Improved laminar specificity and sensitivity by combining SE and GE BOLD signals

The most widely used gradient-echo (GE) blood oxygenation level-dependent (BOLD) contrast has high sensitivity, but low specificity due to draining vein contributions, while spin-echo (SE) BOLD approach at ultra-high magnetic fields is highly specific to neural active sites but has lower sensitivity. To obtain high specificity and sensitivity, we propose to utilize a vessel-size-sensitive filter to the GE-BOLD signal, which suppresses macrovascular contributions and to combine selectively retained microvascular GE-BOLD signals with the SE-BOLD signals. To investigate our proposed idea, fMRI with 0.8 mm isotropic resolution was performed on the primary motor and sensory cortices in humans at 7 T by implementing spin- and gradient-echo (SAGE) echo planar imaging (EPI) acquisition. Microvascular-passed sigmoidal filters were designed based upon the vessel-size-sensitive ??R2*/??R2 value for retaining GE-BOLD signals originating from venous vessels with ??? 45 ??m and ??? 65 ??m diameter. Unlike GE-BOLD fMRI, the laminar profile of SAGE-BOLD fMRI with the vessel-size-sensitive filter peaked at ??? 1.0 mm from the surface of the primary motor and sensory cortices, demonstrating an improvement of laminar specificity over GE-BOLD fMRI. Also, the functional sensitivity of SAGE BOLD at middle layers (0.75???1.5 mm) was improved by ??? 80% to ???100% when compared with SE BOLD. In summary, we showed that combined GE- and SE-BOLD fMRI with the vessel-size-sensitive filter indeed yielded improved laminar specificity and sensitivity and is therefore an excellent tool for high spatial resolution ultra-high filed (UHF)-fMRI studies for resolving mesoscopic functional units

Cation exchange chromatography removes FXIa from a 10% intravenous immunoglobulin preparation

The presence of residual activated coagulation factor XI (FXIa) in some commercial intravenous immunoglobulin (IVIG) products has been identified as the root cause of a small number of thromboembolic events in patients who had received such therapy. Our objectives here were to design and evaluate the manufacturing process of GC5107, a 10% glycine-stabilized IVIG product, for its capacity to remove FXIa. The manufacturing process included a cation exchange chromatography (CEX) step, which employs a resin that binds immunoglobulin G (IgG) with high capacity. Procoagulant activity was assessed using Western blot analysis, enzyme-linked immunosorbent assay, thrombin generation assay, chromogenic FXIa assay, and non-activated partial thromboplastin time (NaPTT) assay. A spiking study in which large quantities of FXIa were added to samples before CEX chromatography was used to examine the robustness of the process to remove FXIa. Western blot and ELISA analyses demonstrated that residual FXIa remained in the intermediate manufacturing products until after CEX chromatography, when it was reduced to undetectable levels. The spiking study demonstrated that CEX chromatography removed >99% of FXI protein and reduced FXI activity to below detection limits, even in samples containing 158-fold greater FXIa levels than that of normal samples. Procoagulant activity in 9 consecutive lots of GC5107 was reduced to below the detection limits of the thrombin generation and chromogenic FXIa assays (<1.56 IU/ml and <0.16 IU/ml, respectively). The NaPTT of >250 s in all 9 lots indicated very low levels of procoagulant activity. We demonstrate that a novel 10% IVIG manufacturing process including CEX chromatography is a robust means of removing FXIa from the final preparation

The miR-15b-Smurf2-HSP27 axis promotes pulmonary fibrosis

Background Heat shock protein 27 (HSP27) is overexpressed during pulmonary fibrosis (PF) and exacerbates PF; however, the upregulation of HSP27 during PF and the therapeutic strategy of HSP27 inhibition is not well elucidated. Methods We have developed a mouse model simulating clinical stereotactic body radiotherapy (SBRT) with focal irradiation and validated the induction of RIPF. HSP25 (murine form of HSP27) transgenic (TG) and LLC1-derived orthotropic lung tumor models were also used. Lung tissues of patients with RIPF and idiopathic pulmonary fibrosis, and lung tissues from various fibrotic mouse models, as well as appropriated cell line systems were used. Public available gene expression datasets were used for therapeutic response rate analysis. A synthetic small molecule HSP27 inhibitor, J2 was also used. Results HSP27 expression with its phosphorylated form (pHSP27) increased during PF. Decreased mRNA expression of SMAD-specific E3 ubiquitin-protein ligase 2 (Smurf2), which is involved in ubiquitin degradation of HSP27, was responsible for the increased expression of pHSP27. In addition, increased expression of miRNA15b was identified with decreased expression of Smurf2 mRNA in PF models. Inverse correlation between pHSP27 and Smurf2 was observed in the lung tissues of PF animals, an irradiated orthotropic lung cancer models, and PF tissues from patients. Moreover, a HSP27 inhibitor cross-linked with HSP27 protein to ameliorate PF, which was more effective when targeting the epithelial to mesenchymal transition (EMT) stage of PF. Conclusions Our findings identify upregulation mechanisms of HSP27 during PF and provide a therapeutic strategy for HSP27 inhibition for overcoming PF.This work was supported by grants from the National Research Foundation of Korea, (NRF-2018R1A5A2025286, NRF-2020R1A2C3013255, NRF-2020M2D9A2093974, NRF-2020R1I1A1A01070841, NRF-2020M2D9A2093976 and NRF-2022R1A2C3011611), funded by the Korean government (Ministry of Science and ICT)

Phantom Acupuncture Induces Placebo Credibility and Vicarious Sensations: A Parallel fMRI Study of Low Back Pain Patients

Although acupuncture is an effective therapeutic intervention for pain reduction, the exact difference between real and sham acupuncture has not been clearly understood because a somatosensory tactile component is commonly included in the existing sham acupuncture protocols. In an event-related fMRI experiment, we implemented a novel form of sham acupuncture, phantom acupuncture, that reproduces the acupuncture needling procedure without somatosensory tactile stimulation while maintaining the credibility of the acupuncture treatment context. Fifty-six non-specific low back pain patients received either real (REAL) or phantom (PHNT) acupuncture stimulation in a parallel group study. The REAL group exhibited greater activation in the posterior insula and anterior cingulate cortex, reflecting the needling-specific components of acupuncture. We demonstrated that PHNT could be delivered credibly. Interestingly, the PHNT-credible group exhibited bilateral activation in SI/SII and also reported vicarious acupuncture sensations without needling stimulation. The PHNT group showed greater activation in the bilateral dorsolateral/ventrolateral prefrontal cortex (dlPFC/vlPFC). Moreover, the PHNT group exhibited significant pain reduction, with a significant correlation between the subjective fMRI signal in the right dlPFC/vlPFC and a score assessing belief in acupuncture effectiveness. These results support an expectation-related placebo analgesic effect on subjective pain intensity ratings, possibly mediated by right prefrontal cortex activity

Detection of Infectious Hypodermal and Hematopoietic Necrosis Virus (IHHNV, Decapod Penstylhamaparvovirus 1) in Commodity Red Claw Crayfish (Cherax quadricarinatus) Imported into South Korea

Freshwater crayfish, which are cultivated in aquaculture, are economically important for food and ornamental purposes. However, relatively few studies have focused on potentially pathogenic viruses in crayfish compared to in penaeid shrimp. Commodity red claw crayfish (Cherax quadricarinatus; 400 crayfish in 10 batches) and red swamp crayfish (Procambarus clarkii; 40 crayfish in 2 batches) imported into South Korea from Indonesia and China were screened by PCR to detect infectious hypodermal and hematopoietic necrosis virus (IHHNV or Decapod penstylhamaparvovirus 1). IHHNV was detected in tissue samples pooled from nine out of ten batches of red claw crayfish imported from Indonesia. Phylogenetic analysis of PCR amplicons from representative pools clustered the IHHNV strain with infectious-type II sequences commonly detected in Southeast Asian countries rather than with type III strains detected previously in whiteleg shrimp (Penaeus vannamei) cultured in South Korea. IHHNV DNA was detected most frequently in the muscle (eight batches, 66.7% samples), followed by in the hepatopancreas (five batches, 41.7% samples) and gills tissue (three batches, 25.0% samples). These data suggest that red claw crayfish could be a potential carrier of the virus and that quarantine procedures must be strengthened in South Korea to avoid importing infectious types of IHHNV in commodity crustaceans such as red claw crayfish. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.1

Evaluating the Precision of Automatic Segmentation of Teeth, Gingiva and Facial Landmarks for 2D Digital Smile Design Using Real-Time Instance Segmentation Network

Digital smile design (DSD) technology, which takes pictures of patients’ faces together with anterior dentition and uses them for prosthesis design, has been recently introduced. However, the limitation of DSD is that it evaluates a patient with only one photograph taken in a still state, and the patient’s profile cannot be observed from various viewpoints. Therefore, this study aims to segment the patient’s anterior teeth, gingiva and facial landmarks using YOLACT++. We trained YOLACT++ on the annotated data of the teeth, lips and gingiva from the Flickr-Faces-HQ (FFHQ) data. We evaluated that the model trained by 2D candid facial images for the detection and segmentation of smile characteristics. The results show the possibility of an automated smile characteristic identification system for the automatic and accurate quantitative assessment of a patient’s smile

Deactivation of the attention-shifting ventromedial prefrontal cortex during the encoding and hold phases predicts working memory performance

Objectives Recent neuroimaging studies have suggested that the deactivation of the ventromedial prefrontal cortex (VMPFC) works with the attention shifting area to facilitate the encoding of behaviorally relevant inputs. These findings have led to the notion that the deactivation of VMPFC substantially contributes to the cognitive control of emotions. Although VMPFC deactivation during working memory tasks is established, whether it contributes to performance in emotionally distracted working memory tasks remains unclear. This study aimed to investigate whether the magnitude of VMPFC deactivation predicts better performance in emotionally distracted working memory tasks. Methods Twenty-nine female participants performed delayed-response working memory tasks with emotional distracters presented during the hold phase of working memory while undergoing functional MRI. A GLM and a paired t-test were used to observe brain responses to emotional distracters. The correlation between brain response and working memory performance was also computed to investigate brain areas that predict working memory performance in emotionally distracted tasks. Results Three trends in brain activity were strongly correlated with high working memory performance: (1) increased activity in cognitive control areas (dorsolateral prefrontal cortex), (2) lower activity in emotional reactivity areas (fusiform gyrus), and (3) deactivation of the attention shifting area, mainly VMPFC. In addition, all three trends correlated with high working memory performance during the hold phase of working memory, whereas only (2) and (3) correlated with high working memory performance during the encoding phase. Conclusions These results provide further evidence of the functional importance of VMPFC and demonstrate that VMPFC deactivation is particularly important during the encoding and hold phases of working memory.11Nsciescopu

Brain functional connectivity changes by low back extension pain model in low back pain patients.

PURPOSE:Low back pain (LBP) is a common ailment in most developed countries. Because most cases of LBP are known as 'non-specific', it has been challenging to develop experimental pain models of LBP which reproduce patients' clinical pain. In addition, previous models have limited applicability in a steady-pain-state neuroimaging environment. Thus, this study aims to devise a low back pain model with a simple methodology to induce experimental LBP, which has similar pain properties to patients' clinical pain, and to apply the model in a steady-pain-state neuroimaging study. METHODS:Our low back extension (LBE) pain model was tested on 217 LBP patients outside the magnetic resonance imaging (MRI) scanner to determine the reproducibility of endogenous pain and the similarity to their own clinical pain (STUDY1), and applied in a steady-pain-state functional MRI study (47 LBP patients and 23 healthy controls) to determine its applicability (induced head motions and brain functional connectivity changes; STUDY2). RESULTS:By the LBE pain model, 68.2% of the LBP patients reported increased LBP with high similarity of sensations to their own clinical pain (STUDY1), and the head motions were statistically similar to and correlated with those in resting state (STUDY2). Furthermore, the LBE model altered brain functional connectivity by decreasing the default-mode and the sensorimotor networks, and increasing the salience network, which was significantly associated with the intensity of the induced pain. Conversely, the healthy controls showed increased somatosensory network (but not of the cognitive pain processing). CONCLUSION:Our investigations suggest that our LBE pain model, which increased LBP with high similarity to the LBP patients' own pain sensation and induced patient-specific brain responses with acceptable head motion, could be applied to neuroimaging studies investigating brain responses to different levels of endogenous LBP