Rapid eye movement (REM) sleep is an important component of the natural sleep/wake cycle, yet the mechanisms that regulate REM sleep remain incompletely understood. Cholinergic neurons in the ...mesopontine tegmentum have been implicated in REM sleep regulation, but lesions of this area have had varying effects on REM sleep. Therefore, this study aimed to clarify the role of cholinergic neurons in the pedunculopontine tegmentum (PPT) and laterodorsal tegmentum (LDT) in REM sleep generation. Selective optogenetic activation of cholinergic neurons in the PPT or LDT during non-REM (NREM) sleep increased the number of REM sleep episodes and did not change REM sleep episode duration. Activation of cholinergic neurons in the PPT or LDT during NREM sleep was sufficient to induce REM sleep.
The mosquitoes Aedes aegypti (Linnaeus, 1762) (Diptera: Culicidae) and Culex quinquefasciatus Say, 1823 (Diptera: Culicidae) are two major vectors of arthropod-borne pathogens in Grenada, West ...Indies. As conventional vector control methods present many challenges, alternatives are urgently needed. Manipulation of mosquito microbiota is emerging as a field for the development of vector control strategies. Critical to this vector control approach is knowledge of the microbiota of these mosquitoes and finding candidate microorganisms that are common to the vectors with properties that could be used in microbiota modification studies. Results showed that bacteria genera including Asaia, Escherichia, Pantoea, Pseudomonas, and Serratia are common to both major arboviral vectors in Grenada and have previously been shown to be good candidates for transgenetic studies. Also, for the first time, the presence of Grenada mosquito rhabdovirus 1 is reported in C. quinquefasciatus.
A sedentary lifestyle, inadequate diet, and obesity are substantial risk factors for Type 2 diabetes mellitus (T2DM) development. A major picture of T2DM is insulin resistance (IR), which causes many ...impairments in brain physiology, such as increased proinflammatory state and decreased brain-derived neurotrophic factor (BDNF) concentration, hence reducing cognitive function. Physical exercise is a non-pharmacological tool for managing T2DM/IR and its complications. Thus, this study investigated the effects of IR induction and the acute effects of resistance exercise (RE) on memory, neurotrophic, and inflammatory responses in the hippocampus and prefrontal cortex of insulin-resistant rats. IR was induced by a high-fat diet and fructose-rich beverage. Insulin-resistant rats performed acute resistance exercise (IR.RE; vertical ladder climb at 50–100% of the maximum load) or rest (IR.REST; 20 min). Cognitive parameters were assessed by novel object recognition (NOR) tasks, and biochemical analyses were performed to assess BDNF concentrations and inflammatory profile in the hippocampus and prefrontal cortex. Insulin-resistant rats had 20% worse long-term memory (LTM) (
p
< 0.01) and lower BDNF concentration in the hippocampus (−14.6%;
p
< 0.05) when compared to non-insulin-resistant rats (CON). An acute bout of RE restored LTM (−9.7% pre vs. post;
p
> 0.05) and increased BDNF concentration in the hippocampus (9.1%;
p
< 0.05) of insulin-resistant rats compared to REST. Thus, an acute bout of RE can attenuate the adverse effects of IR on memory and neurotrophic factors in rats, representing a therapeutic tool to alleviate the IR impact on the brain.
Human induced pluripotent stem cell (iPSC) lines are a powerful tool for studying development and disease, but the considerable phenotypic variation between lines makes it challenging to replicate ...key findings and integrate data across research groups. To address this issue, we sub-cloned candidate human iPSC lines and deeply characterized their genetic properties using whole genome sequencing, their genomic stability upon CRISPR-Cas9-based gene editing, and their phenotypic properties including differentiation to commonly used cell types. These studies identified KOLF2.1J as an all-around well-performing iPSC line. We then shared KOLF2.1J with groups around the world who tested its performance in head-to-head comparisons with their own preferred iPSC lines across a diverse range of differentiation protocols and functional assays. On the strength of these findings, we have made KOLF2.1J and its gene-edited derivative clones readily accessible to promote the standardization required for large-scale collaborative science in the stem cell field.
Display omitted
•Deep genotyping and phenotyping identified KOLF2.1J as a reference human iPSC line•KOLF2.1J and its gene-edited derivates are readily obtainable with minimal restrictions•Human iPSC lines remain genetically stable after our CRISPR-Cas9-based gene editing•Our multifactorial pipeline serves as a blueprint to identify other lead iPSC lines
Merkle and colleagues deeply characterized candidate human induced pluripotent stem cell (iPSC) lines to identify a common reference line. The KOLF2.1J line performed well across all tested assays and was therefore selected for large scale genomic engineering and distribution.
To truly understand the current status of tropical diversity and to forecast future trends, we need to increase emphasis on the study of biodiversity in rural landscapes that are actively managed or ...modified by people. We present an integrated landscape approach to promote research in human-modified landscapes that includes the effects of landscape structure and dynamics on conservation of biodiversity, provision of ecosystem services, and sustainability of rural livelihoods. We propose research priorities encompassing three major areas: biodiversity, human-environment interactions, and restoration ecology. We highlight key areas where we lack knowledge and where additional understanding is most urgent for promoting conservation and sustaining rural livelihoods. Finally, we recommend participatory and multidisciplinary approaches in research and management. Lasting conservation efforts demand new alliances among conservation biologists, agroecologists, agronomists, farmers, indigenous peoples, rural social movements, foresters, social scientists, and land managers to collaborate in research, co-design conservation programs and policies, and manage human-modified landscapes in ways that enhance biodiversity conservation and promote sustainable livelihoods.
BACKGROUNDSpinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein. New SMN-enhancing therapeutics are associated with variable clinical benefits. ...Limited knowledge of baseline and drug-induced SMN levels in disease-relevant tissues hinders efforts to optimize these treatments.METHODSSMN mRNA and protein levels were quantified in human tissues isolated during expedited autopsies.RESULTSSMN protein expression varied broadly among prenatal control spinal cord samples, but was restricted at relatively low levels in controls and SMA patients after 3 months of life. A 2.3-fold perinatal decrease in median SMN protein levels was not paralleled by comparable changes in SMN mRNA. In tissues isolated from nusinersen-treated SMA patients, antisense oligonucleotide (ASO) concentration and full-length (exon 7 including) SMN2 (SMN2-FL) mRNA level increases were highest in lumbar and thoracic spinal cord. An increased number of cells showed SMN immunolabeling in spinal cord of treated patients, but was not associated with an increase in whole-tissue SMN protein levels.CONCLUSIONSA normally occurring perinatal decrease in whole-tissue SMN protein levels supports efforts to initiate SMN-inducing therapies as soon after birth as possible. Limited ASO distribution to rostral spinal and brain regions in some patients likely limits clinical response of motor units in these regions for those patients. These results have important implications for optimizing treatment of SMA patients and warrant further investigations to enhance bioavailability of intrathecally administered ASOs.FUNDINGSMA Foundation, SMART, NIH (R01-NS096770, R01-NS062869), Ionis Pharmaceuticals, and PTC Therapeutics. Biogen provided support for absolute real-time RT-PCR.
The iPSC Neurodegenerative Disease Initiative (iNDI) is the largest-ever iPSC genome engineering project. iNDI will model more than 100 mutations associated with Alzheimer's disease and related ...dementias (ADRD) in isogenic iPSC lines. Resulting cell lines and phenotypic datasets will be broadly shared.
Abstract Background Context Blood transfusions in spine surgery are shown to be associated with increased patient morbidity. The association between transfusion performed using a liberal hemoglobin ...trigger—defined as an intraoperative hemoglobin level of ≥10 g/dL, a postoperative level of ≥8 g/dL, or a whole hospital nadir between 8-10 g/dL—and perioperative morbidity and cost in spine surgery patients is unknown and thus was investigated in this study. Purpose To describe the perioperative outcomes and economic cost associated with liberal hemoglobin trigger transfusion among spine surgery patients. Study Design/Setting Retrospective study. Patient Sample The surgical billing database at our institution was queried for inpatients discharged between 2008 and 2015 after the following procedures: atlantoaxial fusion, anterior cervical fusion, posterior cervical fusion, anterior lumbar fusion, posterior lumbar fusion, lateral lumbar fusion, other procedures, and tumor-related surgeries. In total, 6931 patients were included for analysis. Outcome Measures The primary outcome was composite morbidity which was comprised of: (1) infection (sepsis, surgical-site infection, Clostridium dificile, or drug-resistant infection), (2) thrombotic event (pulmonary embolus, deep venous thrombosis, or disseminated intravascular coagulation), (3) kidney injury, (4) respiratory event, and/or (5) ischemic event (transient ischemic attack, myocardial infarction, or cerebrovascular accident). Methods Data on intraoperative transfusion were obtained from an automated prospectively collected anesthesia data management system. Data on postoperative hospital transfusion was obtained through a Web-based intelligence portal. Based on previous research, we analyzed the data using three definitions of a liberal transfusion trigger in patients who received an RBC transfusion: a liberal intraoperative Hb trigger as a nadir Hb level of 10 g/dL or greater, a liberal postoperative Hb trigger as a nadir Hb level of 8 g/dL or greater, or a whole hospital nadir Hb level of 8-10 g/dL. Variables analyzed included in-hospital morbidity, mortality, length of stay, and total costs associated with a liberal transfusion strategy. Results Among patients with a whole hospital stay nadir hemoglobin between 8 to 10 g/dL, transfused patients demonstrated a longer in-hospital stay (median IQR, 6 5-9 vs. 4 3-6 days; P<0.0001) and a higher perioperative morbidity (n=145, 11.5% vs. n=74, 6.1%; P<0.0001) than those not transfused. Even after adjusting for age, gender, race, ASA class, CCI score, estimated blood loss, baseline hemoglobin value, number of operated levels, and surgery type, logistic regression analysis revealed that patients with a nadir hemoglobin of 8-10 g/dL who were transfused had an independently higher risk of perioperative morbidity (odds ratio OR = 2.12; 95% confidence interval CI, 1.24-3.64; P=0.006). Estimated additional costs associated with liberal trigger use, defined as a transfusion occurring in patients with a whole hospital stay nadir Hb of 8-10 g/dL, ranged from $202,675 to $700,151 annually. Conclusions Transfusion using a liberal trigger is associated with increased morbidity, even after controlling for possible confounders. Our results suggest that modification of transfusion practice may be a potential area for improving patient outcomes and reducing costs.
Despite advances in spinal oncology, research in patient-based prognostic calculators for metastatic spine disease is lacking. Much of the literature in this area investigates the general predictive ...accuracy of scoring systems in heterogeneous populations, with few studies considering the accuracy of scoring systems based on patient specifics such as type of primary tumor.
The aim of the present study was to compare the ability of widespread scoring systems to estimate both overall survival at various time points and tumor-specific survival for patients undergoing surgical treatment for metastatic spine disease in order to provide surgeons with information to determine the most appropriate scoring system for a specific patient and timeline.
This is a retrospective study.
Patients who underwent surgical resection for metastatic spine disease at a single institution were included.
Areas under the receiver operating characteristic curves were generated from comparison of actual survival of patients and survival as predicted by application of prevalent scoring systems.
A preoperative score for all 176 patients was retrospectively calculated utilizing the Skeletal Oncology Research Group (SORG) Classic Scoring Algorithm, SORG Nomogram, original Tokuhashi, revised Tokuhashi, Tomita, original Bauer, modified Bauer, Katagiri, and van der Linden scoring systems. Univariate and multivariate Cox proportional hazard models were constructed to assess the association of patient variables with survival. Receiver operating characteristic analysis modeling was utilized to quantify the accuracy of each test at different end points and for different primary tumor subgroups. No funds were received in support of this work. The authors have no conflicts of interest to disclose.
Among all patients surgically treated for metastatic spine disease, the SORG Nomogram demonstrated the highest accuracy at predicting 30-day (area under the curve AUC 0.81) and 90-day (AUC 0.70) survival after surgery. The original Tokuhashi was the most accurate at predicting 365-day survival (AUC 0.78). Multivariate analysis demonstrated multiple preoperative factors strongly associated with survival after surgery for spinal metastasis. The accuracy of each scoring system in determining survival probability relative to primary tumor etiology and time elapsed since surgery was assessed.
Among the nine scoring systems assessed, the present study determined the most accurate scoring system for short-term (30-day), intermediate (90-day), and long-term (365-day) survival, relative to primary tumor etiology. The findings of the present study may be utilized by surgeons in a personalized effort to select the most appropriate scoring system for a given patient.
PDF
