bluuebunny/crossref_metadata_2025_split huggingface dataset:
The comparative and functional anatomy of appendicular musculature of Humboldt’s woolly monkey (Lagothrix lagotricha): What can a (mediocre) suspensory monkey tell us about and human locomotor evolution?
Authors: Deane Andrew Stewart , Organ Jason , Evie Vereecke , Muchlinski Magdalena , Butterfield Tim 
Published: April 2020

Similar to other members of the platyrrhine subfamily Atelinae, Humboldt’s wooly monkey (Lagothrix lagotricha) isa ‘tail‐assisted’ brachiator that more frequently engages in non‐suspensory forms of locomotion (i.e. quadrupedal climbing). As a group the atelines share a suite of derived forelimb skeletal characters that are specialized for brachiation and that are convergent with ‘richochetal’ brachiating apes (Hylobates, Symphalangus), quadrumanus suspensory apes (Pongo) and secondarily terrestrial apes retaining suspensory capabilities (Pan, Gorilla). The skeletal anatomy of lagothrix is similar to more suspensory atelines (Ateles, Brachyteles) and living apes, but is typically less derived for suspension and many skeletal characters are intermediate between highly suspensory and non‐suspensory anthropoids. While the functional morphology of the ateline skeleton is well documented, relatively little is known about the comparative and functional morphology of the forelimb and hindlimb musculature. Specifically, can locomotor differences between Lagothrix and more suspensory atelines and hylobatids be explained, in part, as a result of differences in muscletendon architecture?This study describes preliminary quantitative data on the muscle–tendon architecture (relative muscle mass and relative physiological cross‐sectional area or PCSA) of the fore‐ and hind‐limbs of Lagothrix lagotricha and Macacasp. (n=9). Despite infrequent brachiation, Lagothrix forelimb relative muscle mass and PCSA is identical to similar results reported for hominoids. In contrast, the relative mass and PCSA of the hind‐limb musculature is most similar to quadrupedal monkeys (i.e. Macaca). Specifically, Lagothrix resembles hylobatids in the concentration of muscle mass and force in the flexor compartments of the arm and forearm but is more similar to Macaca in similar measures associated with the extensor and flexor thigh and leg. This suggests that despite a reduced reliance on suspensory postures and brachiation, Lagothrix forelimb muscle‐tendon architecture may be, at least in part, a response to the minimum functional demands of brachiation but that similar selection pressures are not as prevalent in the hind‐limb.
The Sigma1 Receptor Antagonist CM304 Enhances the Antinociceptive Effects of the Cannabinoid Receptor Agonists, but not Mu‐Opioid Receptor Full Agonists in Mice
Authors: Patel Avi , Obeng Samuel , Burns Mallory , Intagliata Sebastiano , Mottinelli Marco , Reeves Morgan E. , Behnke Mira , Restrepo Luis F. , Taylor Victoria A. , Pennington Anna E. , Gamez Jimenez Lea R. , Williamson Morgan R. , McCurdy Christopher R. , McMahon Lance R. , Hiranita Takato 
Published: April 2020

There is an overdose epidemic associated with the use of illicitly manufactured as well as prescription mu‐opioid receptor agonists. Sigma1 receptor (σ1R) antagonists in combination with other drugs may provide a viable, safer pharmacological option than opioids alone for treating pain. The present study compared pharmacological effects of the σ1R antagonist CM304 alone and in combination with high (fentanyl and morphine) and low (buprenorphine) efficacy opioid agonists and the cannabinoid CB (CP55,940 and THC) receptor agonists in C57BL/6J mice. Rectal temperature, tail withdrawal latency (10‐seconds cutoff) from warm water of various temperatures (45°C, 50°C and 55°C) and counts of unhabituated locomotor activity were measured in this order. Basal latency for tail withdrawal systematically decreased from 10 seconds at 45°C to 1.3 seconds at 55°C. Morphine, fentanyl and buprenorphine dose‐dependently increased maximum possible effects (MPEs) up to 100% at 55°C (ED50 values: 7.50, 0.068, and 1.13 mg/kg, respectively), whereas CP55,940 and THC were less effective at 55°C (Emax values: 56.6% and 58.2%, respectively). CM304 (56 mg/kg, i.p.) produced an upward shift in the CP55,940 dose‐effect function such that 100% MPE was achieved at 3.2 mg/kg CP55,940, while CM304 (56 mg/kg) produced a 3‐fold leftward shift in the dose‐effect curve of THC. On the other hand, CM304 did not enhance the antinociceptive effects of morphine and fentanyl but enhanced the effects of buprenorphine. In contrast to tail withdrawal latency, there were no consistent effects of CM304 on cannabinoid‐induced decreases in rectal temperature or locomotor activity. The present results may support the development of a σ1R antagonist as an adjunct to cannabinoid and low efficacy μ‐opioid receptor agonists for the treatment of acute pain.Support or Funding InformationThis work was supported by National Institute on Drug Abuse grants DA23205 and DA48353.
Effects of An Omega‐3 High‐Fat Diet on Skeletal Muscle Protein Degradation in Glucocorticoid‐Induced Muscle Wasting
Authors: Puppa Melissa , Brown Katie , Persinger Aaron 
Published: April 2020

Treatment with synthetic glucocorticoids induces muscle atrophy and are commonly used in the treatment of a variety of inflammatory and autoimmune diseases. Omega‐3 (n‐3) polyunsaturated fatty acids elicit beneficial effects in several muscle atrophy conditions. Therefore, the purpose of this study was to determine if a high‐fat diet rich in n‐3 is protective of glucocorticoid‐induced protein degradation. Male wild type C57BL/6 mice were randomized into two groups: n‐6 (45% fat 177.5 g lard) and n‐3 (45% fat 177.5 g Menhaden oil). After 4 weeks on their diets, groups were divided to receive either daily injections of 3 mg/kg/day dexamethasone (Dex) or sterile phosphate buffered saline, for 1 week while continuing diets. At sacrifice the gastrocnemius muscle was weighed and dissected into red and white portions before being snap frozen and processed for RNA extraction and protein extraction. Dex reduced gastrocnemius weight by 12% independently of diet. Protein degradation signaling in the white gastrocnemius was altered by Dex with increased atrogin‐1 expression (p=0.004) without a change in muscle RING finger 1 (MuRF‐1) expression (p=0.15). There was a large effect of Dex to decreased phosphorylation of forkhead box transcription factor O3a (FOXO3a) (Cohen’s d=1.42), increased phosphorylation of glycogen synthase kinase 3β (GSK‐3β) (Cohen’s d=1.42). However, the negative effects of dexamethasone were not attenuated by an n‐3 high‐fat diet. There was no effect of Dex or diet on phosphorylation of FOXO3a (p=0.17) or GSK3β (p=0.60) in red gastrocnemius muscle. These data support the detrimental effects of dexamethasone on muscle atrophy and report no benefit of an n‐3 high‐fat diet.Support or Funding InformationFunding provided by University of Memphis School of Health Studies
Gut bacteria and lipocalin 2 interplay mediates inflammation and arteriosclerosis in type‐II diabetic kidney
Authors: Pushpakumar Sathnur , Majumder Suravi , Sen Utpal 
Published: April 2020

Genome‐wide association studies report significant correlations of unique gut microbiota and their metabolites with type II diabetes (T2D). Further, a growing body of evidence suggest the gut microbiota plays an important role in the onset and progression of Diabetic nephropathy. Lipocalin 2 (Lcn2) is a small secretory glycoprotein that can act as a mediator or modulator of inflammatory processes in various pathologies. Recently, in addition to its role as a potential biomarker of diseases, Lcn2 was shown to contribute towards the progression of nephrectomy‐induced chronic kidney disease (CKD). High levels of Lcn2 have been reported in obesity and type II diabetes (T2D) however, its role in T2D nephropathy remains unknown. Therefore, the purpose of this study was to investigate the relationship of gut microbiota and Lcn2 in T2D and whether Lcn2 contributes to the development of renal arteriosclerosis and dysfunction. Three‐month‐old mice homozygous for Leprdb mutation (db/db) were used as type – II diabetes models and mice heterozygous for Leprdb mutation (db/+, non‐diabetic) served as controls. Lcn2 was upregulated in db/db kidney compared to db/+. There was differential expression of Lcn2 in the fecal and plasma samples of db/db mice compared to db/+ and correlated with gut and renal inflammation. In db/db mice, high Lcn2 protein levels correlated with poor renal function. Microbial DNA isolation from stools and 16S rRNA sequencing showed abundance of bacteria at phyla level in db/db mice compared to db/+ and rich in alpha and beta diversity. The db/db samples showed decreased Firmicutes/Bacteriodetes ratio and increased Proteobacteria compared to db/+. Further, Actinobateria was absent in the db/db samples. The db/db kidneys showed increased vascular adhesion molecules and inflammation, reduction of vascularity and decreased blood flow. Barium angiography revealed narrowing of renal, segmental and interlobar arteries and rarefaction of terminal branches in db/db kidneys compared to db/+. The db/db kidneys showed injury, vascular thickening and reduced elastin. Our findings of altered gut microbiome and upregulation of Lcn2 suggests a significant crosstalk between the gut and kidney and is associated with renal inflammation, arteriosclerosis and dysfunction.Support or Funding InformationNIH: DK116591 and DK104653 to Utpal SenAHA: 15SDG25840013 to Sathnur Pushpakumar
Altered Cisplatin Pharmacokinetics during Nonalcoholic Steatohepatitis Contributes to Reduced Nephrotoxicity
Authors: Jilek Joseph Lionel , Toth Erica , Frost Kayla , Jacobus Kevyn , He Wenxi , Goedken Michael , Cherrington Nathan 
Published: April 2020

Cisplatin is an alkylating antineoplastic agent that is indicated for the treatment of solid malignancies. Cisplatin is preferentially eliminated from systemic circulation via tubular secretion, whereby it exhibits dose‐limiting nephrotoxicity. Interindividual variability in xenobiotic transporter expression is a known contributor to differential cisplatin toxicity and efficacy, and may be the result of genetic, environmental, and pathological contributions. In this study, we aimed to determine if nonalcoholic steatohepatitis (NASH) alters cisplatin pharmacokinetics and if this change elicits differential nephrotoxicity. Sprague Dawley rats fed a control or methionine and choline deficient (MCD) diet to model NASH were given a single bolus dose of cisplatin and sacrificed after 72 h. The MCD diet resulted in a NASH hepatic phenotype that remained unchanged following cisplatin exposure. Drug‐naïve NASH rats also displayed no evidence of differential renal pathology relative to control rats. However, renal necrosis and inflammation were reduced in NASH by 40 and 63% following cisplatin treatment, respectively, relative to healthy controls. Furthermore, kidney weights of cisplatin‐treated control rats were increased by 31%, compared to an 18% increase in NASH. Plasma cisplatin clearance was reduced from 6.78 (control) to 4.04 mL/min in NASH, and cisplatin plasma AUC was significantly increased by 44% in NASH, relative to control. Cumulative urinary elimination of cisplatin was decreased from 73 to 34% of total dose and renal clearance was reduced from 4.64 to 1.49 mL/min in NASH, compared to control. Subsequently, renal intracellular accumulation of cisplatin after 6 h was reduced by 34% in NASH, relative to control. Supporting these findings, expression of proximal tubule cisplatin uptake transporters, Ctr1 and Ctr2, were reduced by 24 and 64%, respectively compared to healthy control rats, whereas expression of Oct1, Oct2, and Oct3 were unchanged. Interestingly, expression of cisplatin efflux transporters Mate1 and Atp7a were reduced by 52 and 31%, respectively, in NASH compared to control. Taken together, these data suggest that NASH alters renal uptake and efflux transporter expression, thereby attenuating cisplatin uptake and clearance in the kidney with a corresponding reduction in renal cell exposure and nephrotoxicity during NASH. As such, this study demonstrates that NASH can influence pharmacokinetics of drugs cleared by renal elimination, which may contribute to adverse drug reactions.Support or Funding InformationThis work is supported by a NIH grant [R01 ES028668] and the Southwest Environmental Health Sciences Center [P30 ES006694]. JLJ is supported by an institutional training grant [T32 ES007091].
Kinetensin is an Endogenous β‐arrestin‐biased Ligand of Angiotensin AT1 receptor
Authors: Filipeanu Catalin , Ogunlade Blessing , Ghita Ioana , Lazartigues Eric , Fang Yayin 
Published: April 2020

Kinetensin, a nonapeptide having similarities to neurotensin and angiotensin II has been isolated from human plasma more than 30 years ago, but its patho‐physiological functions and signal transduction mechanisms remain elusive. In this work, we investigated the effects of kinetensin on G protein‐coupled receptors (GPCRs), one of the largest families of the human genome and the biological target of many peptides. Using Presto‐tango system, the effects of this peptide were tested on a panel of 178 class A GPCRs. Kinetensin (10−6M) stimulated β‐arrestin activation in HTLA cells transfected with angiotensin type 1 receptor (AT1R) by 638±45% compared to basal levels (n=16). At the same concentration, kinetensin also stimulated β‐arrestin activation by histamine H1 receptor (201+22%), melatonin MT1 (187±12%) and MT2 (183±7%) receptors, MRGPRX3 (179±14%), GPR83 (186±10%) and GPR88 (190±10% n=3 in each case), but these effects were significantly smaller compared to the effects on AT1R. In contrast, kinetensin had no significant effect on β‐arrestin activation in cells transfected with other GPCRs, including receptors related to renin‐angiotensin system like AT2, MAS1 and MAS1L, or with neurotensin receptors (NTS1 and NTS2). The effects of the peptide on AT1R‐stimulated β‐arrestin activation were reproduced in HEK293T cells using nanoBRET method. These experiments demonstrated that maximal effects of kinetensin at 10−6M were 39±8% from the effects of angiotensin II (angII, 10−6M), with an EC50 of 115+21 nM (n=4). We also tested the effects of kinetensin on [Ca2+]i (a marker of G‐protein activation) in AT1R transfected HEK293T cells and we found that its effects were only a fraction of the effects of angII (14±8%, n=4). These data indicate that kinetensin is a β‐arrestin biased agonist at AT1R. Interestingly, angiotensin 1‐7 (ang1‐7), a heptapeptide with opposite actions to angII and favorable effects on the regulation of cardio‐vascular activities, demonstrated comparable effects in cells transfected with AT1R (21+7% stimulation of β‐arrestin activation and 4±8% increases in [Ca2+]i at 10−6 M, n=4). In this respect, kinetensin also resembles the effects of novel AT1R β‐arrestin biased agonist TRV027, which is currently tested in clinical trials for the treatment of acute heart failure. Overall, our results show that the nonapeptide kinetensin differentially modulates AT1R‐induced β‐arrestin and G‐protein activation, and these effects can be relevant to target this GPCR in cardio‐vascular diseases.Support or Funding InformationThis work was supported in part by grants from National Science Foundation (Nos. 1708959 & 1924092) and Office of Naval Research (Nos. N00014‐18‐1‐2145 & N00014‐19‐1‐2602) to YF, U.S. Department of Veterans Affairs (I01 BX004294 to CMF and EL) and National Institutes of Health (HL093178 and COBRE P30GM106392), and LSUHSC‐NO Research Enhancement Program to EL.
Introducing a New Classification System for the Cerebral Arterial Circle of Willis
Authors: Nestor Nicholas , Ritz Brianna , Kumar Anil , Klinkhachorn Penprapa , Zdilla Matthew 
Published: April 2020

The cerebral arterial circle of Willis (CoW) is an arterial ring with an extensive range of variation and implications in cerebrovascular disease. Variations of the CoW are implicated in varied pathologies including aneurysms. This study analyzed the variations of the CoW in 177 cadavers. Each vessel in the CoW was identified as normal, hyperplastic, hypoplastic, aplastic, duplicated, triplicated, or plexiform. There were 73 total variation patterns identified. These variations were used to inform the development of a novel classification system that categorizes a CoW into one of 20 morphological types. The categorization is streamlined by assessing the anterior and posterior CoW vasculature independently. The anterior (A) variations are paired with their corresponding posterior (P) variations for a more complete description of the entire CoW variation. An unremarkable CoW is referenced as “A0P0.” The most common variant type is “A0P1” (16.95%) which has a normal anterior and a hypoplastic P1/hyperplastic P2/hyperplastic PCoA. This is followed by “A0P2” (12.99%) which has a normal anterior and a hypoplastic/aplastic PCoA. The circle is incomplete in 9.03% and bilaterally asymmetric in 49.16%. The proposed classification system will help improve the way CoW variations are classified and improve the understanding of how CoW variations are related to cerebrovascular pathology.Support or Funding InformationFunding: WV Research Challenge Fund [HEPC.dsr.17.06]
Primary and Secondary Bile Acids Activate Hepatic Stellate Cells
Authors: Yarde Shari Shontelle , Cheng Xingguo 
Published: April 2020

The activation and proliferation of hepatic stellate cells (HSCs) is a major etiology contributing to the development and progression of liver fibrosis, cirrhosis and hepatocarcinogenesis. In response to liver injury, such as following oxidative stress, alcohol intoxication, viral infections and obesity, quiescent HSCs are transformed into an activated state. Cholestatic liver disease, which is generally characterized by the accumulation of bile acids in serum and liver, can progress to liver cirrhosis if not treated. However, the regulation of activation and proliferation of HSCs by bile acids is not fully understood. The current study was performed to determine the effects of two unconjugated primary bile acids [cholic acid (CA) and chenodeoxycholic acid (CDCA)] and one unconjugated secondary bile acid lithocholic acid (LCA) on the activation and proliferation of cultured human LX‐2 hepatic stellate cells. Our results showed that all of three bile acids induced activation and proliferation of LX‐2 cells, evidenced by increased mRNA expression of proliferating cell nuclear antigen (PCNA) and cytoglobin. In addition, all of three bile acids are predisposed to induce fibrogenesis as evidenced by increased mRNA expression of α‐smooth muscle actin (SMA) and procollagen‐1 in LX‐2 cells. In conclusion, both primary and secondary bile acids activate hepatic stellate cells and may consequently promote liver fibrogenesis.Support or Funding InformationDepartment of Pharmaceutical Sciences, St. John’s University, Queens, NY 11439, USA.
Development of basicranium in cotton‐top tamarin compared to the development of basicranium in bushbabies : Role of synchondroses and brain growth
Authors: Oladipupo Lanre , Wood Brody , Mano Nanami , Hughes Gabriel , Reynolds Rebecca , Vinyard Chris , DeLeon Valerie , Smith Timothy 
Published: April 2020

The purpose of this study is to describe basicranial and brain growth in sub‐adult cotton‐top tamarin (Saguinus oedipus) and compare their growth with greater bushbabies (Otolemur spp.) based on computed tomographic (CT) imaging. Bilateral synchondroses (alisphenoid‐basisphenoid synchrondrosis, ABS) have been identified within the middle cranial fossa of bushbabies which indicate active growth centers at this stage of development. In Saguinus, the ABS fuses relatively earlier and is oriented more anteriorly than in Otolemur. In this study, we used micro‐computed tomography (CT) and imaging software (Amira) to study heads of Saguinus and Otolemur that died of natural causes at two ages: near birth and at approximately one‐month postnatal age. Using Amira, the endocranial contour of crania were manually segmented throughout serial slices, in order to generate a three‐dimensional view of an endocast. This allowed a comparison of brain shape differences between ages in each species. In both species, the occipital lobe is proportional broader and more posteriorly projected at one‐month of age. In addition, the endocast of both species are more complex in contour in the older specimens (i.e., surfaces were more rounded at birth). In Otolemur, the cerebellum and the temporal lobes are more inferiorly positioned in the older animal. In contrast, in Saguinus, the cerebellum becomes less pronounced due to a relative overgrowth of the cerebrum. Also, in Saguinus the temporal lobes are more laterally projecting and anteriorly displaced at one‐month. These results are consistent with the hypothesis that the ABS fuses early in primates, and bone modeling has a primary role in accommodating postnatal shape changes in the brain. However, we note that the ABS is oriented differently (more anteriorly) in the monkey, associated with the relatively anterior displacement of the temporal lobe.Support or Funding InformationNSF # BCS‐1830894, BCS‐1830919, BCS‐0959438
Cigarette Smoke Exposure in Mice Impairs Force Development of Injured Fast‐Twitch Skeletal Muscles
Authors: Stevens Nicole , Davila Daniel , De-Perio Maribeth , Souresrafil Ehson , Nguyen Namphuong , Vitorino Steven , Hogan Michael C. , Breen Ellen C. , Nogueira Leonardo 
Published: April 2020

The use of tobacco cigarettes is known to impair muscle contractile function and decrease muscle mass. Smokers also show a slower recovery following overuse‐induced muscle injury, but the effects of cigarette smoke exposure on muscle repair are not known. We tested whether a short‐term cigarette smoke exposure would affect the regeneration of locomotor muscles following injury by lengthening contractions. Wild‐type C57Bl/6J mice were nose‐only exposed to the smoke of 10 tobacco research cigarettes (1R6F) a day (CS, n=12 mice), or air‐exposed (Air, n=10 mice), for 5 days per week, lasting 8 weeks. CS mice gained less weight than their Air counterparts over the 8‐week period (2.0 ± 0.5 g vs 3.0 ± 0.4 g, respectively). On the seventh week of the exposure, the mice underwent an in vivo lengthening contraction procedure (LCP) to injure the tibialis anterior (TA) and the extensor digitorum longus (EDL) muscles of the right hindlimb (LCP leg), while the left hindlimb was used as a contralateral control (Control leg). During the LCP, the peroneal nerve of the right hindlimb from each mouse was electrically stimulated to evoke contractions of the anterior crural muscles and the foot was actively moved to produce plantar flexion (150 contractions with 20 s intervals). One week after the LCP, mice were euthanized and the EDL and TA muscles were harvested from both legs to test ex‐vivo contractility and to perform histochemistry of cross‐sections of the muscles. Force development in EDL muscles from the LCP legs were significantly smaller than the control legs for both groups (7 ± 4 % and 14 ± 6 % decrease, for CS Air and CS groups; P<0.01 vs control leg). Air and CS groups did not show differences in force in EDL muscles from the control legs (473 ± 25 vs 469 ± 13 kPa, respectively), but in muscles from the LCP legs, force in the CS group (398 ± 24 kPa) was significantly smaller than the Air group (444 ± 24 kPa; P<0.05). These data suggest that tobacco smoking impairs muscle regeneration when muscles are injured by lengthening contractions.Support or Funding InformationTobacco‐Related Disease Research Program