bluuebunny/crossref_metadata_2025_split huggingface dataset:
Formulating RALA/Au nanocomplexes to enhance nanoparticle internalisation efficiency, sensitising prostate tumour models to radiation treatment
Authors: Bennie Lindsey A. , Feng Jie , Emmerson Christopher , Hyland Wendy B. , Matchett Kyle B. , McCarthy Helen O. , Coulter Jonathan A. 
Published: September 2021

Abstract
Background
Gold nanoparticles (AuNP) are effective radiosensitisers, however, successful clinical translation has been impeded by short systemic circulation times and poor internalisation efficiency. This work examines the potential of RALA, a short amphipathic peptide, to enhance the uptake efficiency of negatively charged AuNPs in tumour cells, detailing the subsequent impact of AuNP internalisation on tumour cell radiation sensitivity.

Results
RALA/Au nanoparticles were formed by optimising the ratio of RALA to citrate capped AuNPs, with assembly occurring through electrostatic interactions. Physical nanoparticle characteristics were determined by UV–vis spectroscopy and dynamic light scattering. Nano-complexes successfully formed at w:w ratios > 20:1 (20 µg RALA:1 µg AuNP) yielding positively charged nanoparticles, sized < 110 nm with PDI values < 0.52. ICP-MS demonstrated that RALA enhanced AuNP internalisation by more than threefold in both PC-3 and DU145 prostate cancer cell models, without causing significant toxicity. Importantly, all RALA-AuNP formulations significantly increased prostate cancer cell radiosensitivity. This effect was greatest using the 25:1 RALA-AuNP formulation, producing a dose enhancement effect (DEF) of 1.54 in PC3 cells. Using clinical radiation energies (6 MV) RALA-AuNP also significantly augmented radiation sensitivity. Mechanistic studies support RALA-AuNP nuclear accumulation resulting in increased DNA damage yields.

Conclusions
This is the first study to demonstrate meaningful radiosensitisation using low microgram AuNP treatment concentrations. This effect was achieved using RALA, providing functional evidence to support our previous imaging study indicating RALA-AuNP nuclear accumulation.

Graphic abstract
Thermo-sensitive electroactive hydrogel combined with electrical stimulation for repair of spinal cord injury
Authors: Liu Wei , Luo Yiqian , Ning Cong , Zhang Wenjing , Zhang Qingzheng , Zou Haifeng , Fu Changfeng 
Published: September 2021

AbstractThe strategy of using a combination of scaffold-based physical and biochemical cues to repair spinal cord injury (SCI) has shown promising results. However, integrating conductivity and neurotrophins into a scaffold that recreates the electrophysiologic and nutritional microenvironment of the spinal cord (SC) remains challenging. In this study we investigated the therapeutic potential of a soft thermo-sensitive polymer electroactive hydrogel (TPEH) loaded with nerve growth factor (NGF) combined with functional electrical stimulation (ES) for the treatment of SCI. The developed hydrogel exhibits outstanding electrical conductance upon ES, with continuous release of NGF for at least 24 days. In cultured nerve cells, TPEH loaded with NGF promoted the neuronal differentiation of neural stem cells and axonal growth, an effect that was potentiated by ES. In a rat model of SCI, TPEH combined with NGF and ES stimulated endogenous neurogenesis and improved motor function. These results indicate that the TPEH scaffold that combines ES and biochemical cues can effectively promote SC tissue repair.
Collaboration on evidence synthesis in Africa: a network study of growing research capacity
Authors: Pan Jiayi , Zhong Yongqi , Young Sarah , Niezink Nynke M. D. 
Published: September 2021

AbstractBackgroundEvidence-based practice in medicine and social policy relies heavily on evidence synthesis. To translate evidence into practical guidelines for low- and middle-income countries, local expertise is essential. The objectives of this study are to assess the change in capacity for conducting evidence synthesis in Africa and to identify key African institutions for regional capacity-building. We take on a network perspective, considering that the position of an institution in the African evidence ecosystem is one constituent of its research capacity.MethodsWe systematically identified 3548 evidence synthesis publications between 2008 and 2019 with at least one author in Africa from the Web of Science Core Collection. These articles involved 3769 institutions. Longitudinal institution-level collaboration network data were constructed based on co-authorship information. We used social network analysis to examine the institutions’ connectivity and tendency for intra- and interregional collaboration. We also identified the degree- and betweenness-central African institutions and explored the structure and composition of their local network neighbourhoods.ResultsThe number of African institutions involved in evidence synthesis has increased substantially over the last decade, from 31 in 2008 to 521 in 2019, and so has the number of evidence synthesis publications with authors in Africa. African institutions in the evidence ecosystem have also become more connected during this period. Although the amount of intercontinental collaboration continues to exceed that of regional collaboration, the tendency for African institutions to collaborate with partners in Africa is increasing. We identified seven institutions—in South Africa, Egypt and Uganda—as central to the collaboration networks between 2008 and 2019, all of whom showed a tendency to collaborate across sectors.ConclusionThe development of more regionally based network-building initiatives would help to foster communities of practice and inter-institutional collaboration, strengthening regional research capacity. Moreover, the analysis in this study adds depth beyond a simple bibliometric analysis and illustrates that network analysis could provide a useful tool to evaluate the effectiveness of capacity-building strategies and programmes in the future.
Cost-effectiveness analysis for SilAtro-5-90 adjuvant treatment in the management of recurrent tonsillitis, compared with usual care only
Authors: Ostermann Thomas , Park A-La , De Jaegere Sabine , Fetz Katharina , Klement Petra , Raak Christa , McDaid David 
Published: September 2021

Abstract
Purpose
Antibiotics are one possible treatment for patients with recurrent acute throat infections (ATI), but effectiveness can be modest. In view of worries over antibiotic resistance, treatment pathways that reduce recurrence of ATI are essential from a public health perspective. Integrative treatment strategies can be an option but there is still a high demand to provide evidence of their cost effectiveness.

Methods
We constructed a 4-state Markov model to compare the cost-effectiveness of SilAtro-5-90 as adjuvant homeopathic therapy to care as usual with care as usual alone in reducing the recurrence of ATI for children and adults with suspected moderate recurrent tonsillitis. The analysis was performed from a societal perspective in Germany over a 2-year period. Results are reported separately for children < 12 and for individuals aged 12 and over. The model draws on evidence from a multi-centre randomised clinical trial that found this strategy effective in reducing recurrence of ATI. Costs in 2019 € and outcomes after 1 year are discounted at a rate of 3% per annum.

Results
For adults and adolescents aged 12 years and over, incremental cost per ATI averted in the adjuvant therapy group was €156.64. If individuals enter the model on average with a history of 3.33 previous ATIs, adjuvant therapy has both lower costs and better outcomes than care as usual. For children (< 12 years) adjuvant therapy had both lower costs and ATI than care as usual. The economic case is stronger if adjuvant treatment reduces surgical referral. At a hypothetical cost per ATI averted threshold of €1000 probabilistic sensitivity analysis suggests Silatro-5-90 has a 65% (adults) and 71% (children) chance of being cost-effective.

Conclusion
Our results indicate the importance of considering homeopathy as adjuvant therapy in the treatment of ATIs in individuals with recurrent tonsillitis from a socio-economic perspective. Further evaluation should assess how differences in uptake and sustained use of homeopathic adjuvant therapy, as well as changing patterns of antibiotic prescribing, impact on cost effectiveness.
Walking cadence (steps/min) and intensity in 61–85-year-old adults: the CADENCE-Adults study
Authors: Tudor-Locke Catrine , Mora-Gonzalez Jose , Ducharme Scott W. , Aguiar Elroy J. , Schuna John M. , Barreira Tiago V. , Moore Christopher C. , Chase Colleen J. , Gould Zachary R. , Amalbert-Birriel Marcos A. , Chipkin Stuart R. , Staudenmayer John 
Published: September 2021

Abstract
Background
Heuristic (i.e., evidence-based, rounded) cadences of ≥100 and ≥ 130 steps/min have consistently corresponded with absolutely-defined moderate (3 metabolic equivalents [METs]) and vigorous (6 METs) physical activity intensity, respectively, in adults 21–60 years of age. There is no consensus regarding similar thresholds in older adults.

Purpose
To provide heuristic cadence thresholds for 3, 4, 5, and 6 METs in 61–85-year-old adults.

Methods
Ninety-eight community-dwelling ambulatory and ostensibly healthy older adults (age = 72.6 ± 6.9 years; 49% women) walked on a treadmill for a series of 5-min bouts (beginning at 0.5 mph with 0.5 mph increments) in this laboratory-based cross-sectional study until: 1) transitioning to running, 2) reaching ≥75% of their age-predicted maximum heart rate, or 3) reporting a Borg rating of perceived exertion > 13. Cadence was directly observed and hand-tallied. Intensity (oxygen uptake [VO2] mL/kg/min) was assessed with indirect calorimetry and converted to METs (1 MET = 3.5 mL/kg/min). Cadence thresholds were identified via segmented mixed effects model regression and using Receiver Operating Characteristic (ROC) curves. Final heuristic cadence thresholds represented an analytical compromise based on classification accuracy (sensitivity, specificity, positive and negative predictive value, and overall accuracy).

Results
Cadences of 103.1 (95% Prediction Interval: 70.0–114.2), 116.4 (105.3–127.4), 129.6 (118.6–140.7), and 142.9 steps/min (131.8–148.4) were identified for 3, 4, 5, and 6 METs, respectively, based on the segmented regression. Comparable values based on ROC analysis were 100.3 (95% Confidence Intervals: 95.7–103.1), 111.5 (106.1–112.9), 116.0 (112.4–120.2), and 128.6 steps/min (128.3–136.4). Heuristic cadence thresholds of 100, 110, and 120 were associated with 3, 4, and 5 METs. Data to inform a threshold for ≥6 METs was limited, as only 6/98 (6.0%) participants achieved this intensity.

Conclusions
Consistent with previous data collected from 21–40 and 41–60-year-old adults, heuristic cadence thresholds of 100, 110, and 120 steps/min were associated with 3, 4, and 5 METs, respectively, in 61–85-year-old adults. Most older adults tested did not achieve the intensity of ≥6 METs; therefore, our data do not support establishing thresholds corresponding with this intensity level.

Trial registration
Clinicaltrials.gov NCT02650258. Registered 24 December
2015.
Longitudinal analysis of symptom-based clustering in patients with primary Sjogren’s syndrome: a prospective cohort study with a 5-year follow-up period
Authors: Lee Jennifer Jooha , Park Young Jae , Park Misun , Yim Hyeon Woo , Park Sung Hwan , Kwok Seung-Ki 
Published: September 2021

Abstract
Background
Sjogren’s syndrome (SS) is a heterogenous disease with various phenotypes. We aimed to provide a relevant subclassification based on symptom-based clustering for patients with primary (p) SS.

Methods
Data from patients in a prospective pSS cohort in Korea were analysed. Latent class analysis (LCA) was performed using patient reported outcomes, including pain, fatigue, dryness, and anxiety/depression. Clinical and laboratory differences between the classes were analysed. Latent transition analysis (LTA) was applied to the longitudinal data (annually for up to 5 years) to assess temporal stability of the classifications.

Results
LCA identified three classes among 341 patients with pSS (i.e., ‘high symptom burden’, ‘dryness dominant’, ‘low symptom burden’). Each group had distinct laboratory and clinical phenotypes. LTA revealed that class membership remained stable over time. Baseline class predicted future salivary gland function and damage accrual represented by a Sjogren’s syndrome disease damage index.

Conclusion
Symptom-based clustering of heterogenous patients with primary Sjogren’s syndrome provided a relevant classification supported by temporal stability over time and distinct phenotypes between the classes. This clustering strategy may provide more homogenous groups of pSS patients for novel treatment development and predict future phenotypic evolvement.
A new Mfn-2 related synthetic peptide promotes vascular smooth muscle cell apoptosis via regulating the mitochondrial apoptotic pathway by inhibiting Akt signaling
Authors: Zhang Xinxin , Xu Xiangyu , Lu Li , Wan Xiaoning , Qin Yating , Ruan Weibin , Lv Chao , He Lin , Guo Xiaomei 
Published: September 2021

Abstract
Background
Restenosis after angioplasty is a major challenge for the treatment of coronary artery diseases. Facilitation of vascular smooth muscle cell (VSMC) apoptosis may be an attractive approach to decrease the incidence of restenosis. We synthesized a 16-amino acid mitofusin-2 (Mfn-2) gene related peptide (MRSP) based on the sequence of the p21ras signature motif, the smallest functional sequence of the Mfn-2 gene with proapoptotic properties in VSMC. We investigated whether MRSP enhanced apoptotic activities to inhibit VSMC accumulation and neointimal hyperplasia in rats with carotid balloon injury.

Methods
VSMCs were treated with different concentrations of MRSP, the PI3K agonist 740 Y-P and the inhibitor LY294002. Cell apoptosis and related pathway molecules were assessed. MRSP was also given to rats with carotid artery balloon injury. Neointimal hyperplasia and cell apoptotic pathways were detected.

Results
In vitro experiments revealed that MRSP treatment significantly increased VSMC apoptosis and induced increases in procaspase-9 cleavage, caspase-3 activation, cytochrome c release from mitochondria to the cytoplasm and the Bax/Bcl-2 ratio but not caspase-8 expression, indicating that the mitochondrial apoptotic cascade was activated by MRSP, which might be attributed to suppression of the PI3K/Akt signaling pathway. We further found that the PI3K agonist 740 Y-P prevented and that the inhibitor LY294002 strengthened the proapoptotic effects of MRSP. MRSP strongly inhibited neointimal hyperplasia and VSMC accumulation, but increased VSMC apoptosis in the vascular wall after balloon injury. Moreover, MRSP substantially enhanced Bax and cleaved caspase-3 expression and decreased Bcl-2 levels in intima, accompanied by decreased levels of phosphorylated Akt and PI3K in vivo.

Conclusions
Taken together, the present study showed that MRSP treatment results in a strong proapoptotic effect by activating the mitochondrial apoptotic cascade through suppression of the PI3K/Akt pathway.
An emerging and variant viral promoter of HIV-1 subtype C exhibits low-level gene expression noise
Authors: Ali Haider , Bhange Disha , Mehta Kavita , Gohil Yuvrajsinh , Prajapati Harshit Kumar , Byrareddy Siddappa N. , Buch Shilpa , Ranga Udaykumar 
Published: September 2021

Abstract
Background
We observe the emergence of several promoter-variant viral strains in India during recent years. The variant viral promoters contain additional copies of transcription factor binding sites present in the viral modulatory region or enhancer, including RBEIII, LEF-1, Ap-1 and/or NF-κB. These sites are crucial for governing viral gene expression and latency. Here, we infer that one variant viral promoter R2N3-LTR containing two copies of RBF-2 binding sites (an RBEIII site duplication) and three copies of NF-κB motifs may demonstrate low levels of gene expression noise as compared to the canonical RN3-LTR or a different variant R2N4-LTR (a duplication of an RBEIII site and an NF-κB motif). To demonstrate this, we constructed a panel of sub-genomic viral vectors of promoter-variant LTRs co-expressing two reporter proteins (mScarlet and Gaussia luciferase) under the dual-control of Tat and Rev. We established stable pools of CEM.NKR-CCR5 cells (CEM-CCR5RL reporter cells) and evaluated reporter gene expression under different conditions of cell activation.

Results
The R2N3-LTR established stringent latency that was highly resistant to reversal by potent cell activators such as TNF-α or PMA, or even to a cocktail of activators, compared to the canonical RN3- or the variant R2N4-LTR. The R2N3-LTR exhibited low-level basal gene expression in the absence of cell activation that enhanced marginally but significantly when activated. In the presence of Tat and Rev, trans-complemented in the form of an infectious virus, the R2N3-LTR demonstrated gene expression at levels comparable to the wild-type viral promoter. The R2N3-LTR is responsive to Tat and Rev factors derived from viral strains representing diverse genetic subtypes.

Conclusion
With extremely low-level transcriptional noise, the R2N3-LTR can serve as an excellent model to examine the establishment, maintenance, and reversal of HIV-1 latency. The R2N3-LTR would also be an ideal viral promoter to develop high-throughput screening assays to identify potent latency-reversing agents since the LTR is not affected by the usual background noise of the cell.
Multiple phenotypic traits as triggers of host attacks towards ant symbionts: body size, morphological gestalt, and chemical mimicry accuracy
Authors: von Beeren Christoph , Brückner Adrian , Hoenle Philipp O. , Ospina-Jara Bryan , Kronauer Daniel J. C. , Blüthgen Nico 
Published: September 2021

Abstract
Background
Ant colonies are plagued by a diversity of arthropod guests, which adopt various strategies to avoid or to withstand host attacks. Chemical mimicry of host recognition cues is, for example, a common integration strategy of ant guests. The morphological gestalt and body size of ant guests have long been argued to also affect host hostility, but quantitative studies testing these predictions are largely missing. We here evaluated three guest traits as triggers of host aggression—body size, morphological gestalt, and accuracy in chemical mimicry—in a community of six Eciton army ant species and 29 guest species. We quantified ant aggression towards 314 guests in behavioral assays and, for the same individuals, determined their body size and their accuracy in mimicking ant cuticular hydrocarbon (CHC) profiles. We classified guests into the following gestalts: protective, myrmecoid, staphylinid-like, phorid-like, and larval-shaped. We expected that (1) guests with lower CHC mimicry accuracy are more frequently attacked; (2) larger guests are more frequently attacked; (3) guests of different morphological gestalt receive differing host aggression levels.

Results
Army ant species had distinct CHC profiles and accuracy of mimicking these profiles was variable among guests, with many species showing high mimicry accuracy. Unexpectedly, we did not find a clear relationship between chemical host similarity and host aggression, suggesting that other symbiont traits need to be considered. We detected a relationship between the guests’ body size and the received host aggression, in that diminutive forms were rarely attacked. Our data also indicated that morphological gestalt might be a valuable predictor of host aggression. While most ant-guest encounters remained peaceful, host behavior still differed towards guests in that ant aggression was primarily directed towards those guests possessing a protective or a staphylinid-like gestalt.

Conclusion
We demonstrate that CHC mimicry accuracy does not necessarily predict host aggression towards ant symbionts. Exploitation mechanisms are diverse, and we conclude that, besides chemical mimicry, other factors such as the guests’ morphological gestalt and especially their body size might be important, yet underrated traits shaping the level of host hostility against social insect symbionts.
HoMEcare aRm rehabiLItatioN (MERLIN): preliminary evidence of long term effects of telerehabilitation using an unactuated training device on upper limb function after stroke
Authors: Rozevink Samantha G. , van der Sluis Corry K. , Hijmans Juha M. 
Published: September 2021

AbstractBackgroundWhile short term effects on upper limb function of stroke patients after training with robotic devices have been studied extensively, long term effects are often not addressed. HoMEcare aRm rehabiLItatioN (MERLIN) is a combination of an unactuated training device using serious games and a telerehabilitation platform in the patient’s home situation. Short term effects showed that upper limb function improved after training with MERLIN. The aim was to determine long term effects on upper limb function and quality of life.MethodsSix months after cessation of the 6 week MERLIN training program, the upper limb function and quality of life of 11 chronic stroke patients were assessed. Upper limb function was measured using the Wolf Motor Function Test (WMFT), Action Research Arm Test (ARAT) and Fugl-Meyer Assessment-Upper Extremity (FMA-UE). EuroQoL-5D (EQ-5D) was used to measure quality of life.ResultsThe WMFT, ARAT and EQ-5D did not show significant differences 6 months after the training period compared to directly after training. At 6 months follow-up, FMA-UE results were significantly better than at baseline. Time plots showed a decreasing trend in all tests.ConclusionTraining effects were still present at 6 months follow-up, since arm function seemed similar to directly after training and FMA-UE results were better than at baseline. However, because of the decreasing trend shown in all tests, it is questionable if improvements will be maintained longer than 6 months. Due to the sample size and study design, results should be interpreted with caution.Trial registration This study is registered at the Netherlands Trial Register (NL7535). Registered 18-02-2019,https://www.trialregister.nl/trial/7535