the sequence-specific modulation of a target gene within the central nervous system (CNS). However, an siRNA modality capable of simultaneously modulating gene pairs would be invaluable for treating complex neurodegenerative disorders, where more than one pathway contributes to pathogenesis. Currently, the parameters and scaffold considerations for multi-targeting nucleic acid modalities in the CNS are undefined. Here, we propose a framework for designing unimolecular ‘dual-targeting’ divalent siRNAs capable of co-silencing two genes in the CNS. We systematically adjusted the original CNS-active divalent siRNA and identified that connecting two sense strands 3′ and 5′ through an intra-strand linker enabled a functional dual-targeting scaffold, greatly simplifying the synthetic process. Our findings demonstrate that the dual-targeting siRNA supports at least two months of maximal distribution and target silencing in the mouse CNS. The dual-targeting divalent siRNA is highly programmable, enabling simultaneous modulation of two different disease-relevant gene pairs (e.g. Huntington's disease: MSH3 and HTT; Alzheimer's disease: APOE and JAK1) with similar potency to a mixture of single-targeting divalent siRNAs against each gene. This work enhances the potential for CNS modulation of disease-related gene pairs using a unimolecular siRNA.
Time trends in preemptive kidney transplantation in Europe: an ERA registry study
Authors: Kramer Anneke , Boenink Rianne , Mercado Vergara Cynthia G , Bell Samira , Kerschbaum Julia , Rodríguez Arévalo Olga L , Mazuecos Auxiliadora , de Vries Aiko P J , Reisæter Anna V , Wong Esther H S , Lundgren Torbjörn , Valentin María O , Ordoñez Alvarez Flor A , Melilli Edoardo , Finne Patrik , Segelmark Mårten , Couchoud Cécile , Sørensen Søren S , Ferraro Pietro Manuel , Arnol Miha , Arici Mustafa , Ortiz Alberto , Jager Kitty J , Abramowicz Daniel , Stel Vianda S , Hellemans Rachel
Published: May 2024

Background

Preemptive kidney transplantation (PEKT) has better outcomes when compared with transplantation after dialysis. We aimed to examine trends in PEKT between 2000 and 2019 in Europe and to provide an overview of associated policies, barriers and initiatives.

Methods

Adult patients from 12 European countries who received a preemptive kidney transplant were included. The representatives of the registries providing these data were questioned on the policies, barriers and initiatives around PEKT.

Results

Between 2000 and 2019, 20 251 adults underwent PEKT [11 169 from living donors (LDs), 8937 from deceased donors (DDs)]. The proportion of first kidney transplantations that were preemptive more than doubled from 7% in 2000 to 18% in 2019, reflecting a similar relative increase for LD kidney recipients (from 21% to 43%) and DD kidney recipients (from 4% to 11%). Large international differences were found. The increase in PEKT was observed across all age, sex and primary renal disease groups. Countries had similar criteria for preemptive waitlisting. Barriers mentioned included donor shortage, late referral to the transplant center and long donor

or recipient work-up. Suggested initiatives included raising awareness on the possibility of PEKT, earlier start and shorter work-up time for recipient and LD.

Conclusions

Over the last two decades the proportion of patients receiving a first kidney transplant preemptively has more than doubled, reflecting a similar relative increase for living and DD kidney recipients.
Effective re-induction regimen for children with recurrent medulloblastoma
Authors: O’Halloran Katrina , Phadnis Sheetal , Friedman Gregory K , Metrock Katie , Davidson Tom B , Robison Nathan J , Tamrazi Benita , Cotter Jennifer A , Dhall Girish , Margol Ashley S
Published: May 2024

Background

There is no standard treatment for the recurrence of medulloblastoma, the most common malignant childhood brain tumor, and prognosis remains dismal. In this study, we introduce a regimen that is well-tolerated and effective at inducing remission.

Methods

The primary objectives of this study were to assess tolerability of the regimen and overall response rate (ORR). A retrospective chart review of patients with recurrent medulloblastoma, treated at two institutions with a re-induction regimen of intravenous irinotecan and cyclophosphamide with oral temozolomide and etoposide, was performed. Demographic, clinicopathologic, toxicity, and response data were collected and analyzed.

Results

Nine patients were identified. Median age was 5.75 years. Therapy was well-tolerated with no therapy-limiting toxicities and no toxic deaths. Successful stem cell collection was achieved in all 5 patients in whom it was attempted. ORR after 2 cycles was 78%. Three patients had a complete response, 4 patients had a partial response, 1 patient had stable disease, and 1 patient had progressive disease. Four patients are alive with no evidence of disease (NED), 2 patients are alive with disease, 2 patients have died of disease, and 1 patient died of toxicity related to additional therapy (NED at time of death).

Conclusions

This regimen is well-tolerated and effective. Tumor response was noted in the majority of cases, allowing patients to proceed to additional treatment with no or minimal disease. Further study of this regimen in a clinical trial setting is an important next step.
Pulsed reduced-dose rate re-irradiation for patients with recurrent grade 2 gliomas
Authors: Harari Colin M , Burr Adam R , Morris Brett A , Tomé Wolfgang A , Bayliss Adam , Bhatia Ankush , Grogan Patrick T , Robins H Ian , Howard Steven P
Published: May 2024

Background

Patients with grade 2 glioma exhibit highly variable survival. Re-irradiation for recurrent disease has limited mature clinical data. We report treatment results of pulsed reduced-dose rate (PRDR) radiation for patients with recurrent grade 2 glioma.

Methods

A retrospective analysis of 58 patients treated with PRDR from 2000 to 2021 was performed. Radiation was delivered in 0.2 Gy pulses every 3 minutes encompassing tumor plus margin. Survival outcomes and prognostic factors on outcome were Kaplan–Meier and Cox regression analyses.

Results

The median survival from the date of initial surgery was 8.6 years (95% CI: 5.5–11.8 years). 69% of patients showed malignant transformation to grade 3 (38%) or grade 4 (31%) glioma. Overall survival following PRDR was 12.6 months (95% CI: 8.3–17.0 months) and progression-free survival was 6.2 months (95% CI: 3.8–8.6 months). Overall response rate based on post-PRDR MRI was 36%. In patients who maintained grade 2 histology at recurrence, overall survival from PRDR was 22.0 months with 5 patients remaining disease-free, the longest at 8.2 and 11.4 years. PRDR was generally well tolerated.

Conclusions

To the best of our knowledge, this is the largest reported series of patients with recurrent grade 2 gliomas treated with PRDR radiation for disease recurrence. We demonstrate promising survival and acceptable toxicity profiles following re-irradiation. In the cohort of patients who maintain grade 2 disease, prolonged survival (>5 years) is observed in selected patients. For the entire cohort, 1p19q codeletion, KPS, and longer time from initial diagnosis to PRDR were associated with improved survival.
Crosstalk between Brassinosteroids and Other Phytohormones during Plant Development and Stress Adaptation
Authors: Guo Feimei , Lv Minghui , Zhang Jingjie , Li Jia
Published: May 2024

Brassinosteroids (BRs) are a group of polyhydroxylated phytosterols that play essential roles in regulating plant growth and development as well as stress adaptation. It is worth noting that BRs do not function alone, but rather they crosstalk with other endogenous signaling molecules, including the phytohormones auxin, cytokinins, gibberellins, abscisic acid, ethylene, jasmonates, salicylic acid and strigolactones, forming elaborate signaling networks to modulate plant growth and development. BRs interact with other phytohormones mainly by regulating each others’ homeostasis, transport or signaling pathway at the transcriptional and posttranslational levels. In this review, we focus our attention on current research progress in BR signal transduction and the crosstalk between BRs and other phytohormones.
Persulfidation and phosphorylation of transcription factor SlWRKY6 differentially regulate tomato fruit ripening
Authors: Zhang Min , Hu Kangdi , Ma Lin , Geng Meihui , Zhang Conghe , Yao Gaifang , Zhang Hua
Published: May 2024

Cysteine desulfhydrase catalyses the generation of the signaling molecule hydrogen sulfide (H2S) in plants. In this study, we found that H2S can inhibit tomato (Solanum lycopersicum) fruit ripening and SlWRKY6 undergoes differential protein persulfidation in SlLCD1-overexpressing leaves. Then, further study indicated that SlWRKY6 could be persulfidated by H2S at Cys396. By construction of slwrky6 mutants and SlWRKY6-OE lines, we found that SlWRKY6 positively regulates leaf senescence and fruit ripening by activating the transcription of ripening-related genes STAYGREEN 1 (SlSGR1) and Senescence-Associated Gene 12 (SlSAG12). In addition, SlWRKY6 interacted with kinase SlMAPK4 and was phosphorylated at Ser33. Dual-luciferase transient expression assays and electrophoretic mobility shift assays indicated that SlWRKY6 persulfidation attenuated its transcriptional regulation of target genes SlSGR1 and SlSAG12, whereas SlWRKY6 phosphorylation by SlMAPK4 activated the transcription of target genes to promote fruit ripening. Moreover, we provided evidence that SlWRKY6 persulfidation attenuated its SlMAPK4-mediated phosphorylation to inhibit tomato fruit ripening. By transient expression of SlWRKY6, SlWRKY6C396A, SlWRKY6S33A, and SlWRKY6S33D in slwrky6 fruits, we found that SlWRKY6 persulfidation attenuated the expression of SlSGR1 and SlSAG12 thereby delaying tomato fruit ripening, while SlWRKY6 phosphorylation increased the expression of target genes. As tomato fruits ripened, endogenous H2S production decreased, while SlMAPK4 expression increased. Therefore, our findings reveal a model in which SlWRKY6 persulfidation due to higher endogenous H2S levels in un-ripened fruit inhibits its ability to activate SlSGR1 and SlSAG12 expression, while SlWRKY6 phosphorylation by SlMAPK4 activates its transcriptional activity, thereby promoting tomato fruit ripening.
Oral delivery of nanomedicine for genetic kidney disease
Authors: Huang Yi , Wang Jonathan , Mancino Valeria , Pham Jessica , O’Grady Colette , Li Hui , Jiang Kairui , Chin Deborah , Poon Christopher , Ho Pei-Yin , Gyarmati Georgina , Peti-Peterdi János , Hallows Kenneth R , Chung Eun Ji
Published: May 2024

Chronic and genetic kidney diseases such as autosomal dominant polycystic kidney disease (ADPKD) have few therapeutic options, and clinical trials testing small molecule drugs have been unfavorable due to low kidney bioavailability and adverse side effects. Although nanoparticles can be designed to deliver drugs directly to the diseased site, there are no kidney-targeted nanomedicines clinically available, and most FDA-approved nanoparticles are administered intravenously which is not ideal for chronic diseases. To meet these challenges of chronic diseases, we developed a biomaterials-based strategy using chitosan particles (CP) for oral delivery of therapeutic, kidney-targeting peptide amphiphile micelles (KMs). We hypothesized that encapsuling KMs into CP would enhance the bioavailability of KMs upon oral administration given the high stability of chitosan in acidic conditions and mucoadhesive properties enabling absorption within the intestines. To test this, we evaluated the mechanism of KM access to the kidneys via intravital imaging and investigated the KM biodistribution in a porcine model. Next, we loaded KMs carrying the ADPKD drug metformin into CP (KM-CP-met) and measured in vitro therapeutic effect. Upon oral administration in vivo, KM-CP-met showed significantly greater bioavailability and accumulation in the kidneys as compared to KM only or free drug. As such, KM-CP-met treatment in ADPKD mice (Pkd1fl/fl;Pax8-rtTA;Tet-O-Cre which develops the disease over 120 days and mimics the slow development of ADPKD) showed enhanced therapeutic efficacy without affecting safety despite repeated treatment. Herein, we demonstrate the potential of KM-CP as a nanomedicine strategy for oral delivery for the long-term treatment of chronic kidney diseases.
Is the Coleman–de Luccia Action Minimum?: An AdS/CFT Approach
Authors: Oshita Naritaka , Shoji Yutaro , Yamaguchi Masahide
Published: May 2024

We use the anti-de Sitter/conformal field theory (AdS/CFT) correspondence to find the least bounce action in an AdS false vacuum state, i.e. the most probable decay process of the metastable AdS vacuum within the Euclidean formalism by Callan and Coleman. It was shown that the O(4) symmetric bounce solution leads to the action minimum in the absence of gravity, but it is nontrivial in the presence of gravity. The AdS/CFT duality is used to evade the difficulties particular to a metastable gravitational system. To this end, we show that the Fubini bounce solution in CFT, corresponding to the Coleman–de Luccia (CdL) bounce in AdS, gives the least action among all finite bounce solutions in a conformal scalar field theory. Thus, we prove that the CdL action is the least action among all possible large and thin-wall configurations under certain conditions.
Arthritis in patients with very early systemic sclerosis: a comprehensive clinical and prognostic analysis
Authors: Muraru Sinziana , Mihai Carina , Elhai Muriel , Becker Mike , Jordan Suzana , Garaiman Alexandru , Bruni Cosimo , Petelytska Liubov , Hoffmann-Vold Anna-Maria , Distler Oliver , Dobrota Rucsandra
Published: May 2024

Objective

Arthritis is associated with a worse prognosis in established SSc. However, knowledge about its relevance in very early SSc (veSSc) is scarce. We aimed to assess the prevalence and phenotype of arthritis, as well as its prognostic impact, in patients with veSSc.

Methods

We analysed patients with veSSc, defined as presence of Raynaud’s phenomenon (RP) and/or at least one of: puffy fingers, antinuclear antibodies (ANA), abnormal capillaroscopy, not fulfilling the ACR/EULAR classification criteria for SSc at baseline. We investigated associations between arthritis and clinical parameters, followed by a longitudinal analysis to investigate arthritis as a potential predictor of progression towards established SSc.

Results

We included 159 patients, of whom 108 had at least one follow-up visit. SSc-related arthritis occurred in 22/159 (13.8%) patients at baseline. Arthritis was mostly seronegative, symmetrical, oligo- or polyarticular, non-erosive, and rarely associated with elevation of inflammatory markers. More than half of the patients needed treatment with DMARDs. Anti-centromere antibodies (ACA) were negatively associated with arthritis (odds ratio 0.707, 95% CI 0.513–0.973, P = 0.033). Overall, 43/108 (39.8%) patients with follow-up progressed to established SSc during the observation time. Arthritis was not a significant predictor for progression to established SSc in a multivariable Cox regression.

Conclusion

In this first comprehensive analysis, we found a similar prevalence of arthritis in veSSc as seen in established SSc. Moreover, the use of DMARDs indirectly suggests a relevant disease burden.
Effects of PFAS on human liver transporters: implications for health outcomes
Authors: Vujic Ena , Ferguson Stephen S , Brouwer Kim L R
Published: May 2024

Per- and polyfluoroalkyl substances (PFAS) have become internationally recognized over the past three decades as persistent organic pollutants used in the production of various consumer and industrial goods. Research efforts continue to gauge the risk that historically used, and newly produced, PFAS may cause to human health. Numerous studies report toxic effects of PFAS on the human liver as well as increased serum cholesterol levels in adults. A major concern with PFAS, also dubbed “forever chemicals,” is that they accumulate in the liver and kidney and persist in serum. The mechanisms responsible for their disposition and excretion in humans are poorly understood. A better understanding of the interaction of PFAS with liver transporters, as it pertains to the disposition of PFAS and other xenobiotics, could provide mechanistic insight into human health effects and guide efforts toward risk assessment of compounds in development. This review summarizes the current state of the literature on the emerging relationships (eg, substrates, inhibitors, modulators of gene expression) between PFAS and specific hepatic transporters. The adaptive and toxicological responses of hepatocytes to PFAS that reveal linkages to pathologies and epidemiological findings are highlighted. The evidence suggests that our understanding of the molecular landscape of PFAS must improve to determine their impact on the expression and function of hepatocyte transporters that play a key role in PFAS or other xenobiotic disposition. From here, we can assess what role these changes may have in documented human health outcomes.
Rifaximin plus lactulose versus lactulose alone for reducing the risk of HE recurrence
Authors: Sanyal Arun J. , Kowdley Kris V. , Reau Nancy S. , Pyrsopoulos Nikolaos T. , Allen Christopher , Heimanson Zeev , Bajaj Jasmohan S.
Published: May 2024

Background:

The aim was to examine rifaximin plus lactulose efficacy in patients with cirrhosis at a risk of developing overt HE who were stratified by important baseline characteristics such as comorbid ascites or diabetes.

Methods:

Pooled post hoc subgroup analysis of adults receiving rifaximin 550 mg twice daily plus lactulose or lactulose alone for 6 months in a phase 3 randomized, double-blind trial and a phase 4 open-label trial was conducted.

Results and Conclusion:

Rifaximin plus lactulose was more efficacious than lactulose alone for reducing the risk of overt HE recurrence and HE-related hospitalization in adults grouped by select baseline disease characteristics.