bluuebunny/crossref_metadata_2025 huggingface dataset:
IL-6-induced skeletal muscle atrophy
Authors: Haddad F. , Zaldivar F. , Cooper D. M. , Adams G. R.
Published: November 2004

Chronic, low-level elevation of circulating interleukin (IL)-6 is observed in disease states as well as in many outwardly healthy elderly individuals. Increased plasma IL-6 is also observed after intense, prolonged exercise. In the context of skeletal muscle, IL-6 has variously been reported to regulate carbohydrate and lipid metabolism, increase satellite cell proliferation, or cause muscle wasting. In the present study, we used a rodent local infusion model to deliver modest levels of IL-6, comparable to that present after exercise or with chronic low-level inflammation in the elderly, directly into a single target muscle in vivo. The aim of this study was to examine the direct effects of IL-6 on skeletal muscle in the absence of systemic changes in this cytokine. Data included cellular and molecular markers of cytokine and growth factor signaling (phosphorylation and mRNA content) as well as measurements to detect muscle atrophy. IL-6 infusion resulted in muscle atrophy characterized by a preferential loss of myofibrillar protein (−17%). IL-6 induced a decrease in the phosphorylation of ribosomal S6 kinase (−60%) and STAT5 (−33%), whereas that of STAT3 was increased approximately twofold. The changes seen in the IL-6-infused muscles suggest alterations in the balance of growth factor-related signaling in favor of a more catabolic profile. This suggests that downregulation of growth factor-mediated intracellular signaling may be a mechanism contributing to the development of muscle atrophy induced by elevated IL-6.
Spike-triggered average torque and muscle fiber conduction velocity of low-threshold motor units following submaximal endurance contractions
Authors: Farina Dario , Arendt-Nielsen Lars , Graven-Nielsen Thomas
Published: November 2004

The motor unit twitch torque is modified by sustained contraction, but the association to changes in muscle fiber electrophysiological properties is not fully known. Thus twitch torque, muscle fiber conduction velocity, and action potential properties of single motor units were assessed in 11 subjects following an isometric submaximal contraction of the tibialis anterior muscle until endurance. The volunteers activated a target motor unit at the minimum discharge rate in eight 3-min-long contractions, three before and five after an isometric contraction at 40% of the maximal torque, sustained until endurance. Multichannel surface electromyogram signals and joint torque were averaged with the target motor unit potential as trigger. Discharge rate (mean ± SE, 6.6 ± 0.2 pulses/s) and interpulse interval variability (33.3 ± 7.0%) were not different in the eight contractions. Peak twitch torque and recruitment threshold increased significantly (93 ± 29 and 12 ± 5%, P < 0.05) in the contraction immediately after the endurance task with respect to the preendurance values (0.94 ± 0.26 mN·m and 3.7 ± 0.5% of the maximal torque), whereas time to peak of the twitch torque did not change (74.4 ± 10.1 ms). Muscle fiber conduction velocity decreased and action potential duration increased in the contraction after the endurance (6.3 ± 1.8 and 9.8 ± 1.8%, respectively, P < 0.05; preendurance values, 3.9 ± 0.2 m/s and 11.1 ± 0.8 ms), whereas the surface potential peak-to-peak amplitude did not change (27.1 ± 3.1 μV). There was no significant correlation between the relative changes in muscle fiber conduction velocity or surface potential duration and in peak twitch torque ( R2 = 0.04 and 0.10, respectively). In conclusion, modifications in peak twitch torque of low-threshold motor units with sustained contraction are mainly determined by mechanisms not related to changes in action potential shape and in its propagation velocity.
PKCδ plays opposite roles in growth mediated by wild-type Kit and an oncogenic Kit mutant
Authors: Jelacic Tanya , Linnekin Diana
Published: November 2004

The Kit receptor tyrosine kinase is critical for normal hematopoiesis. Mutation of the aspartic acid residue encoded by codon 816 of human c-kit or codon 814 of the murine gene results in an oncogenic form of Kit. Here we investigate the role of protein kinase Cδ (PKCδ) in responses mediated by wild-type murine Kit and the D814Y mutant in a murine mast cell-like line. PKCδ is activated after wild-type (WT) Kit binds stem cell factor (SCF), is constitutively active in cells expressing the Kit catalytic domain mutant, and coprecipitates with both forms of Kit. Inhibition of PKCδ had opposite effects on growth mediated by wild-type and mutant Kit. Both rottlerin and a dominant-negative PKCδ construct inhibited the growth of cells expressing mutant Kit, while SCF-induced growth of cells expressing wild-type Kit was not inhibited. Further, overexpression of PKCδ inhibited growth of cells expressing wild-type Kit and enhanced growth of cells expressing the Kit mutant. These data demonstrate that PKCδ contributes to factor-independent growth of cells expressing the D814Y mutant, but negatively regulates SCF-induced growth of cells expressing wild-type Kit. This is the first demonstration that PKCδ has different functions in cells expressing normal versus oncogenic forms of a receptor.
The CXC chemokine MIP-2 stimulates neutrophil mobilization from the rat bone marrow in a CD49d-dependent manner
Authors: Burdon Peter C. E. , Martin Coralie , Rankin Sara M.
Published: November 2004

The acute release of neutrophils from the bone marrow is a critical step in their trafficking to sites of inflammation. This process is stimulated by systemically acting inflammatory mediators, such as the CXC chemokines. In this study we have used a novel in situ perfusion system of the rat femoral bone marrow to directly investigate the role of specific adhesion molecules in chemokine-stimulated neutrophil mobilization. We show here that neutrophils mobilized in response to rat macrophage inflammatory protein-2 (MIP-2) shed l-selectin and expressed significantly higher levels of CD11b and CD49d. However, inhibition of l-selectin sheddase activity with KD-IX-73-4 had no effect on the number of neutrophils mobilized in response to rat MIP-2. Blockade of CD18, using a neutralizing monoclonal antibody (mAb), did not inhibit neutrophil mobilization but unexpectedly increased the rate and number of neutrophils released from the bone marrow in response to chemokine, suggesting that CD18 could play a role in neutrophil retention within the bone marrow. Blockade of CD49d using either a selective mAb or a specific antagonist resulted in a dramatic inhibition (> 75%) of the chemokine-stimulated neutrophil mobilization from the bone marrow. These data reveal contrasting roles for CD18 and CD49d in the retention and release of neutrophils from the bone marrow.
A genomic timescale of prokaryote evolution: insights into the origin of methanogenesis, phototrophy, and the colonization of land
Authors: Battistuzzi Fabia U , Feijao Andreia , Hedges S Blair
Published: November 2004

Background

The timescale of prokaryote evolution has been difficult to reconstruct because of a limited fossil record and complexities associated with molecular clocks and deep divergences. However, the relatively large number of genome sequences currently available has provided a better opportunity to control for potential biases such as horizontal gene transfer and rate differences among lineages. We assembled a data set of sequences from 32 proteins (~7600 amino acids) common to 72 species and estimated phylogenetic relationships and divergence times with a local clock method.

Results

Our phylogenetic results support most of the currently recognized higher-level groupings of prokaryotes. Of particular interest is a well-supported group of three major lineages of eubacteria (Actinobacteria, Deinococcus, and Cyanobacteria) that we call Terrabacteria and associate with an early colonization of land. Divergence time estimates for the major groups of eubacteria are between 2.5–3.2 billion years ago (Ga) while those for archaebacteria are mostly between 3.1–4.1 Ga. The time estimates suggest a Hadean origin of life (prior to 4.1 Ga), an early origin of methanogenesis (3.8–4.1 Ga), an origin of anaerobic methanotrophy after 3.1 Ga, an origin of phototrophy prior to 3.2 Ga, an early colonization of land 2.8–3.1 Ga, and an origin of aerobic methanotrophy 2.5–2.8 Ga.

Conclusions

Our early time estimates for methanogenesis support the consideration of methane, in addition to carbon dioxide, as a greenhouse gas responsible for the early warming of the Earths' surface. Our divergence times for the origin of anaerobic methanotrophy are compatible with highly depleted carbon isotopic values found in rocks dated 2.8–2.6 Ga. An early origin of phototrophy is consistent with the earliest bacterial mats and structures identified as stromatolites, but a 2.6 Ga origin of cyanobacteria suggests that those Archean structures, if biologically produced, were made by anoxygenic photosynthesizers. The resistance to desiccation of Terrabacteria and their elaboration of photoprotective compounds suggests that the common ancestor of this group inhabited land. If true, then oxygenic photosynthesis may owe its origin to terrestrial adaptations.
Comparison of frozen and RNALater solid tissue storage methods for use in RNA expression microarrays
Authors: Mutter George L , Zahrieh David , Liu Chunmei , Neuberg Donna , Finkelstein David , Baker Heather E , Warrington Janet A
Published: November 2004

Background

Primary human tissues are an invaluable widely used tool for discovery of gene expression patterns which characterize disease states. Tissue processing methods remain unstandardized, leading to unanswered concerns of how to best store collected tissues and maintain reproducibility between laboratories. We subdivided uterine myometrial tissue specimens and stored split aliquots using the most common tissue processing methods (fresh, frozen, RNALater) before comparing quantitative RNA expression profiles on the Affymetrix U133 human expression array. Split samples and inclusion of duplicates within each processing group allowed us to undertake a formal genome-wide analysis comparing the magnitude of result variation contributed by sample source (different patients), processing protocol (fresh vs. frozen vs. 24 or 72 hours RNALater), and random background (duplicates). The dataset was randomly permuted to define a baseline pattern of ANOVA test statistic values against which the observed results could be interpreted.

Results

14,639 of 22,283 genes were expressed in at least one sample. Patient subjects provided the greatest sources of variation in the mixed model ANOVA, with replicates and processing method the least. The magnitude of variation conferred by processing method (24 hours RNALater vs 72 hours RNALater vs. fresh vs frozen) was similar to the variability seen within replicates. Subset analysis of the test statistic according to gene functional class showed that the frequency of "outlier" ANOVA results within each functional class is overall no greater than expected by chance.

Conclusions

Ambient storage of tissues for 24 or 72 hours in RNALater did not contribute any systematic shift in quantitative RNA expression results relative to the alternatives of fresh or frozen tissue. This nontoxic preservative enables decentralized tissue collection for expression array analysis without a requirement for specialized equipment.
Rationale and design of a multicenter randomized controlled trial on a 'minimal intervention' in Dutch army personnel with nonspecific low back pain [ISRCTN19334317]
Authors: Helmhout Pieter H , Harts Chris C , Staal J Bart , de Bie Rob A
Published: November 2004

Background

Researchers from the Royal Netherlands Army are studying the potential of isolated lumbar extensor training in low back pain in their working population. Currently, a randomized controlled trial is carried out in five military health centers in The Netherlands and Germany, in which a 10-week program of not more than 2 training sessions (10–15 minutes) per week is studied in soldiers with nonspecific low back pain for more than 4 weeks. The purpose of the study is to investigate the efficacy of this 'minimal intervention program', compared to usual care. Moreover, attempts are made to identify subgroups of different responders to the intervention.

Methods

Besides a baseline measurement, follow-up data are gathered at two short-term intervals (5 and 10 weeks after randomization) and two long-term intervals (6 months and one year after the end of the intervention), respectively. At every test moment, participants fill out a compound questionnaire on a stand-alone PC, and they undergo an isometric back strength measurement on a lower back machine.

Primary outcome measures in this study are: self-assessed degree of complaints and degree of handicap in daily activities due to back pain. In addition, our secondary measurements focus on: fear of movement/(re-) injury, mental and social health perception, individual back extension strength, and satisfaction of the patient with the treatment perceived. Finally, we assess a number of potential prognostic factors: demographic and job characteristics, overall health, the degree of physical activity, and the attitudes and beliefs of the physiotherapist towards chronic low back pain.

Discussion

Although a substantial number of trials have been conducted that included lumbar extension training in low back pain patients, hardly any study has emphasized a minimal intervention approach comparable to ours. For reasons of time efficiency and patient preferences, this minimal sports medicine approach of low back pain management is interesting for the population under study, and possibly for comparable working populations with physical demanding job activities.
Nursing home residents with multiple sclerosis: comparisons of African American residents to white residents at admission
Authors: Buchanan Robert J , Martin Raymond A , Zuniga Miguel , Wang Suojin , Kim MyungSuk
Published: November 2004

This research profiles African American residents with multiple sclerosis (MS) at admission to the nursing facility and compares them to profiles of white residents with MS using the Minimum Data Set (MDS). We analysed MDS admission assessments for 1367 African Americans with MS and 9294 whites with MS. African American residents with MS were significantly younger at admission than white residents with MS, with almost one half of these African Americans 50 years or younger compared to only one quarter of these whites. African American residents with MS were significantly more physically disabled and cognitively impaired at admission than white residents with MS. Although there were significant racial differences in disability, there were no significant racial differences among these MS residents in the use of various therapies provided by qualified therapists. These observed racial differences among MS residents in disease manifestations, severity, progression and disability are due to multiple variables and point out the need for more research. By combining discoveries from genetics, immunology, epidemiology and virology we can gain a better understanding of the complex pathophysiology of MS and develop more effective treatments and preventive measures. Our findings also indicate potential racial disparities in the use of MS-related care, illustrating that a greater outreach effort may be needed to evaluate and treat African Americans with MS.
Estimation of the macromolecular proton fraction and bound pool T2 in multiple sclerosis
Authors: GR Davies , DJ Tozer , M Cercignani , A Ramani , CM Dalton , AJ Thompson , GJ Barker , PS Tofts , DH Miller
Published: November 2004

This study used a model for magnetization transfer (MT) to estimate two underlying parameters: the macromolecular proton fraction (f) and the bound pool T2 (T2b) in patients with multiple sclerosis (MS). Sixty patients with clinically definite MS and 27 healthy controls were imaged using: (1) a dual echo fast spin echo sequence, (2) a MT sequence (with ten MT power and offset frequency combinations) and (3) proton density and T1 weighted sequences (for T1 relaxation time estimation). Fourteen normal-appearing white matter (NAWM) regions of interest (ROI) and six normal-appearing gray matter (NAGM) ROIs were outlined in all subjects. Lesions were also contoured in subjects affected by MS. The model was fitted to the data leading to estimates of T2b and f. Results showed that T2b was increased in lesions whereas f was reduced. In NAWM, f was decreased while T2b was only increased in secondary progressive MS. NAWM f correlated modestly with disability. Further studies are needed to investigate the pathological basis of the abnormalities observed.
Multiple sclerosis and celiac disease: is there an increased risk?
Authors: Salvatore S , Finazzi S , Ghezzi A , Tosi A , Barassi A , Luini C , Bettini B , Zibetti A , Nespoli L , d'Eril G V.Melzi
Published: November 2004

Multiple sclerosis and celiac disease are both considered immune-mediated diseases. Recently, improved serological screening methods provided a higher prevalence of celiac disease (CD) in the general population worldwide and also demonstrated gastrointestinal symptoms may be lacking. The aim of this study was to determine the prevalence of (CD) in an unselected group of 95 adults with multiple sclerosis using transglutaminase antibodies. No patients showed pathological values. Different immune and genetic basis between the two diseases may represent crucial insights to explain our results.
CD45 (PTPRC) as a candidate gene in multiple sclerosis
Authors: Vyshkina Tamara , Leist Thomas P , Shugart Yin Yao , Kalman Bernadette
Published: November 2004

The 77C→ G polymorphism in exon 4 of CD45 or protein tyrosine phosphatase receptor-type C (PTPRC) has been investigated in families with multiple sclerosis (MS) and in several cohorts of sporadic patients and controls, however, with conflicting results. To better understand the role of this functionally important polymorphism in MS, we investigated the transmission of the ‘G’ allele from unaffected parents to their affected children in 176 families by using linkage and association statistics. The ‘G’ allele was transmitted to the affected offspring in five of the seven pedigrees carrying this allele and the TRANSMIT program detected association with a P -0.0342. We conclude that the 77C→ G PTPRC polymorphism is present and preferentially transmitted in a small subgroup (< 5%) of MS families, which may only be detected with complementary methods of analysis.
Prothrombin Complex Concentrate vs Conservative Management in ICH Associated With Direct Oral Anticoagulants
Authors: Ip Bonaventure , Pan Sangqi , Yuan Zhong , Hung Trista , Ko Ho , Leng Xinyi , Liu Yuying , Li Shuang , Lee Sing Yau , Cheng Cyrus , Chan Howard , Mok Vincent , Soo Yannie , Wu Xiaoli , Lui Leong Ting , Chan Rosa , Abrigo Jill , Dou Qi , Seiffge David , Leung Thomas
Published: February 2024

Importance

Intracerebral hemorrhage (ICH) associated with direct oral anticoagulant (DOAC) use carries extremely high morbidity and mortality. The clinical effectiveness of hemostatic therapy is unclear.

Objective

To compare the clinical and radiological outcomes of DOAC-associated ICH treated with prothrombin complex concentrate (PCC) vs conservative management.

Design, Setting, and Participants

In this population-based, propensity score–weighted retrospective cohort study, patients who developed DOAC-associated ICH from January 1, 2016, to December 31, 2021, in Hong Kong were identified. The outcomes of patients who received 25 to 50 IU/kg PCC with those who received no hemostatic agents were compared. Data were analyzed from May 1, 2022, to June 30, 2023.

Main Outcomes and Measures

The primary outcome was modified Rankin scale of 0 to 3 or returning to baseline functional status at 3 months. Secondary outcomes were mortality at 90 days, in-hospital mortality, and hematoma expansion. Weighted logistic regression was performed to evaluate the association of PCC with study outcomes. In unweighted logistic regression models, factors associated with good neurological outcome and hematoma expansion in DOAC-associated ICH were identified.

Results

A total of 232 patients with DOAC-associated ICH, with a mean (SD) age of 77.2 (9.3) years and 101 (44%) female patients, were included. Among these, 116 (50%) received conservative treatment and 102 (44%) received PCC. Overall, 74 patients (31%) patients had good neurological recovery and 92 (39%) died within 90 days. Median (IQR) baseline hematoma volume was 21.7 mL (3.6-66.1 mL). Compared with conservative management, PCC was not associated with improved neurological recovery (adjusted odds ratio [aOR], 0.62; 95% CI, 0.33-1.16; P = .14), mortality at 90 days (aOR, 1.03; 95% CI, 0.70-1.53; P = .88), in-hospital mortality (aOR, 1.11; 95% CI, 0.69-1.79; P = .66), or reduced hematoma expansion (aOR, 0.94; 95% CI, 0.38-2.31; P = .90). Higher baseline hematoma volume, lower Glasgow coma scale, and intraventricular hemorrhage were associated with lower odds of good neurological outcome but not hematoma expansion.

Conclusions and Relevance

In this cohort study, Chinese patients with DOAC-associated ICH had large baseline hematoma volumes and high rates of mortality and functional disability. PCC treatment was not associated with improved functional outcome, hematoma expansion, or mortality. Further studies on novel hemostatic agents as well as neurosurgical and adjunctive medical therapies are needed to identify the best management algorithm for DOAC-associated ICH.
Trends in Firearm Injury Prevention Research Funding, Clinical Trials, and Publications in the US, 1985-2022
Authors: Lin John C. , Chang Christopher , McCarthy Madison S. , Baker-Butler Abe , Tong Guangyu , Ranney Megan L.
Published: February 2024

This cross-sectional study examines federal funding, registered clinical trials, and publications to quantify trends in firearm injury prevention research in the US from 1985 to 2022.
Characterization of fish‐specific IFNγ‐related binding with a unique receptor complex and signaling through a novel pathway
Authors: Shibasaki Yasuhiro , Yabu Takeshi , Shiba Hajime , Moritomo Tadaaki , Mano Nobuhiro , Nakanishi Teruyuki
Published: February 2024

Unlike mammals, fish express two type II interferons, IFNγ and fish‐specific IFNγ (IFNγ‐related or IFNγrel). We previously reported the presence of two IFNγrel genes, IFNγrel 1 and IFNγrel 2, which exhibit potent antiviral activity in the Ginbuna crucian carp, Carassius auratus langsdorfii. We also found that IFNγrel 1 increased allograft rejection; however, the IFNγrel 1 receptor(s) and signaling pathways underlying this process have not yet been elucidated. In this study, we examined the unique signaling mechanism of IFNγrel 1 and its receptors. The phosphorylation and transcriptional activation of STAT6 in response to recombinant Ginbuna IFNγrel 1 (rgIFNγrel 1) was observed in Ginbuna‐derived cells. Binding of rgIFNγrel 1 to Class II cytokine receptor family members (Crfbs), Crfb5 and Crfb17, which are also known as IFNAR1 and IFNGR1‐1, respectively, was detected by flow cytometry. Expression of the IFNγrel 1‐inducible antiviral gene, Isg15, was highest in Crfb5‐ and Crfb17‐overexpressing GTS9 cells. Dimerization of Crfb5 and Crfb17 was detected by chemical crosslinking. The results indicate that IFNγrel 1 activates Stat6 through an interaction with unique pairs of receptors, Crfb5 and Crfb17. Indeed, this cascade is distinct from not only that of IFNγ but also that of known IFNs in other vertebrates. IFNs may be classified by their receptor and signal transduction pathways. Taken together, IFNγrel 1 may be classified as a novel type of IFN family member in vertebrates. Our findings provide important information on interferon gene evolution in bony fish.
Automatic end‐to‐end VMAT treatment planning for rectal cancers
Authors: Huang Kai , Chung Christine , Ludmir Ethan B. , Zhang Lifei , Owens Constance A. , Vega Jean Gumma‐De La , Duryea Jack , Zhao Yao , Chen Xinru , Fuentes David , Cardenas Carlos E. , Briere Tina Marie , Beddar Sam , Court Laurence E. , Das Prajnan
Published: February 2024

Background

The treatment planning process from segmentation to producing a deliverable plan is time‐consuming and labor‐intensive. Existing solutions automate the segmentation and planning processes individually. The feasibility of combining auto‐segmentation and auto‐planning for volumetric modulated arc therapy (VMAT) for rectal cancers in an end‐to‐end process is not clear.

Purpose

To create and clinically evaluate a complete end‐to‐end process for auto‐segmentation and auto‐planning of VMAT for rectal cancer requiring only the gross tumor volume contour and a CT scan as inputs.

Methods

Patient scans and data were retrospectively selected from our institutional records for patients treated for malignant neoplasm of the rectum. We trained, validated, and tested deep learning auto‐segmentation models using nnU‐Net architecture for clinical target volume (CTV), bowel bag, large bowel, small bowel, total bowel, femurs, bladder, bone marrow, and female and male genitalia. For the CTV, we identified 174 patients with clinically drawn CTVs. We used data for 18 patients for all structures other than the CTV. The structures were contoured under the guidance of and reviewed by a gastrointestinal (GI) radiation oncologist. The predicted results for CTV in 35 patients and organs at risk (OAR) in six patients were scored by the GI radiation oncologist using a five‐point Likert scale. For auto‐planning, a RapidPlan knowledge‐based planning solution was modeled for VMAT delivery with a prescription of 25 Gy in five fractions. The model was trained and tested on 20 and 34 patients, respectively. The resulting plans were scored by two GI radiation oncologists using a five‐point Likert scale. Finally, the end‐to‐end pipeline was evaluated on 16 patients, and the resulting plans were scored by two GI radiation oncologists.

Results

In 31 of 35 patients, CTV contours were clinically acceptable without necessary modifications. The CTV achieved a Dice similarity coefficient of 0.85 (±0.05) and 95% Hausdorff distance of 15.25 (±5.59) mm. All OAR contours were clinically acceptable without edits, except for large and small bowel which were challenging to differentiate. However, contours for total, large, and small bowel were clinically acceptable. The two physicians accepted 100% and 91% of the auto‐plans. For the end‐to‐end pipeline, the two physicians accepted 88% and 62% of the auto‐plans.

Conclusions

This study demonstrated that the VMAT treatment planning technique for rectal cancer can be automated to generate clinically acceptable and safe plans with minimal human interventions.
Automatic image quality evaluation in digital radiography using for‐processing and for‐presentation images
Authors: Tsalafoutas Ioannis A. , AlKhazzam Shady , Tsapaki Virginia , Kharita Mohammed Hassan
Published: February 2024

Purpose

To investigate the impact of digital image post‐processing algorithms on various image quality (IQ) metrics of radiographic images under different exposure conditions.

Methods

A custom‐made phantom constructed according to the instructions given in the IAEA Human Health Series No.39 publication was used, along with the respective software that automatically calculates various IQ metrics. Images with various exposure parameters were acquired with a digital radiography unit, which for each acquisition produces two images: one for‐processing (raw) and one for‐presentation (clinical). Various examination protocols were used, which incorporate diverse post‐processing algorithms. The IQ metrics’ values (IQ‐scores) obtained were analyzed to investigate the effects of increasing incident air kerma (IAK) on the image receptor, tube potential (kVp), additional filtration, and examination protocol on image quality, and the differences between image type (raw or clinical).

Results

The IQ‐scores were consistent for repeated identical exposures for both raw and clinical images. The effect that changes in exposure parameters and examination protocol had on IQ‐scores were different depending on the IQ metric and image type. The expected positive effect that increasing IAK and decreasing tube potential should have on IQ was clearly exhibited in two IQ metrics only, the signal difference‐to‐noise‐ratio (SDNR) and the detectability index (d’), for both image types. No effect of additional filtration on any of the IQ metrics was detected on images of either type. An interesting finding of the study was that for all different image acquisition selections the d’ scores were larger in raw images, whereas the other IQ metrics were larger in clinical images for most of the cases.

Conclusions

Since IQ‐scores of raw and their respective clinical images may be largely different, the same type of image should be consistently used for monitoring IQ constancy and when results from different X‐ray systems are compared.
SPTLC2 variants are associated with early‐onset ALS and FTD due to aberrant sphingolipid synthesis
Authors: Naruse Hiroya , Ishiura Hiroyuki , Esaki Kayoko , Mitsui Jun , Satake Wataru , Greimel Peter , Shingai Nanoka , Machino Yuka , Kokubo Yasumasa , Hamaguchi Hirotoshi , Oda Tetsuya , Ikkaku Tomoko , Yokota Ichiro , Takahashi Yuji , Suzuki Yuta , Matsukawa Takashi , Goto Jun , Koh Kishin , Takiyama Yoshihisa , Morishita Shinichi , Yoshikawa Takeo , Tsuji Shoji , Toda Tatsushi
Published: February 2024

Objective

Amyotrophic lateral sclerosis (ALS) is a devastating, incurable neurodegenerative disease. A subset of ALS patients manifests with early‐onset and complex clinical phenotypes. We aimed to elucidate the genetic basis of these cases to enhance our understanding of disease etiology and facilitate the development of targeted therapies.

Methods

Our research commenced with an in‐depth genetic and biochemical investigation of two specific families, each with a member diagnosed with early‐onset ALS (onset age of <40 years). This involved whole‐exome sequencing, trio analysis, protein structure analysis, and sphingolipid measurements. Subsequently, we expanded our analysis to 62 probands with early‐onset ALS and further included 440 patients with adult‐onset ALS and 1163 healthy controls to assess the prevalence of identified genetic variants.

Results

We identified heterozygous variants in the serine palmitoyltransferase long chain base subunit 2 (SPTLC2) gene in patients with early‐onset ALS. These variants, located in a region closely adjacent to ORMDL3, bear similarities to SPTLC1 variants previously implicated in early‐onset ALS. Patients with ALS carrying these SPTLC2 variants displayed elevated plasma ceramide levels, indicative of increased serine palmitoyltransferase (SPT) activity leading to sphingolipid overproduction.

Interpretation

Our study revealed novel SPTLC2 variants in patients with early‐onset ALS exhibiting frontotemporal dementia. The combination of genetic evidence and the observed elevation in plasma ceramide levels establishes a crucial link between dysregulated sphingolipid metabolism and ALS pathogenesis. These findings expand our understanding of ALS's genetic diversity and highlight the distinct roles of gene defects within SPT subunits in its development.
Finite‐dimensional, output‐predictor‐based, adaptive observer for heat PDEs with sensor delay
Authors: Rafia H. , Benabdelhadi A. , Giri F. , Ouadi H. , Chaoui F. Z.
Published: February 2024

We are considering the problem of designing observers for heat partial differential equations (PDEs) that are subject to sensor delay and parameter uncertainty. In order to get finite‐dimensional observers, described by ordinary differential equations (ODE), we develop a design method based on the modal decomposition approach. The approach is extended so that both parameter uncertainty and sensor delay effects are compensated for. To cope more effectively with sensor delay, an output predictor is designed and the online provided output predictions are substituted to the future output values in the observer. To compensate for parameter uncertainty, we design a parameter estimator providing online parameter estimates, which are substituted to the unknown parameters in the observer. The parameter estimator design is made decoupled from the observer gain design by using an appropriate decoupling transformation. Using an analysis of the small‐gain‐theorem type, the whole (state and parameter) estimation error system is shown to be exponentially stable, under well‐defined conditions on the observer dimension, the sensor delay, and signal persistent excitation (PE).
Multifunctional Dual Network Hydrogel Loaded with Novel Tea Polyphenol Magnesium Nanoparticles Accelerates Wound Repair of MRSA Infected Diabetes
Authors: Hu Xulin , He Jian , Qiao Liang , Wang Chun , Wang Yao , Yu Rongxin , Xu Wei , Wang Fan , Yang Shuhao , Zhang Xiangchun , Qian Zhiyong
Published: February 2024

Methicillin‐resistant Staphylococcus aureus (MRSA) biofilm infection, caused by impaired glucose metabolism in diabetic foot patients, poses a significant obstacle to the healing process and carries a high risk of being life‐threatening. Due to microvascular occlusion and the entrenchment of MRSA biofilms in diabetic foot, controlling and effectively treating MRSA infection remains challenging. Traditional hydrogels suffer from swelling‐related mechanical issues and inadequate drug release control, limiting their applications as biomimetic extracellular matrices for wound healing. Herein, a double‐network hydrogel composed of polyvinyl alcohol, sodium alginate, and gelatin (PSG) loaded with tea polyphenol self‐assembled magnesium nanoparticles (TP‐Mg NPs) with antibacterial and angiogenic properties for treating MRSA‐infected diabetic foot wounds under hyperglycemic conditions is constructed. TP‐Mg@PSG exhibits enhanced mechanical strength and toughness for wound attachment and recovery movement torsion. In the acidic infection microenvironment representative of MRSA‐infected wounds, the TP‐Mg@PSG hydrogel degrades to release TP‐Mg NPs, showing excellent anti‐MRSA biofilm effect and high biocompatibility. Such localized controlled release enhances the inhibition of MRSA infection and reduces the inflammatory response in rats, promoting cell proliferation and rapid wound repair. Therefore, this study presents a multifunctional biomaterial system for managing diabetic foot conditions, highlighting its potential for clinical applications.
Manipulation of Surface Electrical Charge on Nanocomposite Membranes Confers Wide Spectrum Bactericidal Effects and Promotes Tissue Regeneration
Authors: Song Jia , Lu Yanhui , Pan Ting , Wang Jianfeng , Liu Ziqi , Xu Lei , Zhang Siqi , Li Yiping , Bai Yunyang , Heng Boon Chin , Zheng Xiaona , Wu Haoyan , Han Xiaoyu , Guo Yusi , Cui Qun , Deng Xuliang , Zhang Xuehui
Published: February 2024

Utilization of electro‐responsive biomaterials with antibacterial properties is advantageous for facilitating septic wound healing and tissue regeneration. However, the dose‐response effects of electrical stimuli from these materials against bacteria are not rigorously characterized, and achieving synergy of bactericidal and pro‐regenerative effects of biomaterials remains a major challenge. Here, a graded series of flexible BaTiO3/P(VDF‐TrFE) electroactive nanocomposite membranes (EMs) are developed with varying surface charge intensities, to serve as antibacterial dressing for septic wound healing. EMs display broad‐spectrum antibacterial effects against both Gram‐positive and Gram‐negative bacteria in a dose‐dependent manner, depending on the magnitude of their surface electrical potential. Mechanistically, the surface charge of EMs increase intracellular levels of reactive oxygen species within bacteria cells, which in turn caused oxidative damage to the bacterial membrane, thereby suppressing bacterial activity and biofilm formation. Moreover, in vivo studies demonstrated that EMs effectively inhibited S. aureus infection and accelerated wound healing in a mouse skin defect model, as well as ameliorated P. gingivalis‐mediated periodontal inflammation in a mouse periodontitis model. Hence, this study optimizes the antibacterial properties of electroactive materials and characterizes the dose‐response effects of surface electrical charge against bacteria, thus validating the therapeutic applications of electroactive biomaterials in combating bacterial infection.
Mechanically Programmable Composite Metamaterials with Switchable Positive/Negative Poisson's Ratio
Authors: Du Lamei , Shi Wei , Gao Han , Jia Hongxing , Zhang Qiuting , Liu Mingjie , Xu Ye
Published: February 2024

Design of mechanical metamaterials with a negative Poisson's ratio (NPR), known as auxetics, is of great importance in the development of flexible electronics and tissue engineering. However, the mechanical performance of conventional auxetic metamaterials is largely hindered by the high porosity and lack of tunability, which restricts their practical engineering applications. Here, this study presents a programmable approach for designing integrated two‐phase auxetic composite metamaterials with pore‐free structure, robust interfaces, and customized mechanical properties by substituting the vacancy of the auxetic lattices (frame phase) with hydrogel‐based soft fillers (matrix phase). Manipulated by two‐phase stiffness contrast, integrated composite metamaterials exhibit a functional transition between auxetic and non‐auxetic behaviors. Rationally designing Young's modulus ratios in spatial domains endows the programming of composite metamaterials with the desired spatial heterogeneity. Furthermore, the incorporation of temperature‐responsive hydrogels to auxetic frames also enbles the development of dynamic programmable composites with the thermo‐driven adaptability. As a practical application demonstration, designed programmable composites are used to dynamically tune the phononic bandgaps. The design strategy of integrated two‐phase composite metamaterials paves the way for the development of advanced auxetic engineering materials with programmable mechanical properties, providing opportunity for conformal electronic patches, bio‐scaffolds, and smart functionality applications.
Light‐Responsive Nanoassemblies: Advancing Biomedical Innovation
Authors: Sia Chin Siew , Tey Beng Ti , Low Liang Ee
Published: February 2024

The integrative use of light and nanoassemblies has made a profound impact in the biomedical field for diagnosis, drug delivery, and phototherapy. Recent advances in the development of light‐responsive nanoassemblies showcase their capabilities in facilitating targeted diagnosis and therapy with minimal invasiveness, shaping the future of personalized medicine. In this work, the fundamental differences between types of light in biomedical applications, and the application of light‐responsive nanoassemblies in diagnosis and therapy are described, their biosafety profile is overviewed and discussed, and the translational challenges and potential clinical outlook of this emerging field are outlined.
Insights into Civilian Electromagnetic Absorption Materials: Challenges and Innovative Solutions
Authors: Lv Hualiang , Cui Jiacheng , Li Bangxin , Yuan Mingyue , Liu Jiajun , Che Renchao
Published: February 2024

The emergence and widespread adoption of fifth‐generation wireless technology in civilian sectors have advanced the information revolution, while simultaneously leading to a variety of negative impacts. Foremost issues in the civilian domain include electromagnetic (EM) pollution, interference, and the inefficient use of EM energy. Despite growing global awareness, progress in devising effective solutions is sluggish, underlining the complexity of these issues. The delay in addressing EM concerns arises from several factors, including a considerable gap in comprehensive understanding and the absence of a unified stance on these critical issues. Moreover, the emergence of new challenges like EM interference and energy inefficiency indicates a clear need for innovative ideas and approaches. Addressing these civilian issues extends beyond the inherent properties of EM absorbers, requiring combination of tailored macro‐structural designs and external energy field management for a comprehensive solution. This situation emphasizes the urgent need for diverse strategies and creative thinking to navigate the challenges posed by the civilian EM issues. This perspective underscores these identified challenges and systematically proposes practical approaches to each, aiming to foster both conversation and action in this crucial area. The insights provided are expected to substantially aid in confronting and alleviating these pressing EM concerns.
Bio‐Inspired Porous Microneedles Dwelled Stem Cells for Diabetic Wound Treatment
Authors: Fan Lu , Zhang Xiaoxuan , Wang Li , Song Yizuo , Yi Kexin , Wang Xiaoju , Zhang Hongbo , Li Ling , Zhao Yuanjin
Published: February 2024

Diabetic wound healing is a serious, complex, and chronic process; one current promising and focusing technology in this area is stem cell treatment. Here, novel porous microneedle (MN) arrays is fabricated, which can highly mimetic stem cell niches, through template filling, and particle etching method. The human adipose‐derived stem cells (ADSCs) are encapsulated in Matrigel then loaded into the porous MN arrays by post‐perfusion. Because of the extracellular matrix‐mimicking, the biocompatible Matrigel offers a bionic microenvironment of stem cell nest suitable for growth. Benefiting from the numerous pore structures of MNs, the loaded ADSCs have enough space to fully absorb nutrients, proliferate greatly and exhibit prompted function. In addition, the cell‐loaded MN arrays have enough mechanical strength to penetrate the skin, allowing the ADSCs to get into the deep wound areas. Based on these features, the performance of the resultant MN arrays in promoting tissue regeneration is demonstrated, collagen deposition and angiogenesis in diabetes wounds of rat models. Thus, it is believe that the bioinspired porous MNs can act as excellent stem cell scaffolds and will find many practical values in clinic wound healing.
Integrated Bilayer Microneedle Dressing and Triboelectric Nanogenerator for Intelligent Management of Infected Wounds
Authors: Wang Kun , Ding Qihang , Qi Manlin , Zhang Wei , Hou Yuxiao , Cao Ruida , Li Chunyan , Xu Lin , Wang Lin , Kim Jong Seung
Published: February 2024

The integration of real‐time monitoring and on‐demand treatment has substantial potential to accelerate wound healing processes. In this context, versatile bilayer microneedles (MNs) and a triboelectric nanogenerator (TENG) are developed as a theranostic platform for efficient wound management. This platform provides benefits including controlling infection, promoting cell migration and proliferation, and the capability for biochemical sensing. The bilayer MNs comprise a solvable polyvinylpyrrolidone MN (pMN) affixed atop a conductive stainless‐steel MN (sMN). The robust sMN penetrates the requisite skin depth, while the pMN, infused with antibiotics, ensures sustained drug release upon dissolution in the interstitial fluids. Concurrently, the TENG generates electrical stimulation transmitted to the wound site through the conductive sMN, contributing to accelerated wound closure. Furthermore, the sMN, coated with silver and carbon nanotubes (CNT/Ag/sMN), functions as a transdermal electrochemical sensor to assess the wound state by detecting hydrogen peroxide and uric acid. Notably, in vivo animal studies have demonstrated that the MN‐TENG device not only effectively inhibits bacterial growth and expedites wound healing but also monitors wound biomarkers, thereby validating its utility in improving infected wound recovery. Consequently, this MN‐TENG based transdermal strategy fosters advancements in diagnostic and therapeutic technologies within wound management and related biomedical domains.
Bioinspired Bioinks for the Fabrication of Chemomechanically Relevant Standalone Disease Models of Hepatic Steatosis
Authors: Guagliano Giuseppe , Volpini Cristina , Sardelli Lorenzo , Briatico Vangosa Francesco , Visai Livia , Petrini Paola
Published: February 2024

Hepatotoxicity‐related issues are poorly predicted during preclinical experimentation, as its relevance is limited by the inadequacy to screen all the non‐physiological subclasses of the population. These pitfalls can be solved by implementing complex in vitro models of hepatic physiology and pathologies in the preclinical phase. To produce these platforms, extrusion‐based bioprinting is focused on, since it allows to manufacture tridimensional cell‐laden constructs with controlled geometries, in a high‐throughput manner. Different bioinks, whose formulation is tailored to mimic the chemomechanical environment of hepatic steatosis, the most prevalent hepatic disorder worldwide, are proposed. Internally crosslinked alginate hydrogels are chosen as structural components of the inks. Their viscoelastic properties (G′ = 512–730 Pa and G″ = 94–276 Pa, depending on frequency) are tuned to mimic those of steatotic liver tissue. Porcine hepatic ECM is introduced as a relevant biochemical cue. Sodium oleate is added to recall the accumulation of lipids in the tissue. Downstream analyses on 14‐layered bioprinted structures cultured for 10 days reveal the establishment of steatotic‐like features (intracellular lipid vesicles, viability decrease up to ≈50%) without needing external conditionings. The presented bioinks are thus suitable to fabricate complex models of hepatic steatosis to be implemented in a high‐throughput experimental frame.
All‐in‐One Self‐Powered Microneedle Device for Accelerating Infected Diabetic Wound Repair
Authors: Li Weikun , Liu Zonghao , Tan Xin , Yang Ning , Liang Yanling , Feng Diyi , Li Han , Yuan Renqiang , Zhang Qianli , Liu Ling , Ge Liqin
Published: February 2024

Diabetic wound healing remains a significant clinical challenge due to the complex microenvironment and attenuated endogenous electric field. Herein, a novel all‐in‐one self‐powered microneedle device (termed TZ@mMN‐TENG) is developed by combining the multifunctional microneedle carried tannin@ZnO microparticles (TZ@mMN) with the self‐powered triboelectric nanogenerator (TENG). In addition to the delivery of tannin and Zn2+, TZ@mMN also effectively conducts electrical stimulation (ES) to infected diabetic wounds. As a self‐powered device, the TENG can convert biomechanical motion into exogenous ES to accelerate the infected diabetic wound healing. In vitro experiment demonstrated that TZ@mMN shows excellent conductive, high antioxidant ability, and effective antibacterial properties against both Staphylococcus aureus and Escherichia coli (>99% antibacterial rates). Besides, the TZ@mMN‐TENG can effectively promote cell proliferation and migration. In the diabetic rat full‐thickness skin wound model infected with Staphylococcus aureus, the TZ@mMN‐TENG can eliminate bacteria, accelerate epidermal growth (regenerative epidermis: ≈303.3 ± 19.1 µm), enhance collagen deposition, inhibit inflammation (lower TNF‐α and IL‐6 expression), and promote angiogenesis (higher CD31 and VEGF expression) to accelerate infected wound repair. Overall, the TZ@mMN‐TENG provides a promising strategy for clinical application in diabetic wound repair.