bluuebunny/crossref_metadata_2025_split huggingface dataset:
Small-molecule modulation of the p75 neurotrophin receptor inhibits a wide range of tau molecular pathologies and their sequelae in P301S tauopathy mice
Authors: Yang Tao , Liu Harry , Tran Kevin C. , Leng Albert , Massa Stephen M. , Longo Frank M. 
Published: September 2020

AbstractIn tauopathies, phosphorylation, acetylation, cleavage and other modifications of tau drive intracellular generation of diverse forms of toxic tau aggregates and associated seeding activity, which have been implicated in subsequent synaptic failure and neurodegeneration. Suppression of this wide range of pathogenic species, seeding and toxicity mechanisms, while preserving the physiological roles of tau, presents a key therapeutic goal. Identification and targeting of signaling networks that influence a broad spectrum of tau pathogenic mechanisms might prevent or reverse synaptic degeneration and modify disease outcomes. The p75 neurotrophin receptor (p75NTR) modulates such networks, including activation of multiple tau kinases, calpain and rhoA-cofilin activity. The orally bioavailable small-molecule p75NTR modulator, LM11A-31, was administered to tauP301S mice for 3 months starting at 6 months of age, when tau pathology was well established. LM11A-31 was found to reduce: excess activation of hippocampal cdk5 and JNK kinases and calpain; excess cofilin phosphorylation, tau phosphorylation, acetylation and cleavage; accumulation of multiple forms of insoluble tau aggregates and filaments; and, microglial activation. Hippocampal extracts from treated mice had substantially reduced tau seeding activity. LM11A-31 treatment also led to a reversal of pyramidal neuron dendritic spine loss, decreased loss of dendritic complexity and improvement in performance of hippocampal behaviors. These studies identify a therapeutically tractable upstream signaling module regulating a wide spectrum of basic mechanisms underlying tauopathies.
Atmospheric resonances and their coupling to vibrations of the ground and waves in the ocean
Authors: Godin Oleg A. , Zabotin Nikolay A. , Zabotina Liudmila 
Published: September 2020

AbstractObservations of the ionosphere with the airglow, GPS-TEC, and HF radar techniques reveal a resonant response of the middle and upper atmosphere to broad-band excitation by earthquakes, volcano eruptions, and convective storms. The resonances occur at such frequencies that an atmospheric wave, which is radiated at the ground level and is reflected from a turning point in the middle or upper atmosphere, upon return to the ground level satisfies boundary conditions on the ground. Using asymptotic and numerical models of atmospheric waves, this paper investigates atmospheric resonances and their excitation by seismic waves and infragravity waves in the ocean. It is found that “buoyancy” resonances with periods up to several hours arise in addition to “acoustic” resonances with periods of about 3–5 min. The acoustic and buoyancy resonances occur, respectively, on the acoustic and gravity branches of the dispersion curve of acoustic-gravity waves. Buoyancy of the atmosphere is important for the resonances of both kinds. Acoustic resonances are found to be sensitive to the temperature profile, especially around mesopause and tropopause, and are predicted to be a seasonal phenomenon in polar atmosphere. Unlike acoustic resonances, buoyancy resonances exhibit high sensitivity to the wind velocity profile and its variations. The resonances correspond to most efficient coupling between the atmosphere and its lower boundary and are promising for detection of such coupling.
Balloon-assisted coil embolization (BACE) of a wide-necked aneurysm of the inferior pancreaticoduodenal artery
Authors: Modestino Francesco , Cappelli Alberta , Mosconi Cristina , Peta Giuliano , Bruno Antonio , Vara Giulio , De Benedictis Caterina , Golfieri Rita 
Published: September 2020

Abstract
Background
Aneurysms of the pancreaticoduodenal arcades are an uncommon pathology, with a prevalence of 2%, and could be congenital or acquired. Treatment of visceral aneurysms is therefore generally recommended when the aneurysmal sac equals or exceeds 2 cm. Wide-necked (> 4 mm) and main artery branch aneurysms represent a challenge for conventional endovascular coil embolization due to the risk of coil migration.

Main body
This case describes the technical feasibility of balloon-assisted coil embolization (BACE) in the treatment a wide neck aneurysm of inferior pancreatic duodenal artery due to celiac axis occlusion.

Short conclusion
In case of celiac trunk occlusion, BACE is a safe procedure associated with optimal technical success rates, in order to treat the aneurysms and to preserve splanchnic vascularization.
Successful re-entry using the outback® elite catheter via retrograde popliteal access with IVUS guidance for femoropopliteal occlusion: a case report
Authors: Hayakawa Naoki , Kodera Satoshi , Arakawa Masataka , Kanda Junji 
Published: September 2020

Abstract
Background
There are still cases that are difficult to treat for femoropopliteal chronic total occlusion (CTO). The Outback® Elite catheter is effective re-entry device to treat such kind of difficult cases, however, it might be difficult to use the Outback® Elite catheter antegradely in cases with severely calcified lesions. In this case, we performed EVT using the Outback Elite® catheter via the retrograde popliteal approach.

Case presentation
We report a case of a 77-year-old male with end-stage renal disease who presented with pain and cyanosis of his left foot. Control angiography showed total occlusion from the middle of the left superficial femoral artery to the proximal portion of the popliteal artery. The CTO lesion was severely calcified, which prevented the antegrade advancement of any guidewire. Retrograde popliteal puncture was performed with the patient in the supine position. After intentional retrograde subintimal wiring, the Outback® Elite catheter was advanced via the retrograde approach after the identification of a suitable re-entry site using intravascular ultrasound. After wire crossing, one nitinol stent was deployed and sufficient antegrade flow was achieved without any complications.

Conclusions
Using Outback® Elite from retrograde should be considered in cases where antegrade advancement fails and bidirectional wiring cannot pass through the CTO lesion.
Global identification of genes associated with xylan biosynthesis in cotton fiber
Authors: CHEN Feng , GUO Yanjun , CHEN Li , GAN Xinli , LIU Min , LI Juan , XU Wenliang 
Published: September 2020

Abstract
Background
Mature cotton fiber secondary cell wall comprises largely of cellulose (> 90%) and small amounts of xylan and lignin. Little is known about the cotton fiber xylan biosynthesis by far.

Results
To comprehensively survey xylan biosynthetic genes in cotton fiber, we identified five IRX9, five IRX10, one IRX14, six IRX15, two FRA8, one PARVUS, eight GUX, four GXM, two RWA, two AXY9, 13 TBL genes by using phylogenetic analysis coupled with expression profile analysis and co-expression analyses. In addition, we also identified two GT61 members, two GT47 members, and two DUF579 family members whose homologs in Arabidopsis were not functionally characterized. These 55 genes were regarded as the most probable genes to be involved in fiber xylan biosynthesis. Further complementation analysis indicated that one IRX10 like and two FRA8 related genes were able to partially recover the irregular xylem phenotype conferred by the xylan deficiency in their respective Arabidopsis mutant. We conclude that these genes are functional orthologs of respective genes that are implicated in GX biosynthesis.

Conclusion
The list of 55 cotton genes presented here provides not only a solid basis to uncover the biosynthesis of xylan in cotton fiber, but also a genetic resource potentially useful for future studies aiming at fiber improvement via biotechnological approaches.
A Prospective Study of Children Aged 0–8 Years with CAH and Adrenal Insufficiency Treated with Hydrocortisone Granules
Authors: Neumann Uta , Braune Katarina , Whitaker Martin J , Wiegand Susanna , Krude Heiko , Porter John , Digweed Dena , Voet Bernard , Ross Richard J M , Blankenstein Oliver 
Published: September 2020

Abstract

Context
Children with congenital adrenal hyperplasia (CAH) and adrenal insufficiency (AI) require daily hydrocortisone replacement with accurate dosing.

Objective
Prospective study of efficacy and safety of hydrocortisone granules in children with AI and CAH monitored by 17-OHP (17-hydroxyprogesterone) saliva profiles.

Methods
Seventeen children with CAH (9 male) and 1 with hypopituitarism (male), aged from birth to 6 years, had their hydrocortisone medication changed from pharmacy compounded capsules to hydrocortisone granules. Patients were followed prospectively for 2 years. In children with CAH, the therapy was adjusted by 17-OHP salivary profiles every 3 months. The following parameters were recorded: hydrocortisone dose, height, weight, pubertal status, adverse events, and incidence of adrenal crisis.

Results
The study medication was given thrice daily, and the median duration of treatment (range) was 795 (1–872) days, with 150 follow-up visits. Hydrocortisone doses were changed on 40/150 visits, with 32 based on salivary measurements and 8 on serum 17-OHP levels. The median daily mg/m2 hydrocortisone dose (range) at study entry for the different age groups 2–8 years, 1 month to 2 years, &lt;28 days was 11.9 (7.2–15.5), 9.9 (8.6–12.2), and 12.0 (11.1–29.5), respectively, and at end of the study was 10.2 (7.0–14.4), 9.8 (8.9–13.1), and 8.6 (8.2–13.7), respectively. There were no trends for accelerated or reduced growth. No adrenal crises were observed despite 193 treatment-emergent adverse events, which were mainly common childhood illnesses.

Interpretation
This first prospective study of glucocorticoid treatment in children with AI and CAH demonstrates that accurate dosing and monitoring from birth results in hydrocortisone doses at the lower end of the recommended dose range and normal growth, without occurrence of adrenal crises.
Update on the Role of NFκB in Promoting Aggressive Phenotypes of Estrogen Receptor–Positive Breast Cancer
Authors: Smart Emily , Semina Svetlana E , Frasor Jonna 
Published: September 2020

AbstractThe majority of breast cancers are diagnosed as estrogen receptor–positive (ER+) and respond well to ER-targeted endocrine therapy. Despite the initial treatability of ER+ breast cancer, this subtype still accounts for the majority of deaths. This is partly due to the changing molecular characteristics of tumors as they progress to aggressive, metastatic, and frequently therapy resistant disease. In these advanced tumors, targeting ER alone is often less effective, as other signaling pathways become active, and ER takes on a redundant or divergent role. One signaling pathway whose crosstalk with ER has been widely studied is the nuclear factor kappa B (NFκB) signaling pathway. NFκB is frequently implicated in ER+ tumor progression to an aggressive disease state. Although ER and NFκB frequently co-repress each other, it has emerged that the 2 pathways can positively converge to play a role in promoting endocrine resistance, metastasis, and disease relapse. This will be reviewed here, paying particular attention to new developments in the field. Ultimately, finding targeted therapies that remain effective as tumors progress remains one of the biggest challenges for the successful treatment of ER+ breast cancer. Although early attempts to therapeutically block NFκB activity frequently resulted in systemic toxicity, there are some effective options. The drugs parthenolide and dimethyl fumarate have both been shown to effectively inhibit NFκB, reducing tumor aggressiveness and reversing endocrine therapy resistance. This highlights the need to revisit targeting NFκB in the clinic to potentially improve outcome for patients with ER+ breast cancer.
Genetic and Pharmacological Inhibition of PAPP-A Protects Against Visceral Obesity in Mice
Authors: Ramakrishna Akhila , Bale Laurie K , West Sally A , Conover Cheryl A 
Published: September 2020

Abstract
Pathogenicity of visceral adipose tissue (VAT) has been linked to the metabolic stress of enlarging mature adipocytes and a limited ability to recruit new adipocytes. One of the major distinguishing features of VAT preadipocytes is the high expression of the zinc metalloprotease, pregnancy-associated plasma protein-A (PAPP-A), when compared to subcutaneous adipose tissue (SAT). In this study we used 2 different approaches to investigate the effect of PAPP-A inhibition on different fat depots in mice on a high-fat diet (HFD) for 15 weeks. Conditional knockdown of PAPP-A gene expression in female adult mice resulted in significant decreases of 30% to 40% in adipocyte size in VAT (mesenteric and pericardial depots) compared to control mice. There was no effect on SAT (inguinal) or intra-abdominal perigonadal fat. Liver lipid was also significantly decreased without any effect on heart and skeletal muscle lipid. We found similar effects when using a pharmacological approach. Weekly injections of a specific immunoneutralizing monoclonal antibody (mAb-PA 1/41) or isotype control were given to male and female wild-type mice on HFD for 15 weeks. Adipocyte size was significantly decreased (30%-50%) only in VAT with mAb-PA 1/41 treatment. In this model, cell number was significantly increased in mesenteric fat in mice treated with mAb-PA 1/41, suggesting hyperplasia along with reduced hypertrophy in this VAT depot. Gene expression data indicated a significant decrease in F4/80 (macrophage marker) and interleukin-6 (proinflammatory cytokine) and a significant increase in adiponectin (anti-inflammatory adipokine with beneficial metabolic effects) in mesenteric fat compared to inguinal fat in mice treated with mAb-PA 1/41. Furthermore, there was significantly decreased liver lipid content with mAb-PA 1/41 treatment. Thus, using 2 different models systems we provide proof of principle that PAPP-A inhibition is a potential therapeutic target to prevent visceral obesity and its metabolic sequelae, such as fatty liver.
Dexmedetomidine Provides Cardioprotection During Early or Late Reperfusion Mediated by Different Mitochondrial K+-Channels
Authors: Raupach Annika , Karakurt Elif , Torregroza Carolin , Bunte Sebastian , Feige Katharina , Stroethoff Martin , Brandenburger Timo , Heinen André , Hollmann Markus W. , Huhn Ragnar 
Published: September 2020

Background:
Cardioprotective interventions—such as pharmacological postconditioning—are a promising strategy to reduce deleterious consequences of ischemia and reperfusion injury (I/RI) in the heart, especially as timing and onset of myocardial infarction are unpredictable. Pharmacological postconditioning by treatment with dexmedetomidine (Dex), an α2-adrenoreceptor agonist, during reperfusion protects hearts from I/RI, independently of time point and duration of application during the reperfusion phase. The mitochondrial ATP-sensitive K+ (mKATP) and mitochondrial large-conductance calcium-sensitive potassium channel (mBKCa) play a pivotal role in mediating this cardioprotective effect. Therefore, we investigated whether Dex-induced cardioprotection during early or late reperfusion is mediated variously by these mitochondrial K+-channels.

METHODS:
Hearts of male Wistar rats were randomized into 8 groups and underwent a protocol of 15 minutes adaption, 33 minutes ischemia, and 60 minutes reperfusion in an in vitro Langendorff-system. A 10-minute treatment phase was started directly (first subgroup, early reperfusion) or 30 minutes (second subgroup, late reperfusion) after the onset of reperfusion. Control (Con) hearts received vehicle only. In the first subgroup, hearts were treated with 3 nM Dex, 100 µM mKATP-channel blocker 5-hydroxydecanoate (5HD) or 1 µM mBKCa-channel blocker Paxilline (Pax) alone or with respective combinations (5HD + Dex, Pax + Dex). Hearts of the second subgroup received Dex alone (Dex30’) or in combination with the respective blockers (5HD + Dex30’, Pax + Dex30’). Infarct size was determined with triphenyltetrazoliumchloride staining. Hemodynamic variables were recorded during the whole experiment.

RESULTS:
During early reperfusion (first subgroup), the infarct size reducing effect of Dex (Con: 57% ± 9%, Dex: 31% ± 7%; P< .0001 versus Con) was completely abolished by 5HD and Pax (52% ± 6%; Pax + Dex: 53% ± 4%; each P< .0001 versus Dex), while both blockers alone had no effect on infarct size (5HD: 54% ± 8%, Pax: 53% ± 11%). During late reperfusion (second subgroup) the protective effect of Dex (Dex30’: 33% ± 10%, P< .0001 versus Con) was fully abrogated by Pax (Pax + Dex30’: 58% ± 7%, P < .0001 versus Dex30’), whereas 5HD did not block cardioprotection (5HD + Dex30’: 36% ± 7%). Between groups and within each group throughout reperfusion no significant differences in hemodynamic variables were detected.

CONCLUSIONS:
Cardioprotection by treatment with Dex during early reperfusion seems to be mediated by both mitochondrial K+-channels, whereas during late reperfusion only mBKCa-channels are involved.
Opioid-Sparing Cardiac Anesthesia: Secondary Analysis of an Enhanced Recovery Program for Cardiac Surgery
Authors: Grant Michael C. , Isada Tetsuro , Ruzankin Pavel , Gottschalk Allan , Whitman Glenn , Lawton Jennifer S. , Dodd-o Jeffrey , Barodka Viachaslau 
Published: September 2020

BACKGROUND:
Cardiac anesthetics rely heavily on opioids, with the standard patient receiving between 70 and 105 morphine sulfate equivalents (MSE; 10–15 µg/kg of fentanyl). A central tenet of Enhanced Recovery Programs (ERP) is the use of multimodal analgesia. This study was performed to assess the association between nonopioid interventions employed as part of an ERP for cardiac surgery and intraoperative opioid administration.

METHODS:
This study represents a post hoc secondary analysis of data obtained from an institutional ERP for cardiac surgery. Consecutive patients undergoing cardiac surgery received 5 nonopioid interventions, including preoperative gabapentin and acetaminophen, intraoperative dexmedetomidine and ketamine infusions, and regional analgesia via serratus anterior plane block. The primary objective, the association between intraoperative opioid administration and the number of interventions provided, was assessed via a linear mixed-effects regression model. To assess the association between intraoperative opioid administration and postoperative outcomes, patients were stratified into high (>50 MSE) and low (≤50 MSE) opioids, 1:1 propensity matched based on 15 patients and procedure covariables and assessed for associations with postoperative outcomes of interest. To investigate the impact of further opioid restriction, ultralow (≤25 MSE) opioid participants were then identified, 1:3 propensity matched to high opioid patients, and similarly compared.

RESULTS:
A total of 451 patients were included in the overall analysis. Analysis of the primary objective revealed that intraoperative opioid administration was inversely related to the number of interventions employed (estimated −7.96 MSE per intervention, 95% confidence interval [CI], −9.82 to −6.10, P < .001). No differences were detected between low (n = 136) and high (n = 136) opioid patients in postoperative complications, postoperative pain scores, time to extubation, or length of stay. No differences were found in outcomes between ultralow (n = 63) and high (n = 132) opioid participants.

CONCLUSIONS:
Nonopioid interventions employed as part of an ERP for cardiac surgery were associated with a reduction of intraoperative opioid administration. Low and ultralow opioid use was not associated with significant differences in postoperative outcomes. These findings are hypothesis-generating, and future prospective studies are necessary to establish the role of opioid-sparing strategies in the setting of cardiac surgery.
Gut Microbiota Influences Neuropathic Pain Through Modulating Proinflammatory and Anti-inflammatory T Cells
Authors: Ding Weihua , You Zerong , Chen Qian , Yang Liuyue , Doheny Jason , Zhou Xue , Li Na , Wang Shiyu , Hu Kun , Chen Lucy , Xia Suyun , Wu Xinbo , Wang Changning , Zhang Can , Chen Liang , Ritchie Christine , Huang Peigen , Mao Jianren , Shen Shiqian 
Published: September 2020

BACKGROUND:
Gut microbiota, a consortium of diverse microorganisms residing in the gastrointestinal tract, has emerged as a key player in neuroinflammatory responses, supporting the functional relevance of the “gut–brain axis.” Chronic-constriction injury of the sciatic nerve (CCI) is a commonly used animal model of neuropathic pain with a major input from T cell–mediated immune responses. In this article, we sought to examine whether gut microbiota influences CCI neuropathic pain, and, if so, whether T-cell immune responses are implicated.

METHODS:
We used a mixture of wide-spectrum oral antibiotics to perturbate gut microbiota in mice and then performed CCI in these animals. Nociceptive behaviors, including mechanical allodynia and thermal hyperalgesia, were examined before and after CCI. Additionally, we characterized the spinal cord infiltrating T cells by examining interferon (IFN)-γ, interleukin (IL)-17, and Foxp3. Using a Foxp3-GFP-DTR “knock-in” mouse model that allows punctual depletion of regulatory T cells, we interrogated the role of these cells in mediating the effects of gut microbiota in the context of CCI neuropathic pain.

RESULTS:
We found that oral antibiotics induced gut microbiota changes and attenuated the development of CCI neuropathic pain, as demonstrated by dampened mechanical allodynia and thermal hyperalgesia. Percentages of IFN-γ–producing Th1 cells and Foxp3+ regulatory T cells were significantly different between animals that received oral antibiotics (Th1 mean = 1.0, 95% confidence interval [CI], 0.9–1.2; Foxp3 mean = 8.1, 95% CI, 6.8–9.3) and those that received regular water (Th1 mean = 8.4, 95% CI, 7.8–9.0, P < .01 oral antibiotics versus water, Cohen’s d = 18.8; Foxp 3 mean = 2.8, 95% CI, 2.2–3.3, P < .01 oral antibiotics versus water, Cohen’s d = 6.2). These T cells characterized a skewing from a proinflammatory to an anti-inflammatory immune profile induced by gut microbiota changes. Moreover, we depleted Foxp3+ regulatory T cells and found that their depletion reversed the protection of neuropathic pain mediated by gut microbiota changes, along with a dramatic increase of IFN-γ–producing Th1 cell infiltration in the spinal cord (before depletion mean = 2.8%, 95% CI, 2.2–3.5; after depletion mean = 9.1%, 95% CI, 7.2–11.0, p < .01 before versus after, Cohen’s d = 5.0).

CONCLUSIONS:
Gut microbiota plays a critical role in CCI neuropathic pain. This role is mediated, in part, through modulating proinflammatory and anti-inflammatory T cells.