Reduction in Insulin Uncovers a Novel Effect of VEGFB on Cardiac Substrate Utilization.

BACKGROUND: The heart relies heavily on external fatty acid (FA) for energy production. VEGFB (vascular endothelial growth factor B) has been shown to promote endothelial FA uptake by upregulating FA transporters. However, its impact on LPL (lipoprotein lipase)-mediated lipolysis of lipoproteins, a major source of FA for cardiac use, is unknown. METHODS: VEGFB transgenic (Tg) rats were generated by using the α-myosin heavy chain promoter to drive cardiomyocyte-specific overexpression. To measure coronary LPL activity, Langendorff hearts were perfused with heparin. In vivo positron emission tomography imaging with [18F]-triglyceride-fluoro-6-thia-heptadecanoic acid and [11C]-palmitate was used to determine cardiac FA uptake. Mitochondrial FA oxidation was evaluated by high-resolution respirometry. Streptozotocin was used to induce diabetes, and cardiac function was monitored using echocardiography. RESULTS: In Tg hearts, the vectorial transfer of LPL to the vascular lumen is obstructed, resulting in LPL buildup within cardiomyocytes, an effect likely due to coronary vascular development with its associated augmentation of insulin action. With insulin insufficiency following fasting, VEGFB acted unimpeded to facilitate LPL movement and increase its activity at the coronary lumen. In vivo PET imaging following fasting confirmed that VEGFB induced a greater FA uptake to the heart from circulating lipoproteins as compared with plasma-free FAs. As this was associated with augmented mitochondrial oxidation, lipid accumulation in the heart was prevented. We further examined whether this property of VEGFB on cardiac metabolism could be useful following diabetes and its associated cardiac dysfunction, with attendant loss of metabolic flexibility. In Tg hearts, diabetes inhibited myocyte VEGFB gene expression and protein secretion together with its downstream receptor signaling, effects that could explain its lack of cardioprotection. CONCLUSIONS: Our study highlights the novel role of VEGFB in LPL-derived FA supply and utilization. In diabetes, loss of VEGFB action may contribute toward metabolic inflexibility, lipotoxicity, and development of diabetic cardiomyopathy.

Chain-like One-Dimensional Assembly of Mesoporous Silica Nanoparticles: An Approach To Improve Hydrogel Adhesion.

Mesoporous silica nanoparticles (MSNPs) are well known for their adhesive properties with hydrogels and living tissues. However, achieving direct contact between the silica nanoparticle surface and the adherend necessitates the removal of capping agents, which can lead to severe aggregation when exposed to wet surfaces. This aggregation is ineffective for simultaneously bridging the two adherends, resulting in a reduced adhesive strength. In this study, we designed and synthesized mesoporous silica nanochains (MSNCs) to enhance the interactions with hydrogels by promoting the formation of coarser structures with increased nanopore exposure. Chain-like one-dimensional assemblies in the MSNCs were generated by depleting the capping ligand, cetyltrimethylammonium bromide, from the surface of the MSNPs. To quantify the porous areas of the MSNCs, we analyzed scanning electron microscopy (SEM) images using an in-house SEM image analysis algorithm. Additionally, we conducted a comparative assessment of the adhesion energies of MSNCs and MSNPs on a poly(dimethylacrylamide) hydrogel using a universal testing machine. The MSNCs exhibited a maximum adhesion energy of 13.7 ± 0.7 J/m2 at 3 wt %, surpassing that of MSNPs (10.9 ± 0.3 J/m2) at 2 wt %. Moreover, the unique stacking structure of the MSNCs enabled them to maintain an adhesion energy of 13.4 ± 1.0 J/m2 at a high concentration of 9 wt %, whereas the adhesion energy of MSNPs decreased to 8.2 ± 0.4 J/m2. This underscores their potential as superior hydrogel adhesives in challenging wet tissue-like environments.

Optimized Design of Hyaluronic Acid-Lipid Conjugate Biomaterial for Augmenting CD44 Recognition of Surface-Engineered NK Cells.

Triple-negative breast cancer (TNBC) presents treatment challenges due to a lack of detectable surface receptors. Natural killer (NK) cell-based adaptive immunotherapy is a promising treatment because of the characteristic anticancer effects of killing malignant cells directly by secreting cytokines and lytic granules. To maximize the cancer recognition ability of NK cells, biomaterial-mediated ex vivo cell surface engineering has been developed for sufficient cell membrane immobilization of tumor-targeting ligands via hydrophobic anchoring. In this study, we optimized amphiphilic balances of NK cell coating materials composed of CD44-targeting hyaluronic acid (HA)-poly(ethylene glycol) (PEG)-lipid to improve TNBC recognition and the anticancer effect. Changes in the modular design of our material by differentiating hydrophilic PEG length and incorporating lipid amount into HA backbones precisely regulated the amphiphilic nature of HA-PEG-lipid conjugates. The optimized biomaterial demonstrated improved anchoring into NK cell membranes and facilitating the surface presentation level of HA onto NK cell surfaces. This led to enhanced cancer targeting via increasing the formation of immune synapse, thereby augmenting the anticancer capability of NK cells specifically toward CD44-positive TNBC cells. Our approach addresses targeting ability of NK cell to solid tumors with a deficiency of surface tumor-specific antigens while offering a valuable material design strategy using amphiphilic balance in immune cell surface engineering techniques.

The 100 most-cited and 100 most-mentioned COVID-19-related radiological articles: a comparative bibliometric analysis.

OBJECTIVES: This study aimed to identify the 100 most-cited and 100 most-mentioned coronavirus disease-2019 (COVID-19)-related radiological articles and compare their characteristics. MATERIALS AND METHODS: We searched the Web of Science and Altmetric.com using the search terms "COVID," "COVID-19," "Coronavirus," "SARS-CoV-2," "nCoV," and "pandemic" to identify the most-cited and most-mentioned COVID-19-related articles. We identified the top 100 most-cited and 100 most-mentioned articles in the field of radiology, regardless of their publication journal. We extracted the information from the listed articles and compared the characteristics between the most-cited and most-mentioned. RESULTS: Thirty (30%) articles were featured in the lists of the most-cited and most-mentioned articles. The comparison of the 100 most-cited and most-mentioned articles on each list showed that the most frequently cited articles were published in November 2020 and before (p < .001), originated from China (p < .001), covered the topic of diagnosis of COVID-19 (p < .001), and were related to the subspecialty of pulmonary imaging (p < .001); the most frequently mentioned articles were published in December 2020 and after (p < .001), originated from the USA (p < .001), covered the topic of diagnosis of sequelae of COVID-19 (p = .013) and post-vaccination complications (p < .001), and were related to the subspecialties of cardiac imaging (p < .001) and neuroradiology (p < .013). CONCLUSION: Significant differences were observed in publication date, country of origin, topic, and subspecialty of scientific knowledge related to COVID-19 in the field of radiology, between citation and public dissemination. CLINICAL RELEVANCE STATEMENT: This bibliometric analysis compares the 100 most-cited and 100 most-mentioned COVID-19-related radiologic articles, aiming to provide valuable insights into the patterns of knowledge dissemination during the pandemic era. KEY POINTS: • Thirty articles were featured on the lists of the 100 most-cited and 100 most-mentioned COVID-19-related articles. • The 70 unique most-cited articles more frequently originated from China (48.6%), while the unique most-mentioned articles more frequently originated from the USA (51.4%) (p < 0.001). • The 70 unique most-mentioned articles were more frequently related to cardiac imaging (25.7% vs.0%, p < 0.001) and neuroradiology (15.7% vs. 1.4%, p < 0.005) compared to the unique most-mentioned articles.

Investigating the safety profiles of exogenous melatonin and associated adverse events: A pharmacovigilance study using WHO-VigiBase.

Melatonin, a pineal hormone that modulates circadian rhythms, sleep, and neurotransmitters, is widely used to treat sleep disorders. However, there are limited studies on the safety of melatonin. Therefore, we aimed to present the overall patterns of adverse events (AEs) following melatonin administration and identify potential safety signals associated with melatonin. Using VigiBase, a global individual case safety report (ICSRs) database managed by the World Health Organization (WHO), we conducted a retrospective, observational, pharmacovigilance study of melatonin between January 1996 and September 2022. Disproportionality analysis was conducted using two comparator settings: all other drugs and other sleep medications. We used multivariable logistic regression to estimate reporting odds ratios (RORs) with 95% confidence intervals (CIs) to compare the frequencies of AEs reporting between melatonin and each comparator setting. Furthermore, we assessed adverse events of special interests (AESIs) that could potentially be associated with melatonin. Signals were identified when the following criteria were met: cases ≥3, x2 ≥ 4, IC025 ≥ 0, and the lower end of the 95% CI of ROR > 2. These signals were then compared with the AE information on the drug labels provided by regulatory bodies. A total of 35 479 AE reports associated with melatonin were identified, with a higher proportion of reports from females (57.1%) and individuals aged 45-64 years (20.8%). We identified 21 AEs that were commonly detected as safety signals in the disproportionality analyses, including tic, educational problems, disturbance in social behavior, body temperature fluctuation, and growth retardation. In AESI analyses, accidents and injuries (adjusted ROR 2.97; 95% CI, 2.80-3.16), fall (2.24; 2.12-2.37), nightmare (4.90; 4.37-5.49), and abnormal dreams (3.68; 3.19-4.25) were detected as a signal of melatonin when compared to all other drugs, whereas those signals were not detected when compared to other sleep medications. In this pharmacovigilance study, exogenous melatonin showed safety profiles comparable to other sleep medications. However, several unexpected potential safety signals were identified, underscoring the need for further investigation at the population level.

Risk factors of internal carotid artery stenosis in patients with proliferative diabetic retinopathy: an analysis using optical coherence tomography and optical coherence tomography angiography.

BACKGROUND: This research investigates the correlation between the severity of internal carotid artery (ICA) stenosis and retinal parameters in patients with proliferative diabetic retinopathy (PDR), aiming to uncover potential risk factors. METHODS: A retrospective analysis of 68 patients (136 eyes) diagnosed with bilateral PDR from January 1, 2017, to December 31, 2021, was conducted. Carotid artery stenosis (CAS) was assessed using neck computed tomography angiography (CTA) and carotid duplex ultrasound (CDUS), with stenosis classified into two groups: normal (group 1) and mild or above (group 2), based on the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria. Optical coherence tomography (OCT) and OCT angiography (OCTA) measured several retinal parameters, including sub foveal choroidal thickness (SFCT), retinal nerve fiber layer (RNFL) thickness, ganglion cell-inner plexiform layer (GCIPL) thickness, vessel density (VD), and foveal avascular zone (FAZ) area. Statistical analyses determined correlations between ICA degrees and retinal parameters. RESULTS: This study showed significant differences between groups in total VD, FAZ area, total RNFL thickness, and temporal RNFL thickness, indicating that patients with more severe ICA stenosis had noticeable retinal changes. Other parameters such as hyperlipidemia, total cholesterol levels, and intraocular pressure (IOP) also differed significantly, while no notable differences were observed in SFCT, central VD, average GCIPL, and superior, nasal, and inferior RNFL thickness. CONCLUSION: The study findings highlight retinal changes, such as an increased FAZ area, decreased total VD, and a total and thinner temporal RNFL, which suggest the need for carotid artery evaluation in patients. These findings have important clinical implications for the need for carotid work up in patients with PDR.

Musculoskeletal Injuries in Table Tennis during Competition: A Systematic Review.

The study aimed to investigate the incidence of musculoskeletal injuries among table tennis players and identify their associated risk factors. We conducted a literature search in online databases using relevant search terms related to "table tennis" and "injury". To compare the rate of injuries according to player-related variables, we extracted information on sex, level of games, circumstances of injury, and duration of sport absence after injury. Furthermore, we calculated the odds ratios based on the number of injuries according to variables. Eight articles included 873 professional table tennis players, revealing an overall musculoskeletal injury rate of 3.6% (31 musculoskeletal injuries). The incidence was 10.0 injuries per 1,000 playing hours (range, 0-27.0). The rate of musculoskeletal injuries for female and male players were 3.2% and 3.8%, respectively, and those for Summer Olympic Games, Asian Games, and domestic national games was 4.8%, 15.4%, and 0%, respectively. More than half (52%) of injuries occurred during training, and most injuries (64%) were of a nature that did not cause time loss. This review provides valuable information about the incidence of musculoskeletal injuries in table tennis competitions. However, owing to the limitations of this study in identifying injury-related risk factors, future studies analyzing comprehensive variables are required.

Which is better? Early versus delayed rehabilitation after arthroscopic rotator cuff repair.

PURPOSE: This study aimed to compare the 5-year clinical and functional outcomes, including repaired tendon healing status, between early and delayed rehabilitation after arthroscopic rotator cuff repair METHODS: A total of 75 patients with rotator cuff tears (less than 5 cm) underwent arthroscopic repairs over a 60-month period. Participants were randomly assigned to early and delayed postoperative rehabilitation groups with distinct protocols. Clinical and functional outcome measures included Constant score, University of California at Los Angeles (UCLA) score, visual analogue scale for pain and isokinetic dynamometer test for muscle strength recovery. Clinical and functional scores were compared between baseline and 5 years postoperatively. Radiologic assessment via magnetic resonance imaging was performed at a minimum of 12 months postoperatively for evaluations of tendon integrity and recurrent tears. RESULTS: Baseline characteristics showed no statistically significant differences between groups. Both groups demonstrated equivalent improvement in range of motion and pain scores with no statistical differences. Clinical scores improved significantly in both groups by postoperative 12 months and plateaued. At the postoperative 5-year mark, the early group showed better improvement in the visual analogue scale and UCLA score, while the delayed group had superior Constant scores. Postoperative magnetic resonance imaging revealed six recurrent tears, two in the early group and four in the delayed group, with no statistical differences. Muscle strength recovery showed no differences between the two groups. CONCLUSION: Both the early and the delayed rehabilitation groups showed similar outcomes in postoperative range of motion, functional scores, muscle strength recovery and tendon healing in the short- and mid-term follow-ups. LEVEL OF EVIDENCE: Level III.

Comparison of a coupling system and the suture method in end-to-side microvascular anastomosis in head and neck reconstruction.

BACKGROUND: Use of coupling devices in microvascular anastomosis continues to increase, but it is not yet actively used in end-to-side (ETS) anastomosis because there is no standard method. Therefore, we propose an easy and time-saving ETS micro-anastomosis method using coupling devices in head and neck reconstruction and compare it with the conventional suture method. MATERIALS AND METHODS: We retrospectively reviewed 30 consecutive cases (43 anastomoses) of ETS anastomosis in head and neck reconstruction from 2018 to 2022. Patient characteristics, operative details, and anastomosis time were evaluated. When using the coupling device, a cross incision was created in the recipient vessel to form vascular flaps. By pulling the flaps out of the ring, the intact vessel lining was fixed. Other procedures were the same as for a traditional anastomosis. RESULTS: The mean anastomosis time was 12.81 min (range, 6.7-24.87) for the suture and 4.96 min (range, 2.02-9.4) for the coupling device, a statistically significant difference (p-value <.00005). There was no venous insufficiency or flap failure with either method. CONCLUSIONS: ETS venous anastomosis using the coupling device is an easy-to-use, safe, and timesaving procedure for head and neck reconstruction.

Transverse division of the rectus abdominis muscle in deep inferior epigastric perforator flap elevation: A rescue technique to include more than one perforator.

BACKGROUND: It is important to include as many perforators as possible in order to enhance the vascularity of a deep inferior epigastric perforator (DIEP) flap. However, the rectus muscle must be transected transversely, which prevents suturing and can cause a defect along the same line as the muscle-sparing procedure. When harvesting the DIEP flap, no specific method was suggested to solve these muscle defects. We found that by transecting the rectus muscle transversely, the muscle could be sutured in the tendinous area more easily while maintaining muscle function. The purpose of this study is to confirm the long-term recovery of the rectus abdominis muscle through the volume change after DIEP flap using this tendinous transection and suture method. PATIENTS AND METHODS: A retrospective review of 28 patients who underwent unilateral breast reconstruction using a DIEP flap and the tendinous transection method for multiple perforators between May 2018 and April 2020 was conducted. The preoperative and postoperative volumes of the rectus abdominis muscle were estimated both the harvest and opposite sides. RESULTS: The preoperative and postoperative muscle volumes from the harvest side were 50.08 ± 8.71 cm3 and 48.56 ± 8.61 cm3, respectively. The volume difference was 1.522 cm3 decrease, which was not statistically significant (p = .070). The preoperative and postoperative muscle volumes from the opposite side were 50.50 ± 8.15 cm3 and 50.08 ± 8.18 cm3, respectively. The volume difference was 0.434 cm3 increase and was not statistically significant (p = .064). Postoperative volume changes in the rectus muscle were not statistically significant on either side. CONCLUSION: The tendinous transection method in the DIEP flap procedure did not significantly affect postoperative rectus muscle volume. Therefore, we expect this harvest method to allow DIEP flap reconstruction that includes multiple perforators and complete donor muscle recovery.

Frontal Sinus Displacement of Silicone Implant After Previous Rhinoplasty.

Rhinoplasty, a historic surgical procedure for facial esthetics, has been actively performed in Asia. The use of autologous tissues or artificial materials, such as silicone, Gore-Tex, and Medpore, is common in achieving cosmetic improvements. However, artificial material poses risks of inflammation and foreign body reactions, leading to complications like infection and necessitating material removal and antibiotic treatment. According to previous reports, various clinical aspects appear across inflammation, skin necrosis, and, in severe cases, systemic symptoms caused by implants. In this case study, the goal is to share a rare case of silicone implant migration into the frontal sinus after augmentation rhinoplasty. A 38-year-old female patient who had previously undergone rhinoplasty surgery visited the outpatient clinic complaining of headaches and a deviated nose. On computed tomography, the silicone implant moved upward, penetrating the nasoethmoid bone and invading the frontal sinus. Fortunately, there was no intracranial invasion. The authors planned the implant removal and performed the complete implant removal with capsulectomy. The patient has been undergoing follow-up without any complications after surgery. Augmentation rhinoplasty with implants, while common, carries long-term risks. This case highlights the severity of complications, emphasizing infection and migration into the frontal sinus and, in extreme cases, the brain cavity. Therefore, surgeons must continually refine operation techniques to minimize iatrogenic causes and consider modifying surgical procedures to prevent potential complications.

Lugol's Solution Reduces Positive Margins and Residual Disease After the Large Loop Excision of Transformation Zone.

OBJECTIVE: This study aimed to examine whether the intraoperative use of Lugol's solution reduces the proportion of positive resection margins (RMs) using the data of women who underwent large loop excision of the transformation zone (LLETZ). MATERIALS AND METHODS: A total of 1,751 consecutive women with cervical intraepithelial neoplasia (CIN) who underwent LLETZ with or without Lugol's solution were retrospectively retrieved from each database of 3 university hospitals in South Korea. Outcomes included positive RMs and residual disease pathologically confirmed within 6 months after LLETZ. RESULTS: Positive RMs were noted in 345 cases (19.7%). Among 1,507 women followed up, residual disease was diagnosed in 100 cases (6.6%) (69/308 cases with positive RMs; 31/1,199 cases with negative RMs). The Lugol's solution group was less likely to have positive RMs (11.8% vs 25.5%, p < .01), to require additional surgical intervention (5.4% vs 10.2%, p < .01), and to have residual disease (4.9% vs 8.0%, p = .02). On multiple logistic regression analysis, Lugol's solution reduced the proportion of positive RMs (adjusted odds ratio [aOR], 0.31). Age (50 years or older; aOR, 1.64), preconization cervical cytology (aOR, 1.53), high-risk human papillomavirus (aOR, 1.75), and CIN 2 or 3 (aOR, 2.65) were independent risk factors for margin positivity ( p < .01 for all except high-risk human papillomavirus of p = .05). CONCLUSIONS: Lugol's solution optimizes CIN treatment by reducing the proportion of positive RMs and residual disease after LLETZ.

10-Eicosanol Alleviates Patulin-Induced Cell Cycle Arrest and Apoptosis by Activating AKT (Protein Kinase B) in Porcine Intestinal Epithelial Cells.

Patulin (PAT) is a fungal toxin prevalent in apples and apple products and associated with several toxic effects, potentially harming multiple organs, including the kidneys, liver, and colon. However, the precise molecular mechanism through which PAT affects the intestines remains comprehensively unclear. Therefore, this study aims to investigate the molecular effects of PAT on the intestinal epithelium. Gene expression profiling was conducted, hypothesizing that PAT induces cell cycle arrest and apoptosis through the PI3K-Akt signaling pathway. Cell cycle analysis, along with Annexin-V and propidium iodide staining, confirmed that PAT induced G2/M phase arrest and apoptosis in IPEC-J2 cells. Additionally, PAT activated the expression of cell cycle-related genes (CDK1, CCNB1) and apoptosis-related genes (BCL6, CASP9). Treatment with SC79, an AKT activator, mitigated cell cycle arrest and apoptosis. To identify natural products that could mitigate the harmful effects of PAT in small intestinal epithelial cells in pigs, the high-throughput screening of a natural product library was conducted, revealing 10-Eicosanol as a promising candidate. In conclusion, our study demonstrates that 10-Eicosanol alleviates PAT-induced cell cycle arrest and apoptosis in IPEC-J2 cells by activating AKT.

Advancements in Flexible Nanogenerators: Polyvinylidene Fluoride-Based Nanofiber Utilizing Electrospinning.

With the gradual miniaturization of electronic devices and the increasing interest in wearable devices, flexible microelectronics is being actively studied. Owing to the limitations of existing battery systems corresponding to miniaturization, there is a need for flexible alternative power sources. Accordingly, energy harvesting from surrounding environmental systems using fluorinated polymers with piezoelectric properties has received significant attention. Among them, polyvinylidene fluoride (PVDF) and PVDF co-polymers have been researched as representative organo-piezoelectric materials because of their excellent piezoelectric properties, mechanical flexibility, thermal stability, and light weight. Electrospinning is an effective method for fabricating nanofibrous meshes with superior surface-to-volume ratios from polymer solutions. During electrospinning, the polymer solution is subjected to mechanical stretching and in situ poling, corresponding to an external strong electric field. Consequently, the fraction of the piezoelectric ß-phase in PVDF can be improved by the electrospinning process, and enhanced harvesting output can be realized. An overview of electrospun piezoelectric fibrous meshes composed of PVDF or PVDF co-polymers to be utilized is presented, and the recent progress in enhancement methods for harvesting output, such as fiber alignment, doping with various nanofillers, and coaxial fibers, is discussed. Additionally, other applications of these meshes as sensors are reviewed.

CBP Expression Contributes to Neuropathic Pain via CREB and MeCP2 Regulation in the Spared Nerve Injury Rat Model.

Background and Objectives: This study aimed to investigate the relationship between neuropathic pain and CREB-binding protein (CBP) and methyl-CpG-binding protein 2 (MeCP2) expression levels in a rat model with spared nerve injury (SNI). Materials and Methods: Rat (male Sprague-Dawley white rats) models with surgical SNI (n = 6) were prepared, and naive rats (n = 5) were used as controls. The expression levels of CBP and MeCP2 in the spinal cord and dorsal root ganglion (DRG) were compared through immunohistochemistry at 7 and 14 days after surgery. The relationship between neuropathic pain and CBP/MeCP2 was also analyzed through intrathecal siRNA administration. Results: SNI induced a significant increase in the number of CBPs in L4 compared with contralateral DRG as well as with naive rats. The number of MeCP2 cells in the dorsal horn on the ipsilateral side decreased significantly compared with the contralateral dorsal horn and the control group. SNI induced a significant decrease in the number of MeCP2 neurons in the L4 ipsilateral DRG compared with the contralateral DRG and naive rats. The intrathecal injection of CBP siRNA significantly inhibited mechanical allodynia induced by SNI compared with non-targeting siRNA treatment. MeCP2 siRNA injection showed no significant effect on mechanical allodynia. Conclusions: The results suggest that CBP and MeCP2 may play an important role in the generation of neuropathic pain following peripheral nerve injury.

Bi-Allelic UQCRFS1 Variants Are Associated with Mitochondrial Complex III Deficiency, Cardiomyopathy, and Alopecia Totalis.

Isolated complex III (CIII) deficiencies are among the least frequently diagnosed mitochondrial disorders. Clinical symptoms range from isolated myopathy to severe multi-systemic disorders with early death and disability. To date, we know of pathogenic variants in genes encoding five out of 10 subunits and five out of 13 assembly factors of CIII. Here we describe rare bi-allelic variants in the gene of a catalytic subunit of CIII, UQCRFS1, which encodes the Rieske iron-sulfur protein, in two unrelated individuals. Affected children presented with low CIII activity in fibroblasts, lactic acidosis, fetal bradycardia, hypertrophic cardiomyopathy, and alopecia totalis. Studies in proband-derived fibroblasts showed a deleterious effect of the variants on UQCRFS1 protein abundance, mitochondrial import, CIII assembly, and cellular respiration. Complementation studies via lentiviral transduction and overexpression of wild-type UQCRFS1 restored mitochondrial function and rescued the cellular phenotype, confirming UQCRFS1 variants as causative for CIII deficiency. We demonstrate that mutations in UQCRFS1 can cause mitochondrial disease, and our results thereby expand the clinical and mutational spectrum of CIII deficiencies.

Whole-brain functional gradients reveal cortical and subcortical alterations in patients with episodic migraine.

Migraine is a type of headache with multiple neurological symptoms. Prior neuroimaging studies in patients with migraine based on functional magnetic resonance imaging have found regional as well as network-level alterations in brain function. Here, we expand on prior studies by establishing whole-brain functional connectivity patterns in patients with migraine using dimensionality reduction techniques. We studied functional brain connectivity in 50 patients with episodic migraine and sex- and age-matched healthy controls. Using dimensionality reduction techniques that project high-dimensional functional connectivity onto low-dimensional representations (i.e., eigenvectors), we found significant between-group differences in the eigenvectors between patients with migraine and healthy controls, particularly in the sensory/motor and limbic cortices. Furthermore, we assessed between-group differences in subcortical connectivity with subcortical weighted manifolds defined by subcortico-cortical connectivity multiplied by cortical eigenvectors and revealed significant alterations in the amygdala. Finally, leveraging supervised machine learning, we moderately predicted headache frequency using cortical and subcortical functional connectivity features, again indicating that sensory and limbic regions play a particularly important role in predicting migraine frequency. Our study confirmed that migraine is a hierarchical disease of the brain that shows alterations along the sensory-limbic axis, and therefore, the functional connectivity in these areas could be a useful marker to investigate migraine symptomatology.

Ethylene signals modulate the survival of Arabidopsis leaf explants.

BACKGROUND: Leaf explants are major materials in plant tissue cultures. Incubation of detached leaves on phytohormone-containing media, which is an important process for producing calli and regenerating plants, change their cell fate. Although hormone signaling pathways related to cell fate transition have been widely studied, other molecular and physiological events occurring in leaf explants during this process remain largely unexplored. RESULTS: Here, we identified that ethylene signals modulate expression of pathogen resistance genes and anthocyanin accumulation in leaf explants, affecting their survival during culture. Anthocyanins accumulated in leaf explants, but were not observed near the wound site. Ethylene signaling mutant analysis revealed that ethylene signals are active and block anthocyanin accumulation in the wound site. Moreover, expression of defense-related genes increased, particularly near the wound site, implying that ethylene induces defense responses possibly by blocking pathogenesis via wounding. We also found that anthocyanin accumulation in non-wounded regions is required for drought resistance in leaf explants. CONCLUSIONS: Our study revealed the key roles of ethylene in the regulation of defense gene expression and anthocyanin biosynthesis in leaf explants. Our results suggest a survival strategy of detached leaves, which can be applied to improve the longevity of explants during tissue culture.

Controlling Morphologies of Redox-Responsive Polymeric Nanocarriers for a Smart Drug Delivery System.

Redox-responsive nanocarriers using disulfides or thiols have received considerable attention owing to the higher levels of glutathione (GSH) in cancer cells than those in extracellular fluids. Nevertheless, the normal-to-cancer-cell selectivity of these nanocarriers has not yet been clarified. Nanocarriers exhibit different cytotoxicities depending on the morphologies they adopt under the redox-active conditions typically existing in cancerous cells. Therefore, not only GSH levels but also reactive oxygen species (ROS) levels and other complex cancerous cell conditions must be considered for the development of smart drug delivery systems. In this article, we review the structural design of redox-responsive polymers that exhibit different morphological changes in environments akin to cancerous cells (e. g., GSH- and ROS-abundant conditions). In addition, we propose a molecular design for the spatiotemporal control of nanocarrier morphology depending on the levels of both GSH and ROS upon photoirradiation to increase the cytotoxicity difference between normal and cancer cells.

SARS-CoV-2 spike protein promotes inflammatory cytokine activation and aggravates rheumatoid arthritis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) induces inflammation, autoantibody production, and thrombosis, which are common symptoms of autoimmune diseases, including rheumatoid arthritis (RA). However, the effect of COVID-19 on autoimmune disease is not yet fully understood. METHODS: This study was performed to investigate the effects of COVID-19 on the development and progression of RA using a collagen-induced arthritis (CIA) animal model. Human fibroblast-like synoviocytes (FLS) were transduced with lentivirus carrying the SARS-CoV-2 spike protein gene in vitro, and the levels of inflammatory cytokine and chemokine expression were measured. For in vivo experiments, CIA mice were injected with the gene encoding SARS-CoV-2 spike protein, and disease severity, levels of autoantibodies, thrombotic factors, and inflammatory cytokine and chemokine expression were assessed. In the in vitro experiments, the levels of inflammatory cytokine and chemokine expression were significantly increased by overexpression of SARS-CoV-2 spike protein in human FLS. RESULTS: The incidence and severity of RA in CIA mice were slightly increased by SARS-CoV-2 spike protein in vivo. In addition, the levels of autoantibodies and thrombotic factors, such as anti-CXC chemokine ligand 4 (CXCL4, also called PF4) antibodies and anti-phospholipid antibodies were significantly increased by SARS-CoV-2 spike protein. Furthermore, tissue destruction and inflammatory cytokine level in joint tissue were markedly increased in CIA mice by SARS-CoV-2 spike protein. CONCLUSIONS: The results of the present study suggested that COVID-19 accelerates the development and progression of RA by increasing inflammation, autoantibody production, and thrombosis. Video Abstract.