bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain Surface Area Alterations Correlate With Gait Impairments in Parkinson’s Disease
Authors: Wei Xuan , Wang Zheng , Zhang Mingkai , Li Min , Chen Yu-Chen , Lv Han , Tuo Houzhen , Yang Zhenghan , Wang Zhenchang , Ba Fang
Published: January 2022

Parkinson’s disease (PD) is a common neurodegenerative disease with progressive gait, cognition, and overall functional decline. Surface area changes are frequently seen with aging. In neurodegenerative diseases, the changes can be evident with disease progression. The current study aimed to study the regional microstructural alterations using surface-based morphometry to correlate with gait measures of the pace and rhythm domains in PD patients. We hypothesize that specific regional surface changes can be associated with PD gait impairments. Surface analysis might provide a useful tool for assessing PD for functional status and specific motor domains, such as gait in PD, and potentially could serve as an imaging marker in conjunction with other imaging markers. Twenty-seven PD patients and 37 healthy controls were included. The clinical assessment included Mini-Mental State Exanimation, PD motor assessment, clinical gait testing, and objective/quantitative gait assessment. For patients with PD, all motor and gait testing were performed during both OFF and ON medication states. Three Tesla MRI and high-resolution 3D structural images were acquired with an MP-RAGE pulse sequence. Structural image data preprocessing was performed using the DPABISurf toolbox. Clinical characteristics between PD and control group were compared, and correlation between the surface area and behavioral data were analyzed. At the left lateral temporal cortex (LTC) and right inferior parietal cortex (IPC), PD patients have significantly larger surface areas when compared to controls (P < 0.05) using surface-based morphometry. The surface area changes of the left LTC and right IPC were associated with the worse performance of gait assessed by Berg Balance Scale and Timed Up and Go during OFF (P < 0.01). The left LTC area changes significantly correlated with the number of steps, velocity, and the stride length of the pace domain in the ON state. Our findings suggest that PD is associated with a characteristic regional pattern of larger surface area in the left LTC and right IPC. These regional changes were associated with the pace domain of the gait in the ON state. Overall, surface-based analyses might provide a useful tool for assessing PD for functional status and specific motor domains, such as gait in PD, and potentially could serve as an imaging marker.
Changes in Sensorimotor Connectivity to dI3 Interneurons in Relation to the Postnatal Maturation of Grasping
Authors: Laliberte Alex M. , Farah Carl , Steiner Kyra R. , Tariq Omar , Bui Tuan V.
Published: January 2022

Primitive reflexes are evident shortly after birth. Many of these reflexes disappear during postnatal development as part of the maturation of motor control. This study investigates the changes of connectivity related to sensory integration by spinal dI3 interneurons during the time in which the palmar grasp reflex gradually disappears in postnatal mice pups. Our results reveal an increase in GAD65/67-labeled terminals to perisomatic Vglut1-labeled sensory inputs contacting cervical and lumbar dI3 interneurons between postnatal day 3 and day 25. In contrast, there were no changes in the number of perisomatic Vglut1-labeled sensory inputs to lumbar and cervical dI3 interneurons other than a decrease between postnatal day 15 and day 25. Changes in postsynaptic GAD65/67-labeled inputs to dI3 interneurons were inconsistent with a role in the sustained loss of the grasp reflex. These results suggest a possible link between the maturation of hand grasp during postnatal development and increased presynaptic inhibition of sensory inputs to dI3 interneurons.
Evaluating the Association of Calcified Neurocysticercosis and Mesial Temporal Lobe Epilepsy With Hippocampal Sclerosis in a Large Cohort of Patients With Epilepsy
Authors: Secchi Thaís Leite , Brondani Rosane , Bragatti José Augusto , Bizzi Jorge Wladimir Junqueira , Bianchin Marino Muxfeldt
Published: January 2022

Background

Neurocysticercosis (NCC) is a parasitic infection of the central nervous system that has been associated with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). However, this association has not been completely established.

Objective

To evaluate the prevalence of calcified NCC (cNCC), its characteristics and a possible association between cNCC and MTLE-HS in a cohort of 731 patients with epilepsy.

Methods

We review clinical, EEG and neuroimaging findings of 731 patients with epilepsy. From these, 659 had CT-scans and 441 patients had complete neuroimaging with CT-scans and MRI. In these patients, we review the prevalence and characteristic of epilepsy in cNCC and in MTLE-HS patients.

Results

Forty-two (6.4%) of the 659 patients studied with CT-scans had cNCC. cNCC lesions were more frequent in women than in men (n= 33–78.6% vs.n= 09–21.4%, respectively; OR = 3.64;(95%CI = 1.71–7.69);p< 0.001). cNCC was more often in patients who developed epilepsy later in life, in older patients, in patients who had a longer history of epilepsy, and in those with a lower educational level. MTLE–HS was observed in 93 (21.1%) of 441 patients that had complete neuroimaging, and 25 (26.9%) of these 93 patients also had cNCC. Calcified NCC was observed in only 17 (4.9%) of the remaining 348 patients that had other types of epilepsy rather than MTLE-HS. Thus, in our cohort, cNCC was more frequently associated with MTLE-HS than with other forms of epilepsy, O.R. = 11.90;(95%CI = 6.10–23.26);p< 0.0001).

Conclusions

As expected, in some patients the epilepsy was directly related to cNCC lesional zone, although this was observed in a surprisingly lower number of patients. Also, cNCC lesions were observed in other forms of epilepsy, a finding that could occur only by chance, with epilepsy probably being not related to cNCC at all. In this cohort, cNCC was very commonly associated with MTLE-HS, an observation in agreement with the hypothesis that NCC can contribute to or directly cause MTLE-HS in many patients. Given the broad world prevalence of NCC and the relatively few studies in this field, our findings add more data suggesting a possible and intriguing frequent interplay between NCC and MTLE-HS, two of the most common causes of focal epilepsy worldwide.
Cognitive Outcome Prediction in Infants With Neonatal Hypoxic-Ischemic Encephalopathy Based on Functional Connectivity and Complexity of the Electroencephalography Signal
Authors: Alotaibi Noura , Bakheet Dalal , Konn Daniel , Vollmer Brigitte , Maharatna Koushik
Published: January 2022

Impaired neurodevelopmental outcome, in particular cognitive impairment, after neonatal hypoxic-ischemic encephalopathy is a major concern for parents, clinicians, and society. This study aims to investigate the potential benefits of using advanced quantitative electroencephalography analysis (qEEG) for early prediction of cognitive outcomes, assessed here at 2 years of age. EEG data were recorded within the first week after birth from a cohort of twenty infants with neonatal hypoxic-ischemic encephalopathy (HIE). A proposed regression framework was based on two different sets of features, namely graph-theoretical features derived from the weighted phase-lag index (WPLI) and entropies metrics represented by sample entropy (SampEn), permutation entropy (PEn), and spectral entropy (SpEn). Both sets of features were calculated within the noise-assisted multivariate empirical mode decomposition (NA-MEMD) domain. Correlation analysis showed a significant association in the delta band between the proposed features, graph attributes (radius, transitivity, global efficiency, and characteristic path length) and entropy features (Pen and SpEn) from the neonatal EEG data and the cognitive development at age two years. These features were used to train and test the tree ensemble (boosted and bagged) regression models. The highest prediction performance was reached to 14.27 root mean square error (RMSE), 12.07 mean absolute error (MAE), and 0.45 R-squared using the entropy features with a boosted tree regression model. Thus, the results demonstrate that the proposed qEEG features show the state of brain function at an early stage; hence, they could serve as predictive biomarkers of later cognitive impairment, which could facilitate identifying those who might benefit from early targeted intervention.
Blast-Induced Mild Traumatic Brain Injury Alterations of Corticotropin-Releasing Factor Neuronal Activity in the Mouse Hypothalamic Paraventricular Nucleus
Authors: Simmons Sarah , Langlois Ludovic D. , Oyola Mario G. , Gouty Shawn , Wu T. John , Nugent Fereshteh S.
Published: January 2022

Blast-induced mild traumatic brain injury (mbTBI) is the most common cause of TBI in US service members and veterans. Those exposed to TBI are at greater risk of developing neuropsychiatric disorders such as posttraumatic stress disorder, anxiety and depressive disorders, and substance use disorders following TBI. Previously, we have demonstrated that mbTBI increases anxiety-like behaviors in mice and dysregulates stress at the level of corticotropin-releasing factor (CRF) neurons in the paraventricular nucleus (PVN). To expand on how mTBI may dysregulate the stress axis centrally, here PVN CRF neuronal activity was evaluated using whole cell-patch clamp recordings in hypothalamic slices from sham and mbTBI adult male CRF:tdTomato mice 7 days post-injury. We found that mbTBI generally did not affect the neuronal excitability and intrinsic membrane properties of PVN CRF neurons; this injury selectively increased the frequency of spontaneous neuronal firing of PVN CRF neurons localized to the dorsal PVN (dPVN) but not ventral PVN (vPVN). Consistently, mbTBI-induced dPVN CRF hyperactivity was associated with pre- and post-synaptic depression of spontaneous GABAergic transmission onto dPVN CRF neurons suggesting that mbTBI-induced GABAergic synaptic dysfunction may underlie dPVN CRF neuronal hyperactivity and increases in dPVN CRF signaling. The present results provide the first evidence for mbTBI-induced alterations in PVN CRF neuronal activity and GABAergic synaptic function that could mediate hypothalamic CRF dysregulation following mbTBI contributing to stress psychopathology associated with blast injury.
Effects of Dietary Barley Starch Contents on the Performance, Nutrient Digestion, Rumen Fermentation, and Bacterial Community of Fattening Hu Sheep
Authors: Ma Xiaowen , Zhou Wenjing , Guo Tongqing , Li Fei , Li Fadi , Ran Tao , Zhang Zhian , Guo Long
Published: January 2022

The objective of this experiment was to investigate the effects of substituting corn starch (CS) with barley starch (BS) on the growth performance, nutrient digestion, rumen fermentation, and bacterial community of fattening Hu sheep. Seventy-two Hu lambs with similar initial body weight (BW, 29.70 ± 1.70 kg) were randomly assigned to four treatments, with 18 lambs per group. The four experimental diets have identical starch contents but with different starch sources as 100% starch from corn (BS-0), 33% starch from barley and 67% starch from corn (BS-33), 67% starch form barley and 33% starch from corn (BS-67), and 100% starch from barley (BS-100). All lambs were reared in individual units and fed high-concentrate diets (85% concentrate in diets based on dry matter [DM]). The experimental period included 7 days for adaptation and 63 days for data collection. Sixteen ruminal cannulated Hu sheep were divided into 4 groups and received the four experimental diets to determine the dynamics of ruminal pH. The average daily gain (ADG), and BW gain of lambs linearly decreased (p < 0.05), whereas the feed to gain ratio linearly increased (p < 0.05) with increasing dietary proportions of BS. Digestibility of DM, organic matter, neutral detergent fiber, acid detergent fiber, starch, and gross energy (GE) decreased (p < 0.05) with increasing dietary BS contents. Ruminal mean pH decreased (p < 0.05) with increasing proportions of dietary BS, accompanied with linearly increased (p < 0.05) time and area of ruminal pH below 5.80 or 5.60. Increasing dietary proportions of BS linearly decreased (p < 0.05) the molar proportion of acetate, but linearly increased (p < 0.05) the molar proportion of propionate. Sheep of the BS-0 and BS-33 treatments had a less (p < 0.05) relative abundance of Selenomonas ruminantium than that of sheep of the BS-67 treatment, but a greater (p < 0.05) relative abundance of Ruminococcus albus than that of sheep of the BS-100 treatment (p < 0.05). In conclusion, feeding a high-concentrate corn-based diet for fattening Hu sheep improved the performance and rumen fermentation parameters when compared to the barley-based diet.
Impact of Body Composition During Neoadjuvant Chemoradiotherapy on Complications, Survival and Tumor Response in Patients With Locally Advanced Rectal Cancer
Authors: Liu Zhenzhen , Lu Siyi , Wang Yuxia , Lin Xinyi , Ran Peng , Zhou Xin , Fu Wei , Wang Hao
Published: January 2022

Background

To explore the impact of body composition before neoadjuvant chemoradiotherapy (pre-NCRT) and after neoadjuvant chemoradiotherapy (post-NCRT) on complications, survival, and tumor response in patients with locally advanced rectal cancer (LARC).

Methods

Patients with LARC who underwent radical surgery after NCRT between Ja 22nuary 2012 and March 2019 were studied. Body composition parameters, including skeletal muscle area (SMA), muscle density (MD), visceral fat area (VFA), total abdominal fat area (TAFA), and subcutaneous fat area (SFA), was identified at the third lumbar vertebra level on computed tomography (CT). The patients were divided into two groups based on the sex-specific quartile values of SMA, MD, VFA, TAFA, SFA, and body composition change. Patient characteristics, short- and long-term postoperative complications, survival, and tumor response were analyzed.

Results

A total of 122 eligible patients were enrolled. Body composition parameters, except MD, were strongly correlated with BMI (p < 0.001). Pre-NCRT low MD (p = 0.04) and TAFA loss (p = 0.02) were significantly correlated with short- and long-term ileus, respectively. Pre-NCRT low SMA was a significant prognostic factor for both disease-free survival (DFS) (HR 2.611, 95% CI 1.129–6.040, p = 0.025) and cancer-specific survival (CSS) (HR 3.124, 95% CI 1.030–9.472, p = 0.044) in the Cox regression multivariate analysis. Multivariate logistic regression analysis identified post-NCRT SFA (OR 3.425, 95% CI 1.392–8.427, p = 0.007) and SFA loss (OR 3.358, 95% CI 1.214–9.289, p = 0.02) as independent risk factors for tumor regression grade (TRG) and downstaging, respectively.

Conclusion

Pre-NCRT low MD and TAFA loss were related to a high incidence of short- and long-term ileus, respectively. Pre-NCRT low SMA was a significant prognostic factor for CSS and DFS. Post-NCRT SFA and SFA loss were independent risk factors for TRG and downstaging, respectively.
Improved Diagnostic Accuracy of Ameloblastoma and Odontogenic Keratocyst on Cone-Beam CT by Artificial Intelligence
Authors: Chai Zi-Kang , Mao Liang , Chen Hua , Sun Ting-Guan , Shen Xue-Meng , Liu Juan , Sun Zhi-Jun
Published: January 2022

Objective

The purpose of this study was to utilize a convolutional neural network (CNN) to make preoperative differential diagnoses between ameloblastoma (AME) and odontogenic keratocyst (OKC) on cone-beam CT (CBCT).

Methods

The CBCT images of 178 AMEs and 172 OKCs were retrospectively retrieved from the Hospital of Stomatology, Wuhan University. The datasets were randomly split into a training dataset of 272 cases and a testing dataset of 78 cases. Slices comprising lesions were retained and then cropped to suitable patches for training. The Inception v3 deep learning algorithm was utilized, and its diagnostic performance was compared with that of oral and maxillofacial surgeons.

Results

The sensitivity, specificity, accuracy, and F1 score were 87.2%, 82.1%, 84.6%, and 85.0%, respectively. Furthermore, the average scores of the same indexes for 7 senior oral and maxillofacial surgeons were 60.0%, 71.4%, 65.7%, and 63.6%, respectively, and those of 30 junior oral and maxillofacial surgeons were 63.9%, 53.2%, 58.5%, and 60.7%, respectively.

Conclusion

The deep learning model was able to differentiate these two lesions with better diagnostic accuracy than clinical surgeons. The results indicate that the CNN may provide assistance for clinical diagnosis, especially for inexperienced surgeons.
Targeting Thyrointegrin αvβ3 Using Fluorobenzyl Polyethylene Glycol Conjugated Tetraiodothyroacetic Acid (NP751) in Acute Myeloid Leukemia
Authors: Darwish Noureldien H. E. , Glinsky Gennadi V. , Sudha Thangirala , Mousa Shaker A.
Published: January 2022

Background

Acute myeloid leukemia (AML) is associated with poor long-term survival, even with newer therapeutic agents. Here, we show the results of our preclinical study, in which we evaluated the efficacy of a new thyrointegrin αvβ3 antagonist, named fluorobenzyl polyethylene glycol conjugated tetraiodothyroacetic acid (fb-PMT).

Methods and Results

fb-PMT (NP751) is a potent αvβ3 antagonist of molecular weight of 2,478.9 Da. it represents a conjugate of tetraiodothyroacetic acid (tetrac) and monodisperse polyethylene glycol (PEG36), with a 4-fluorobenzyl group capping the other end of the PEG. fb-PMT effectively suppresses the malignant growth of human acute myeloid leukemia (AML) after successful engraftment in transgenic NSG-S xenograft mouse models of either established human AML cell line or primary AML cells. Daily treatment with fb-PMT (1–10 mg/kg body weight) subcutaneously (s.c.) for 3–4 weeks was associated with marked regression of leukemogenesis and extended survival in both models. The efficiency of the fb-PMT therapy was verified using in vivo imaging system (IVIS) imaging, flow cytometry, and histopathological examination to monitor the engraftment of leukemic cells in the bone marrow and other organs. fb-PMT therapy for 3–4 weeks at 3 and 10 mg/kg daily doses exhibited significant reduction (p < 0.0001) of leukemic cell burden of 74% and >95%, respectively. All fb-PMT-treated mice in the 10 mg/kg treatment arm successfully maintained remission after discontinuing the daily treatment. Comprehensive fb-PMT safety assessments demonstrated excellent safety and tolerability at multiple folds above the anticipated human therapeutic doses. Lastly, our genome-wide microarray screens demonstrated that fb-PMT works through the molecular interference mechanism with multiple signaling pathways contributing to growth and survival of leukemic cells.

Conclusion

Our preclinical findings of the potent anticancer activities of fb-PMT and its favorable safety profiles warrant its clinical investigation for the effective and safe management of AML.
Ten Years After SINS: Role of Surgery and Radiotherapy in the Management of Patients With Vertebral Metastases
Authors: Serratrice Nicolas , Faddoul Joe , Tarabay Bilal , Attieh Christian , Chalah Moussa A. , Ayache Samar S. , Abi Lahoud Georges N.
Published: January 2022

The objective of the different types of treatments for a spinal metastasis is to provide the best oncological and functional result with the least aggressive side effects. Initially created in 2010 to help clinicians in the management of vertebral metastases, the Spine Instability Neoplastic Score (SINS) has quickly found its place in the decision making and the treatment of patients with metastatic spinal disease. Here we conduct a review of the literature describing the different changes that occurred with the SINS score in the last ten years. After a brief presentation of the spinal metastases’ distribution, with or without spinal cord compression, we present the utility of SINS in the radiological diagnosis and extension of the disease, in addition to its limits, especially for scores ranging between 7 and 12. We take this opportunity to expose the latest advances in surgery and radiotherapy concerning spinal metastases, as well as in palliative care and pain control. We also discuss the reliability of SINS amongst radiologists, radiation oncologists, spine surgeons and spine surgery trainees. Finally, we will present the new SINS-derived predictive scores, biomarkers and artificial intelligence algorithms that allow a multidisciplinary approach for the management of spinal metastases.
Differential Impact of Membrane-Bound and Soluble Forms of the Prognostic Marker Syndecan-1 on the Invasiveness, Migration, Apoptosis, and Proliferation of Cervical Cancer Cells
Authors: Hilgers Katharina , Ibrahim Sherif Abdelaziz , Kiesel Ludwig , Greve Burkhard , Espinoza-Sánchez Nancy A. , Götte Martin
Published: January 2022

Cervical cancer ranks fourth among the most commonly diagnosed malignant tumors in women worldwide. Previously published evidence suggested a possible connection between the expression of the membrane-bound heparan sulfate proteoglycan syndecan-1 (Sdc-1) and the development of cervical carcinoma. Sdc-1 serves as a matrix receptor and coreceptor for receptor tyrosine kinases and additional signaling pathways. It influences cell proliferation, adhesion, and migration and is seen as a modulator of the tumor microenvironment. Following proteolytic cleavage of its extracellular domain in a process called shedding, Sdc-1 can act as a paracrine effector. The loss of Sdc-1 expression is associated with low differentiation of cervical carcinoma and with an increased rate of lymph node metastases. Here, we analyzed the clinical impact of Sdc-1 expression by analysis of public gene expression datasets and studied the effect of an overexpression of Sdc-1 and its membrane-bound and soluble forms on the malignant properties of the human cervical carcinoma cell line HeLa through functional analysis. For this purpose, the HeLa cells were stably transfected with the control plasmid pcDNA3.1 and three different Sdc-1-DNA constructs,encoding wild-type, permanently membrane-bound, and constitutively soluble Sdc-1. In clinical specimens, Sdc-1 mRNA was more highly expressed in local tumor tissues than in normal and metastatic cervical cancer tissues. Moreover, high Sdc-1 expression correlated with a poor prognosis in Kaplan-Meier survival analysis, suggesting the important role of Sdc-1 in the progression of this type of cancer. In vitro, we found that the soluble, as well as the permanently membrane-bound forms of Sdc-1 modulated the proliferation and the cell cycle, while membrane-bound Sdc1 regulated HeLa cell apoptosis. The overexpression of Sdc-1 and its soluble form increased invasiveness. In vitro scratch/wound healing assay, showed reduced Sdc-1-dependent cell motility which was linked to the Rho-GTPase signaling pathway. In conclusion, in cervical cancer Sdc-1 modulates pathogenetically relevant processes, which depend on the membrane-association of Sdc-1.
Cardiac Infiltration as the First Manifestation of Acute Lymphoblastic Leukemia: A Systematic Review
Authors: Luo Zhi , Cheng Jun , Wang Yanggan
Published: January 2022

Cardiac symptoms or signs as the first manifestations in acute lymphoblastic leukemia patients are sporadically reported which lead to misdiagnosis or delayed diagnosis due to lack of clinical experience and improper diagnosis procedures. Here, we documented the clinical features, procedures of diagnosis, treatments, and outcomes from the so-far reported 30 lymphoblastic leukemia cases that initially presented as cardiac problems and provided management recommendations based on the experiences and lessons learned from these patients to help physicians avoid misdiagnosis and improper treatment.
The View Outside of the Box: Reporting Outcomes Following Radical Cystectomy Using Pentafecta From a Multicenter Retrospective Analysis
Authors: Zapała Łukasz , Ślusarczyk Aleksander , Korczak Bartłomiej , Kurzyna Paweł , Leki Mikołaj , Lipiński Piotr , Miłow Jerzy , Niemczyk Michał , Pocheć Kamil , Późniak Michał , Przudzik Maciej , Suchojad Tomasz , Wolański Rafał , Zapała Piotr , Drewa Tomasz , Roslan Marek , Różański Waldemar , Wróbel Andrzej , Radziszewski Piotr
Published: January 2022

We aimed at characterization of the patients undergoing radical cystectomy (RC) using the prognostic model (a modified pentafecta). In the multicenter retrospective study, we enrolled 304 patients with bladder cancer (pTis-4N0-2M0) who underwent RC between 2015 and 2020 in experienced centers. The definition of the pentafecta was as follows: no Clavien–Dindo grade III–V complications at 90 days and no long-term complications related to urinary diversion <12 months, negative surgical margins, ≥10 lymph nodes (LNs) resected, and no recurrence ≤12 months. RC-pentafecta achievement rate was 22% (n = 67), varying from 47% to 88% attainment rate for different pentafecta components, and was the lowest for sufficient LN yield. Both 12-month recurrence-free survival (RFS) and cancer-specific mortality were compromised in pentafecta failers compared with achievers (57.8% vs. 100% and 33.8% vs. 1.5%, respectively). The following were identified as crucial predictors of RC pentafecta achievement: modality of the surgery, type of urinary diversion, histological type of bladder cancer, advanced staging, and elevated preoperative serum creatinine. In conclusion, we found that the pentafecta achievement rate was low even in high-volume centers in patients undergoing cystectomy. The complexity of the procedure directly influenced the attainment rate, which in turn led to an increase in cancer-specific mortality rate among the pentafecta failers.
Deciphering the Roles of Metformin in Alzheimer’s Disease: A Snapshot
Authors: Liao Wang , Xu Jiaxin , Li Bo , Ruan Yuting , Li Tian , Liu Jun
Published: January 2022

Alzheimer’s disease (AD) is a prevalent neurodegenerative disease predominantly affecting millions of elderly people. To date, no effective therapy has been identified to reverse the progression of AD. Metformin, as a first-line medication for Type 2 Diabetes Mellitus (T2DM), exerts multiple beneficial effects on various neurodegenerative disorders, including AD. Evidence from clinical studies has demonstrated that metformin use contributes to a lower risk of developing AD and better cognitive performance, which might be modified by interactors such as diabetic status and APOE-ε4 status. Previous mechanistic studies have gradually unveiled the effects of metformin on AD pathology and pathophysiology, including neuronal loss, neural dysfunction, amyloid-β (Aβ) depositions, tau phosphorylation, chronic neuroinflammation, insulin resistance, impaired glucose metabolism and mitochondrial dysfunction. Current evidence remains ambiguous and even conflicting. Herein, we review the current state of knowledge concerning the mechanisms of metformin in AD pathology while summarizing current evidence from clinical studies.
Poor Sleep Quality is Linked to Elevated Extracellular Vesicle-Associated Inflammatory Cytokines in Warfighters With Chronic Mild Traumatic Brain Injuries
Authors: Gottshall Jackie L. , Guedes Vivian A. , Pucci Josephine U. , Brooks Daniel , Watson Nora , Sheth Phorum , Gabriel Ainslee , Mithani Sara , Leete Jacqueline J. , Lai Chen , Qu Bao-Xi , Devoto Christina , Gill Jessica M. , Kenney Kimbra , Werner J. Kent
Published: January 2022

Background: Elevations of inflammatory cytokine levels occur immediately after mild traumatic brain injury (mTBI) and can persist for years. These elevations have been associated with neuropsychological outcomes, including depression and PTSD symptoms. Sleep disorders, another common sequelae of mTBI, are independently associated with inflammation in otherwise healthy individuals. However, whether sleep and inflammation are linked in chronic mTBI has not been reported.

Methods: A retrospective cross-sectional cohort of warfighters was used to investigate the hypothesis that inflammation may be linked to sleep quality in chronic mTBI. Clinical history, peripheral blood samples, and sleep quality scores were collected from 182 warfighters (n = 138 mTBI; n = 44 controls) during enrollment in the Chronic Effects of Neurotrauma Consortium study. Biomarkers of inflammation (IL-6, IL-10, TNFα cytokines) from plasma and plasma-derived extracellular vesicles (EVs) were quantified using single molecule array. Relationships between sleep quality and cytokine levels were assessed, controlling for age, sex, and BMI. Using clinical cutoff scores for sleep quality, mTBI patients were then divided into “good” and “poor” sleepers and cytokine levels compared between groups.

Results: In mTBI participants, sleep quality was significantly associated with EV levels of IL-10 [ß (SE) = 0.11 (0.04), p = 0.01] and TNFα [ß (SE) = 0.07 (0.03), p < 0.01]. When divided according to “good” versus “poor” sleepers, those reporting poor sleep had significantly elevated EV IL-10 compared to those reporting good sleep [ß (SE) = 0.12 (0.04), p < 0.01]. Plasma-derived associations were not significant. No associations were found between sleep quality and cytokine levels in controls.

Conclusion: These results suggest a significant relationship between sleep quality and chronic inflammation in mTBI patients. Clinically, mTBI patients with a high likelihood of sleep disorders demonstrate elevated levels of inflammatory cytokines. Signal from EVs, though smaller in magnitude, may have stronger clinical associations than from plasma. Sleep-focused interventions may also serve to regulate chronic inflammatory processes in these patients. Larger prospective studies are needed to investigate the mechanisms and therapeutic implications of the likely bi-directional relationship between sleep and inflammation following mTBI.
An Integrative Network Approach to Identify Common Genes for the Therapeutics in Tuberculosis and Its Overlapping Non-Communicable Diseases
Authors: Alam Aftab , Abubaker Bagabir Hala , Sultan Armiya , Siddiqui Mohd Faizan , Imam Nikhat , Alkhanani Mustfa F , Alsulimani Ahmad , Haque Shafiul , Ishrat Romana
Published: January 2022

Tuberculosis (TB) is the leading cause of death from a single infectious agent. The estimated total global TB deaths in 2019 were 1.4 million. The decline in TB incidence rate is very slow, while the burden of noncommunicable diseases (NCDs) is exponentially increasing in low- and middle-income countries, where the prevention and treatment of TB disease remains a great burden, and there is enough empirical evidence (scientific evidence) to justify a greater research emphasis on the syndemic interaction between TB and NCDs. The current study was proposed to build a disease-gene network based on overlapping TB with NCDs (overlapping means genes involved in TB and other/s NCDs), such as Parkinson’s disease, cardiovascular disease, diabetes mellitus, rheumatoid arthritis, and lung cancer. We compared the TB-associated genes with genes of its overlapping NCDs to determine the gene-disease relationship. Next, we constructed the gene interaction network of disease-genes by integrating curated and experimentally validated interactions in humans and find the 13 highly clustered modules in the network, which contains a total of 86 hub genes that are commonly associated with TB and its overlapping NCDs, which are largely involved in the Inflammatory response, cellular response to cytokine stimulus, response to cytokine, cytokine-mediated signaling pathway, defense response, response to stress and immune system process. Moreover, the identified hub genes and their respective drugs were exploited to build a bipartite network that assists in deciphering the drug-target interaction, highlighting the influential roles of these drugs on apparently unrelated targets and pathways. Targeting these hub proteins by using drugs combination or drug repurposing approaches will improve the clinical conditions in comorbidity, enhance the potency of a few drugs, and give a synergistic effect with better outcomes. Thus, understanding the Mycobacterium tuberculosis (Mtb) infection and associated NCDs is a high priority to contain its short and long-term effects on human health. Our network-based analysis opens a new horizon for more personalized treatment, drug-repurposing opportunities, investigates new targets, multidrug treatment, and can uncover several side effects of unrelated drugs for TB and its overlapping NCDs.
Natural Flavonoid Pectolinarigenin Alleviated Hyperuricemic Nephropathy via Suppressing TGFβ/SMAD3 and JAK2/STAT3 Signaling Pathways
Authors: Ren Qian , Wang Bo , Guo Fan , Huang Rongshuang , Tan Zhouke , Ma Liang , Fu Ping
Published: January 2022

Natural flavonoid pectolinarigenin (PEC) was reported to alleviate tubulointerstitial fibrosis of unilateral ureteral obstruction (UUO) mice in our previous study. To further investigate nephroprotective effects of PEC in hyperuricemic nephropathy (HN), adenine and potassium oxonate induced HN mice and uric acid-treated mouse kidney epithelial (TCMK-1) cells were employed in the study. As a result, PEC significantly lowered serum uric acid level and restored hyperuricemia-related kidney injury in HN mice. Meanwhile, PEC alleviated inflammation, fibrosis, and reduced adipokine FABP4 content in the kidneys of HN mice and uric acid-treated TCMK-1 cells. Mechanistically, PEC inhibited the TGF-β1 expression as well as the phosphorylation of transcription factor SMAD3 and STAT3 to regulate the corresponding inflammatory and fibrotic gene expression in kidney tissues. In conclusion, our results suggested that PEC could inhibit the activation of SMAD3 and STAT3 signaling to suppress inflammation and fibrosis, and thereby alleviate HN in mice.
Small Molecule Palmatine Targeting Musashi-2 in Colorectal Cancer
Authors: Zhang Xue , Su Kaiyan , Liu Yifan , Zhu Darong , Pan Yuting , Ke Xisong , Qu Yi
Published: January 2022

Musashi-2 (MSI2) is an evolutionally conserved RNA-binding protein and recently considered as an attractive therapeutic target in a wide spectrum of malignancies. However, MSI2-engaged mRNAs are not well profiled, and no MSI2-dependent antagonist is available so far. In the study, we created MSI2 knockout cancer cells and demonstrated that MSI2 is required for the survival of colorectal cancer HCT116 cells but not non-small cell lung cancer A549 cells. In addition, the global profiling of the transcriptome and proteomics of MSI2 knockout colorectal cells revealed 38 candidate MSI2-targeted genes. In a loss–rescue screening, palmatine was identified as a functional MSI2 antagonist inhibiting the MSI2-dependent growth of colorectal cancer cells. Finally, we confirmed that palmatine is directly bound to MSI2 at its C-terminal. Our findings not only indicated MSI2 as a promising therapeutic target of colorectal cancer but also provided a small molecule palmatine as a direct and functional MSI2 antagonist for cancer therapy.
Arylamine N-Acetyltransferase 1 Activity is Regulated by the Protein Acetylation Status
Authors: Salazar-González Raúl A. , Doll Mark A. , Hein David W.
Published: January 2022

Arylamine N-acetyltransferase 1 (NAT1) is a drug metabolizing enzyme that influences cancer cell proliferation and survival, especially in breast cancer. Lysine-acetylation is an important Post-Translational Modification (PTM) in the regulation of diverse cellular processes. Histone deacetylases (HDACs) and Sirtuins (SIRT) may have an important role on the NAT1 acetylation status, affecting its catalytic capacity and having an impact on the downstream functions of this protein. The aim of the present work is to investigate the acetylation status of NAT1 in human breast cancer. Breast cancer cell lines MDA-MB-231 (ER-, PR-, HER2-) and ZR-75-1 (estrogen receptor+, PR+, HER2+) were cultured in the presence of HDAC inhibitors (SAHA, TSA) or Sirtuin inhibitors (AGK2, EX527, Sirtinol). Under these conditions, NAT1 protein and gene expression as well as enzymatic activity were quantified. Acetylation of NAT1 protein was evaluated following an immunoprecipitation protocol and acetyl-Lysine quantification. Sirt1 and Sirt2 knockdown were performed and NAT1 protein and NAT1 mRNA expression and catalytic activity were quantified. The treatment of MDA-MB-231 or ZR-75-1 cells with increasing HDAC inhibitors resulted in 2 to 15-fold upregulation in NAT1 message expression. Finally, the catalytic activity of NAT1 in the presence of HDAC inhibition increased 2-fold. Conversely, the inhibition of Sirtuin activity did not cause significant changes in NAT1 message but produced a significant decrease in NAT1 catalytic activity. NAT1 acetylation was higher in the cells treated with HDAC inhibitors, as well as Sirtuin inhibitors. Finally, silencing of Sirt1 and Sirt2 genes by siRNA transient knockdown of each or both genes resulted in reduction of NAT1 protein expression and catalytic activity. The use of HDAC and Sirtuin inhibitors has been demonstrated as a promising powerful therapeutic alternative in various cancers. These inhibitors can significantly attenuate tumor burden by limiting tumor growth and metastasis. These compounds can also induce DNA damage, cell cycle arrest, apoptosis, and autophagy to promote cancer cell death. Several studies have shown that NAT1 is upregulated in cancer cells. The results of the present study show that the acetylation status of NAT1 is an important factor that might have a relevant role in the progression of cancer.
Using Polyacrylamide Hydrogels to Model Physiological Aortic Stiffness Reveals that Microtubules Are Critical Regulators of Isolated Smooth Muscle Cell Morphology and Contractility
Authors: Ahmed Sultan , Johnson Robert. T. , Solanki Reesha , Afewerki Teclino , Wostear Finn , Warren Derek. T.
Published: January 2022

Vascular smooth muscle cells (VSMCs) are the predominant cell type in the medial layer of the aortic wall and normally exist in a quiescent, contractile phenotype where actomyosin-derived contractile forces maintain vascular tone. However, VSMCs are not terminally differentiated and can dedifferentiate into a proliferative, synthetic phenotype. Actomyosin force generation is essential for the function of both phenotypes. Whilst much is already known about the mechanisms of VSMC actomyosin force generation, existing assays are either low throughput and time consuming, or qualitative and inconsistent. In this study, we use polyacrylamide hydrogels, tuned to mimic the physiological stiffness of the aortic wall, in a VSMC contractility assay. Isolated VSMC area decreases following stimulation with the contractile agonists angiotensin II or carbachol. Importantly, the angiotensin II induced reduction in cell area correlated with increased traction stress generation. Inhibition of actomyosin activity using blebbistatin or Y-27632 prevented angiotensin II mediated changes in VSMC morphology, suggesting that changes in VSMC morphology and actomyosin activity are core components of the contractile response. Furthermore, we show that microtubule stability is an essential regulator of isolated VSMC contractility. Treatment with either colchicine or paclitaxel uncoupled the morphological and/or traction stress responses of angiotensin II stimulated VSMCs. Our findings support the tensegrity model of cellular mechanics and we demonstrate that microtubules act to balance actomyosin-derived traction stress generation and regulate the morphological responses of VSMCs.
Numerical Simulations of Temporary Plugging-Refracturing Processes in a Conglomerate Reservoir Under Various In-Situ Stress Difference Conditions
Authors: Chen Jiamin , Zhang Qiang , Zhang Jiuchang
Published: January 2022

In this study, a numerical model of the conglomerate reservoir is established using ABAQUS. Cohesive elements are embedded into the numerical model to simulate the hydraulic fracturing behaviours of the conglomerate reservoir. The cohesive elements split by the high-pressure liquid flow are identified by tracing the crack propagation. A USDFLD (user-defined field variable) subroutine is used to increase the liquid flow’s dynamic viscosity in these cracked cohesive elements. Using this method, ABAQUS successfully simulates the temporary plugging-refracturing processes in the conglomerate reservoir under four in-situ stress states. This study found that with the increase of the horizontal in-situ stress difference, the pore pressure at the fluid injection point increased correspondingly. Under the conditions of higher horizontal in-situ stress differences, more complex branch fractures were generated in the conglomerate reservoir.
An Erythropoietin-Independent Mechanism of Erythrocytic Precursor Proliferation Underlies Hypoxia Tolerance in Sea Nomads
Authors: Ilardo Melissa , dos Santos Maria C. Ferreira , Grote Beverborg Niels , Rajan Malini , Said M. Abdullah , Verweij Niek , Van Der Harst Pim , Van Der Meer Peter , Leibold Elizabeth A.
Published: January 2022

The Bajau Sea Nomads were recently demonstrated to have evolved larger spleens as an adaptation to millennia of a marine foraging lifestyle. The large-spleen phenotype appears to derive from increases in thyroid hormone (TH) production as a result of reduced expression of phosphodiesterase 10A (PDE10A), though the exact mechanism remains unknown. Through pharmacological inhibition of PDE10A using the selective inhibitor MP-10 in mice, we were able to mimic the Bajau adaptation and show that treated mice had significantly larger spleens than control animals. This difference appears connected to an excess of early stage erythrocytes and an apparent increase in red blood cell (RBC) precursor proliferation in response to increased TH. However, we determined that the stimulation of RBC production in the mouse model via TH is Erythropoietin (EPO)-independent, unlike in the altitude (chronic hypoxemia) response. We confirmed this using human GWAS data; although the Bajau PDE10A variants are significantly associated with increased TH levels and RBC count, they are not associated with EPO levels, nor are other strongly thyroid-associated SNPs. We therefore suggest that an EPO-independent mechanism of stimulating RBC precursor proliferation via TH upregulation underlies the increase in spleen size observed in Sea Nomad populations.
XBP1u Is Involved in C2C12 Myoblast Differentiation via Accelerated Proteasomal Degradation of Id3
Authors: Hayashi Satoko , Sakata Shotaro , Kawamura Shotaro , Tokutake Yukako , Yonekura Shinichi
Published: January 2022

Myoblast differentiation is an ordered multistep process that includes withdrawal from the cell cycle, elongation, and fusion to form multinucleated myotubes. Id3, a member of the Id family, plays a crucial role in cell cycle exit and differentiation. However, in muscle cells after differentiation induction, the detailed mechanisms that diminish Id3 function and cause the cells to withdraw from the cell cycle are unknown. Induction of myoblast differentiation resulted in decreased expression of Id3 and increased expression of XBP1u, and XBP1u accelerated proteasomal degradation of Id3 in C2C12 cells. The expression levels of the cyclin-dependent kinase inhibitors p21, p27, and p57 were not increased after differentiation induction of XBP1-knockdown C2C12 cells. Moreover, knockdown of Id3 rescued myogenic differentiation of XBP1-knockdown C2C12 cells. Taken together, these findings provide evidence that XBP1u regulates cell cycle exit after myogenic differentiation induction through interactions with Id3. To the best of our knowledge, this is the first report of the involvement of XBP1u in myoblast differentiation. These results indicate that XBP1u may act as a “regulator” of myoblast differentiation under various physiological conditions.
Dynamics of Leaf-Litter Biomass, Nutrient Resorption Efficiency and Decomposition in a Moso Bamboo Forest After Strip Clearcutting
Authors: Zheng Yaxiong , Guan Fengying , Fan Shaohui , Yan Xinrong , Huang Lanying
Published: January 2022

Strip clearcutting can significantly reduce the harvesting costs of moso bamboo forests. Although bamboo is characterized by rapid accumulation of biomass, it is still a concern that this management method may reduce long-term productivity. Nutrient cycling has long been considered essential for forests to maintain high primary productivity. However, nutrient cycling of bamboo forests after strip cutting has not been previously reported. We conducted a strip clearcutting experiment and surveyed the litter dynamics for 1 year. We assessed changes in litter nutrients in response to the cutting and calculated the nutrient resorption efficiency and litter decomposition rate to evaluate the effect on nutrient use efficiency and nutrient return. Our results showed that strip cutting had no significant effect on litter production and nutrient return in the moso bamboo forest (p > 0.05). However, annual litter biomass and nutrient return in reserved belts (RB) were significantly higher than those in the control (CK) (p < 0.05). P and K resorption efficiencies in RB were significantly higher than in CK during certain periods of bamboo growth (p < 0.05). We also observed that the annual decay constant of CK was significantly higher than that of plots that were strip clearcut (SC) (p < 0.05). Our results suggest that strip cutting does not affect nutrient use efficiency or storage in the short term.
Organ-Specific Gene Expression Reveals the Role of the Cymbidium ensifolium-miR396/Growth-Regulating Factors Module in Flower Development of the Orchid Plant Cymbidium ensifolium
Authors: Yang Fengxi , Lu Chuqiao , Wei Yonglu , Wu Jieqiu , Ren Rui , Gao Jie , Ahmad Sagheer , Jin Jianpeng , Xv Yechun , Liang Gang , Zhu Genfa
Published: January 2022

Orchids are some of the most popular ornamental plants worldwide. Orchid floral morphology has increasingly attracted horticultural and commercial attention. Although multiple genes have been shown to be involved in the formation of the orchid flower, the underlying multi-level regulatory networks are largely unknown. In this study, we analyzed the ontogeny of flower development in Cymbidium ensifolium, a traditional orchid in the tropical and subtropical regions of Asia, by performing deep sequencing of the transcriptome of individual flower organs to discover organ-specific genes potentially involved in their growth. We identified 3,017 differentially-expressed genes (DEGs) during the development of various flower organs, and observed over-representation of GROWTH-REGULATING FACTORS (GRFs) specific to flower column (gynostemium). Eleven C. ensifolium GRFs (CeGRFs) from our transcriptome data clustered into five phylogenetic subgroups. Ten of these GRFs shared a region complementary to C. ensifolium microRNA396 (Ce-miR396), and degradome sequencing confirmed the cleavage of transcripts derived from seven CeGRFs. We cloned Ce-miR396 and used a protoplast-based transient expression system to overexpress it in Cymbidium protoplasts. We observed a significant decrease in the transcripts of several CeGRFs in flowers and leaves, indicating a potential role for miR396–GRF module in organ development through the cleavage of distinct CeGRFs. Temporal and spatial expression analysis indicated that most CeGRF transcripts accumulated in flower buds and column tissues, where Ce-miR396 expression was the lowest. Expression dynamics in wild type and floral-defective mutants further confirmed a strong correlation between Ce-miR396, CeGRFs, and flower organ development and column specification. Moreover, overexpression of Ce-miR396 in Nicotiana tabacum resulted in curved pistils and reduced fertility, implying that the conserved role of Ce-miR396 in floral development. These results provide tools to better understand the biological roles of GRFs in orchid development, and open new avenues for the diversification of orchid floral patterns.