bluuebunny/crossref_metadata_2025_split huggingface dataset:
Case Report: An Atypical Innervation to the Gluteus Maximus by the Sciatic Nerve and its Clinical Implications
Authors: Camacho-Quiñones Amarilis , Cárdenas-Suárez Natalia Y. , La Puerta-Resto Marizabel , Jimenez-Dietsch Sofía , Quiñones-Rodríguez Jailenne I. 
Published: April 2020

Anatomical variations, concerning the gluteus maximus (GM), are uncommon and of clinical importance. Usually, the GM is innervated by Inferior Gluteal Nerve (IGN), a branch of the sacral plexus arising from the ventral rami of L5 to S2. An unusual innervation was identified in routine cadaveric dissection in an elderly Puerto Rican female. Here, both the left and right GM were innervated by their corresponding IGN, yet both had an additional innervation by the Sciatic Nerve (SN). The bilateral SN branch to the GM was located proximally, when compared to the IGN, and emerged by the inferior border of the Piriformis muscle. In literature, there have been previous studies reporting multiple forms of innervations to the GM by the SN. Nevertheless, in these cases, the IGN was absent, and this anomaly was usually unilateral.The implications of this variation encompass both clinical and surgical correlations with respect to patient care. Regarding clinical aspects, patients with this dual variation to the GM can present with unique clinical scenarios which might be easily misdiagnosed. For instance, pain caused by inflammation of the GM in these patients might be misinterpreted and associated to pain felt in other conditions related to the SN, such as sciatica and piriformis syndrome. Likewise, women considering surgical intervention in this area might be at a higher risk of an iatrogenic nerve injury due to the anomalous SN branch to the GM.Thus, goal of this case report is to highlight the clinical and surgical implications of this finding based on the variant anatomy of the gluteal region. Physicians need to be aware of the existence of this variation. This might clarify the puzzling clinical manifestations of patients with the latter as well as avoid iatrogenic nerve injuries during surgical interventions.
A Missing Flexor Digitorum Brevis and its Evolutionary and Clinical Implications
Authors: Mantilla Cristian , Rodriquez-Reyes Felix , Villamil-Rios Catalina , Jimenez-Dietsch Sofia , Quinones-Rodriguez Jailenne I. 
Published: April 2020

The flexor digitorum brevis belongs to the superficial layer of muscles of the foot and serves to flex the digits II–V at the proximal interphalangeal joint. Its tendons typically insert on the sides of the middle phalanx of each of the lateral four digits. During routine dissection for a human gross anatomy course, we discovered a bilateral variation in the structure of the flexor digitorum brevis in the feet of an older female cadaver. The variation consists of a bilaterally missing tendon to the digiti minimi (fifth digit). Further dissections were carried out on an additional 10 cadavers in the gross anatomy lab to ascertain the presence or absence of this variation, which is frequent in some populations. Preliminary results indicate that the variation is present in 40% of the Puerto Rican population.The flexor digitorum brevis develops embryologically from anterior condensations of abaxial muscle cell precursors starting at 6 weeks. This variation in particular is not expected to have serious functional or evolutionary consequences in humans, as flexion of the toes is not as important in human locomotor function as it would be in chimpanzees or other hominoids. A lack of functional consequences may result in greater variation than would otherwise be expected. Clinically, the tendon of the flexor digitorum brevis to digit V is often used for flexion of the proximal and intermediate phalanges. Our results suggest that because of the variation’s lack of functional adversities, the absence of this tendon might become increasingly prevalent in the population and that deeper muscles might become hypertrophied to supplement the action of the missing tendon.
Differential spinal tissue oxygen profile during moderate and severe acute intermittent hypoxia
Authors: Perim Raphael Rodrigues , Mitchell Gordon S. 
Published: April 2020

Plasticity is a hallmark of the neural system controlling breathing. A frequently studied model of respiratory motor plasticity is phrenic long‐term facilitation (pLTF), a persistent increase in phrenic burst amplitude induced by acute intermittent hypoxia (AIH). Two independent mechanisms underlie pLTF, depending on details of the AIH protocol. For example, moderate AIH (3, 5 min hypoxic episodes of moderate arterial PO2 with 5 min intervals) elicits a form of pLTF that requires intact carotid bodies, raphe neuron spinal serotonin release, and phrenic motor neuron serotonin type 2 receptor activation; this mechanism is known as the Q pathway to phrenic motor facilitation. The same protocol with more severe hypoxic episodes elicits a distinct cellular mechanism known as the S pathway; severe AIH leads to spinal adenosine accumulation and phrenic motor neuron adenosine 2A receptor activation, initiating the S pathway to pLTF. Since these pathways interact via mutual cross‐talk inhibition, intermediate AIH protocols fail to elicit pLTF since the Q and S pathways cancel one another. Thus, the balance of raphe serotonergic neuron activation (fast) versus spinal tissue hypoxia (slower) is a key determinant in regulating pLTF expression. Since the specific levels of spinal tissue hypoxia tipping this balance are not known, we compared spinal tissue oxygen profiles between moderate (PaO2 40 – 50 mmHg) vs severe AIH (PaO2 25 – 30 mmHg). Ventral cervical spinal tissue oxygen pressure (PtO2) and phrenic nerve activity were recorded in anesthetized, paralyzed and ventilated rats (IFO2 = 60%). As reported before, severe AIH elicited greater short‐term hypoxic phrenic responses and pLTF vs moderate AIH. Severe AIH elicited greater decreases in PtO2, reaching a nadir below ~5 mmHg. Following each episode, a transient overshoot in PtO2 was observed, reaching 90 mmHg above baseline conditions. Following the third hypoxic episode, PtO2 remained above baseline for at least 15 minutes post AIH (~ 10 mmHg). With moderate AIH, tissue hypoxia was less severe (PtO2 nadir ~ 16 mmHg), and post‐hypoxia overshoots far less prominent. In summary, spinal tissue oxygen dynamics are complex during AIH protocols; differences in PtO2 profiles likely underlie mechanistic differences in pLTF observed with moderate vs severe AIH. Understanding these dynamics (including the post‐AIH PtO2 “memory”) may help understand how to optimize AIH protocols to maximize plasticity and, potentially, functional benefits when harnessing AIH to restore breathing deficits with neural injury and/or disease.Support or Funding InformationNIH HL147554 and HL148030
Pro‐inflammatory Cytokines Alter Colonocyte Butyrate Metabolism via p38 Signaling Pathway
Authors: Kim Ji Yeon , Park Bohye , Crumbley Christopher , Wirthwein Kaci L. , Riffey Olivia Faith , Beaird Jacob , Smith Mary , Donohoe Dallas 
Published: April 2020

In ulcerative colitis (UC) and colorectal cancer (CRC), the colonocyte undergoes a metabolic shift. This metabolic shift involves a decrease in the oxidation of the microbial‐derived short‐chain fatty acid, butyrate. The factors that promote this metabolic shift in these diseases are not fully understood. Previously, we showed interleukin‐1β (IL‐1β), a pro‐inflammatory cytokine that is elevated in UC and CRC, decreased the oxidation of butyrate in CRC cells. Experiments identified p38, a mitogen‐activated protein kinase, mediates the diminished butyrate oxidation caused by IL‐1β. We have identified tumor necrosis factor a (TNF‐a) as another pro‐inflammatory cytokine that decreases butyrate oxidation in colorectal cells. The hypothesis is that IL‐1β or TNF‐a drives metabolic shifts in colonocytes that promote disease via the p38 signaling pathway. Both IL‐1β and TNF‐a activate p38 (phosphorylation of p38) in colorectal cancer cells. Next, we utilized the Seahorse XF24 Analyzer to measure butyrate oxidation with and without IL‐1β or TNF‐a treatment. The oxidation of butyrate was lower in cells treated with IL‐1β or TNF‐a compared to untreated controls. Furthermore, IL‐1β or TNF‐a showed a shift in metabolism from oxidative phosphorylation (OXPHOS) to glycolysis. CRC cells treated with IL‐1β or TNF‐a showed increased extracellular acidification rate compared to controls, which indicates that IL‐1β or TNF‐a induces a switch toward glycolysis. Inhibition of p38 or knockdown of p38 decreased IL‐1β or TNF‐a ability to suppress butyrate oxidation. These data provide a mechanism by which cytokines, through p38, regulate metabolism in the diseased colonocyte.Support or Funding InformationUSDA R011770176
MicroRNA‐200a‐3p mediates neuroprotection in Alzheimer‐related deficits and attenuates amyloid‐beta overproduction and tau hyperphosphorylation via co‐regulating BACE1 and PRKACB
Authors: Liu Rui , Wang Lin-lin , Jiang Hai-lun 
Published: April 2020

Alzheimer’s disease (AD) is characterized by two landmark pathologies, the overproduction of amyloid‐beta peptides (Aβ), predominated by the β‐amyloid protein precursor cleaving enzyme 1 (BACE1), and hyperphosphorylation of the microtubule protein, tau, due to an imbalance in a kinase / phosphatase system that involves the activation of the protein kinase A (PKA). Current evidence indicates that brain microRNAs participate in multiple aspects of AD pathology. Here, the role and underlying molecular mechanisms of microRNA‐200a‐3p (miR‐200a‐3p) in mediating neuroprotection against AD‐related deficits were investigated. The expression of miR‐200a‐3p was measured in the hippocampus of APP / PS1 and SAMP8 mice and in an AD cell model in vitro, as well as in blood plasma extracted from AD patients. The targets of miR‐200a‐3p were determined using bioinformatics and dual‐luciferase assay analyses. In addition, cell apoptosis was detected using flow cytometry and related protein levels were measured using Western blot and ELISA techniques. miR‐200a‐3p was confirmed to be depressed in microarray miRNA profile analysis in vitro and in vivo, suggesting that miR‐200a‐3p is a potential biomarker of AD. Subsequently, miR‐200a‐3p was demonstrated to inhibit cell apoptosis accompanied by the inactivation of the Bax / caspase‐3 axis and downregulation of Aβ1‐42 and tau phosphorylation levels in vitro. Further mechanistic studies revealed that miR‐200a‐3p reduced the production of Aβ1‐42 and decreased hyperphosphorylation of tau by regulating the protein translocation of BACE1 and the protein kinase cAMP‐activated catalytic subunit beta (PRKACB) associated with the three prime untranslated regions (3’‐UTRs), respectively. Importantly, the function of miR‐200a‐3p was reversed by overexpression of BACE1 or PRKACB in cultured cells. This resulted in an elevation in cell apoptosis, and an increase in Aβ1‐42, and tau hyperphosphorylation levels, involving the epitopes, threonine 205, serine 202, 214, 396, and 356, the favorable phosphorylated sites of PKA. In conclusion, our study suggests that miR‐200a‐3p is implicated in the pathology of AD, exerting neuroprotective effects against Aβ‐induced toxicity by two possible mechanisms: one involving the inhibition of Aβ overproduction via suppressing the expression of BACE1 and; two, synergistically, decreasing the hyperphosphorylation of tau via attenuating the expression of PKA.Support or Funding Information
This study was supported by the National NaturalScience Foundation of China (No. U1803281 and 81673411), China; the Non‐profitCentral Research Institute Fund of Chinese Academy of Medical Sciences(2018RC350013), China; and Chinese Academy Medical Sciences (CAMS) InnovationFund for Medical Science (2017‐I2M‐1‐016), China.
Immunopathology in Lungs after Intranasal Challenge with Live Virus in an EHV‐1 Murine Model: Lessons Learned from Unexpected Findings
Authors: Awan Aftab , Tulp Orien Lee , Einstein George P. , Field Hugh 
Published: April 2020

Equine herpes virus (EHV‐1) causes wide spread infection among equine populations worldwide. EHV‐1 causes respiratory disease, abortion, neonatal death, paresis, retinopathy and latent viremia. Horses show a transient immunity after natural or experimental EHV‐1 but infection and immune responses to EHV‐1 started to decline after a few months of infection. As a result recovered horses are prone to subsequent EHV‐1 infection. As a result of transient immune responses, effective and lasting vaccination remains a challenge. Human herpesvirus in a murine model provides solid protection to the animals, and re‐infected recovered mice were not easily reinfected after the initial infection. In this study we infected mice with EHV‐1 via intranasal route and after three months mice that had recovered were re‐infected with the same strain of EHV‐1 along with previously placebo control mice that were now infected for the first time in addition to addition of a new new placebo control group. It was proposed that mice that had recovered from a first infection when later challenged with live virus might show some measure of protection, but in fact they showed unexpectedly severe clinical signs. These mice demonstrated severe clinical signs with abdominal breathing, weight loss and a higher mortality rate compared to a same age group of mice who had been exposed to the virus for the first time or the placebo control. The unexpected findings of their worst clinical signs came from postmortem findings and histopathological study, which indicated severe consolidation and profound infiltration of inflammatory cells such that the normal parenchyma and architecture of lungs were completely lost. In this communication Immunopathological findings of the study will be discussed in detail. The results of this study suggest that an immunoreactive mechanism should be considered in designing and selecting epitopes for intranasal vaccine preparation for EHV‐1 and possibly other respiratory infections both in animals and humans.Support or Funding InformationSupported by Institutional Resources of the University of Cambridge, UK, the University of Health and Humanities BVI, the Einstein Institute USA, and the University of Science Arts & Technology, Montserrat, BWI.
Toxoplasma gondii GRA8‐derived peptide immunotherapy improves tumor targeting of colorectal cancer
Authors: Yang Chul-Su 
Published: April 2020

Targeted tumor and efficient, specific biological drug delivery in vivo has been one of the main challenges in protein‐based cancer‐targeted therapies. Mitochondria are potential therapeutic targets for various anti‐cancer drugs. We have previously reported that protein kinase Cα‐mediated phosphorylation of Toxoplasma gondii GRA8 is required for mitochondrial trafficking and regulating the interaction of the C‐terminal of GRA8 with ATP5A1/SIRT3 in mitochondria. Furthermore, SIRT3 facilitates ATP5A1 deacetylation, mitochondrial activation, and subsequent antiseptic activity in vivo. Herein we developed a recombinant acidity‐triggered rational membrane (ATRAM)‐conjugated multifunctional GRA8 peptide (rATRAM‐G8‐M/AS) comprising ATRAM as the cancer‐targeting cell‐penetrating peptide and essential, minimal residues for mitochondrial targeting or ATP5A1/SIRT3 binding. This peptide construct showed considerable improved potency compared with rGRA8 alone in HCT116 human carcinoma cells, reaching an IC50 value of up to 200‐fold lower in vitro and 500‐fold lower in vivo. Notably, rATRAM‐G8‐M/AS treatment showed significant therapeutic effects in a mouse xenograft model through mitochondrial metabolic resuscitation, and it produced negligible immunogenicity and immune responses in vivo. Thus, these results demonstrate that rATRAM‐G8‐M/AS represents a useful therapeutic strategy against tumors, particularly colon cancer. This strategy represents an urgently needed paradigm shift for therapeutic intervention.Support or Funding InformationThis work was supported by the NRF grant funded by the Korea government (MSIP) 2019R1I1A2A01064237.
Will development of human anatomy revolutionize medical education?
Authors: Singh Rajani 
Published: April 2020

The growing trend of vanishing cadaveric dissection, pruning of anatomical curriculum, compression of teaching schedule of Anatomy, deployment of inappropriately qualified tutors and demonstrators and removal of expert and experienced anatomical faculty with closing of Anatomy department all over the world in general and USA, Canada, UK, Australia and New Zealand in particular due to commercialization of medical education has not only eroded standard of medical education but also accelerated the failure cases evidenced by rising medico‐legal cases. So there is worldwide clamor about inadequate knowledge of Anatomy among tomorrows’ doctors causing impediments to comprehend successful clinical practice in general and pathology, surgery, imagery and anestheology in particular. Although many anatomic and clinical stalwarts proposed ways and means to reform delivery/acquisition of Anatomy but hunger of earning chunk of profit from medical institutions never let the quality of medical education improve. Therefore, a new model of Anatomy, to strengthen delivery and acquisition of Anatomy for revolutionizing medical education, has been designed. If adopted divorcing greed of making money from medical schools to save holy and sacred quality medical education from ruining further, the medical profession in general and pathology, surgery, imagery and anestheology in particular will regain their lost glory.The literature was reviewed and factors, continuously contributing to falling standard and growing failure cases due to insufficient knowledge of Anatomy in trainees effecting clinical practice in medical education, were analysed. The analysis evolved model for development of Anatomy as a subject to root out these deficiencies by standardizing curriculum to be taught by medically qualified and experienced faculties with strong background of beautifully blended standalone and collaborative research in variant macro/microanatomy arresting failure cases and litigations. In addition to this, the model will create an environment for easy and necessary interaction of anatomists with clinicians/trainees through providing instant anatomical solution at all levels of medical education during clinical training of medical trainees directly from well guided cadaveric dissection by experienced faculty. The model will also generate readymade records in form of table or charts containing the variant macro/microanatomical information corresponding to relevant clinical complications to help clinicians/clinical trainees during clinical practice. This model will not only provide future reservoir of competent anatomical faculty but also revolutionize clinical skill tremendously among medical trainees.
Discovery and structure‐activity relationship study of novel series of mono‐amine transporter inhibitors for the treatment of neurodegenerative diseases
Authors: Ashraf-Uz-Zaman Md , Ji Guangchen , Alvina Karina , Sajib Md Sanaullah , Mikelis Constantinos , Avila Mirla , Neugebauer Volker , German Nadezhda A. 
Published: April 2020

Monoamines, such as dopamine (DA), serotonin (5‐HT) and norepinephrine (NE), have an important modulatory role in neurotransmission in the central nervous system (CNS). They are involved in numerous physiological functions and pathological conditions. Therapeutic application of selective or mixed monoamine transporter (DAT, SERT or NET) inhibitors includes a variety of neurologic disorders, such as Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, epilepsy, and others. The optimal selectivity profile varies between pathological conditions; however, the exact trend is not well understood yet. Thus, for direct comparison of produced effects, it can be beneficial to identify a class of compounds that includes structurally similar ligands with different selectivity profiles.Recently, we have serendipitously discovered a novel selective DAT inhibitor. Our compound UR118 showed strong DAT inhibition (Ki= 15 nM) with a moderate affinity to SERT (Ki= 1620nM). We design and synthesized a series of analogs of UR118 to initiate a structure‐activity relationship (SAR) study. From the first series of analogs, we obtained selective DAT inhibitors (Ki= 40), as well as DAT‐NET inhibitors (Ki= 6.5 and 167 nM, respectively). In addition to inhibition of transporters, UR118 blocked signaling of H1 (Ki= 32nM) and 5HT‐2C (Ki= 335 nM) receptors. Further, this compound did not affect the remaining 45 GPCRs in the tested panel of CNS‐related receptors. All tested analogs of UR118 have shown similar binding patterns with different selectivity profiles (data obtained from PDSP).Further, UR118 was found to moderately permeate the BBB (Cmax = 1000nM, 10 mg/kg, i.p in mice) with the accumulation in adipose tissue, lung, and liver. UR118 was stable in rat liver microsome (63% remaining at 1 hr.). In pertussis‐induced multiple sclerosis model (mice), we observed a significant improvement of symptoms in the UR118‐treated group when compared to the vehicle‐treated group of animals.In conclusion, we have discovered a novel series of monoamine transporter inhibitors with varying selectivity profile and favorable CNS‐drug‐like characteristics. Compound UR118 with DAT selectivity has shown definite therapeutic potential in in vivo model of multiple sclerosis.Support or Funding InformationSouth Plains Foundation
The Effect of NaCl Concentrations on the NCC and ENaC Interaction
Authors: Walker Michael Austin , King-Medina Keyona , Hoover Robert S. 
Published: April 2020

The kidneys play a key role in maintenance of blood pressure. Within the nephron, the smallest functional unit of the kidney, the sodium chloride cotransporter (NCC) and the epithelial sodium channel (ENaC) are co‐expressed in the second part of the Distal Convoluted Tubule (DCT2). These sodium transport proteins are critically important for regulating blood pressure. Recent studies have established that these two proteins closely associate and are likely bound together. Here, we seek to examine if changes in sodium chloride concentration alter the interaction between NCC and ENaC. We hypothesize that the change in ion concentrations will significantly influence the interaction between NCC and ENaC. After incubating 4 dishes of mouse DCT (mDCT15) cells with different sodium chloride concentrations for 30 minutes, Co‐immunoprecipitation (CO‐IP) was conducted to examine changes in interactions between NCC and ENaC. We have confirmed expression of NCC, ENaC and phospho‐NCC under experimental conditions. Experiments to determine whether the interaction between NCC and ENaC is changed are ongoing. With our results, our knowledge of how different ion concentrations influence the interaction of NCC and ENaC will be enhanced and will be used to better understand how this mechanistic relationship can lead to the development of new therapies or the better utilization of existing therapies that will serve to improve the treatment of hypertension and salt sensitivity.Support or Funding InformationR25 DK 101390: Summer Undergraduate Program in Renal Research (SUPERR)T32: 5T32DK007656‐28 (Dr. Keyona King‐Medina)VA Merit Awards: I01BX002322‐01 (RSH) and I01BX000994 (HC) (Dr. Robert S. Hoover)