bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of retinogeniculate synaptic function in the DBA/2J mouse model of glaucoma
Authors: Smith Jennie C. , Zhang Kevin Yang , Sladek Asia , Thompson Jennifer , Bierlein Elizabeth R. , Bhandari Ashish , Van Hook Matthew J. 
Published: August 2022

AbstractBackgroundRetinal ganglion cell (RGC) axons comprise the optic nerve and carry information to the dorsolateral geniculate nucleus (dLGN) that is relayed to the cortex for conscious vision. Glaucoma is a blinding neurodegenerative disease that commonly results from intraocular pressure (IOP)-associated injury leading to RGC axonal pathology, disruption of RGC outputs to the brain, and eventual apoptotic loss of RGC somata. The consequences of elevated IOP and glaucomatous pathology on RGC signaling to the dLGN are largely unknown and likely to be important contributors to visual system dysfunction in glaucoma. Thus, the goal of this study was to determine how glaucoma affects RGC outputs to the dLGN.MethodsWe used a combination of anatomical and physiological approaches to study the structure and function of retinogeniculate synapses in male and female DBA/2J mice at multiple ages before and after IOP elevation. These included measures of anterograde axonal transport, immunofluorescence staining of RGC axon terminals, patch-clamp recording retinogeniculate (RG) synapses in living brain slices, Sholl analysis of thalamocortical relay neuron dendrites, measurements of RGC somatic density, and treatment with a topical ophthalmic alpha-2 adrenergic agonist (brimonidine).ResultsDBA/2J mice showed progressive loss of anterograde optic tract transport to the dLGN and vGlut2 labeling of RGC axon terminals. Patch-clamp measurements of RG synaptic function showed that the strength of synaptic transmission was lower in 9 and 12-month DBA/2J mice and that this was the result of loss of individual RGC axon contributions. TC neuron dendrites showed a reduction in complexity at 12 months, suggestive of a delayed reorganization following reduced synaptic input. There was no detectable change in RGC soma density in 11-12m DBA/2J retinas indicating that observed effects occurred prior to RGC somatic loss. Finally, treatment with brimonidine eye drops prevented the loss of vGlut2-labeled RGC terminals in the dLGN.ConclusionsThese findings identify glaucoma- and IOP-associated functional deficits in an important subcortical RGC projection target. This sheds light on the processes linking IOP to vision loss and will be critical for informing future diagnostic approaches and vision-restoration therapies.
Minimum effort simulations of split-belt treadmill walking exploit asymmetry to reduce metabolic energy expenditure
Authors: Price Mark , Huber Meghan E. , Hoogkamer Wouter 
Published: August 2022

AbstractWalking on a split-belt treadmill elicits an adaptation response that changes the baseline step length asymmetry of the walker. The underlying causes of this adaptation, however, are difficult to determine. It has been proposed that effort minimization may drive this adaptation, based on the idea that adopting longer steps on the fast belt, or positive step length asymmetry (SLA), can cause the treadmill to exert net-positive mechanical work on a bipedal walker. However, humans walking on split-belt treadmills have not been observed to reproduce this behavior when allowed to freely adapt. To determine if an energy minimization motor control strategy would result in experimentally observed adaptation patterns, we conducted simulations of walking on different combinations of belt speeds with a human musculoskeletal model which minimized muscle effort. The model adopted increasing amounts of positive step length asymmetry and decreased its net metabolic rate with increasing belt speed asymmetry, up to +25.6% SLA and −14.3% metabolic rate at a 3:1 belt speed ratio, relative to tied-belt walking. These gains were primarily enabled by an increase of braking work and a reduction of propulsion work on the fast belt. The results suggest that a purely energy minimization driven split belt walking strategy would involve substantial positive SLA, and that the lack of this characteristic in human behavior points to additional factors influencing the motor control strategy, such as aversion to excessive joint loads, asymmetry, or instability.New & NoteworthyBehavioral observations of split-belt treadmill adaptation have been inconclusive toward its underlying causes. To estimate gait patterns when driven exclusively by one of these possible causes, we simulated split-belt walking with a musculoskeletal model which minimized its energy cost. Our model took significantly longer steps on the fast belt and reduced its metabolic rate below tied-belt walking, unlike experimental observations. This suggests that asymmetry is energetically optimal, but human adaptation involves additional factors.
Phenotype integration improves power and preserves specificity in biobank-based genetic studies of MDD
Authors: Dahl Andrew , Thompson Michael , An Ulzee , Krebs Morten , Appadurai Vivek , Border Richard , Bacanu Silviu-Alin , Werge Thomas , Flint Jonathan , Schork Andrew J. , Sankararaman Sriram , Kendler Kenneth , Cai Na 
Published: August 2022

AbstractBiobanks often contain several phenotypes relevant to a given disorder, and researchers face complex tradeoffs between shallow phenotypes (high sample size, low specificity and sensitivity) and deep phenotypes (low sample size, high specificity and sensitivity). Here, we study an extreme case: Major Depressive Disorder (MDD) in UK Biobank. Previous studies found that shallow and deep MDD phenotypes have qualitatively distinct genetic architectures, but it remains unclear which are optimal for scientific study or clinical prediction. We propose a new framework to get the best of both worlds by integrating together information across hundreds of MDD-relevant phenotypes. First, we use phenotype imputation to increase sample size for the deepest available MDD phenotype, which dramatically improves GWAS power (increases #loci ~10 fold) and PRS accuracy (increases R2 ~2 fold). Further, we show the genetic architecture of the imputed phenotype remains specific to MDD using genetic correlation, PRS prediction in external clinical cohorts, and a novel PRS-based pleiotropy metric. We also develop a complementary approach to improve specificity of GWAS on shallow MDD phenotypes by adjusting for phenome-wide PCs. Finally, we study phenotype integration at the level of GWAS summary statistics, which can increase GWAS and PRS power but introduces non-MDD-specific signals. Our work provides a simple and scalable recipe to improve genetic studies in large biobanks by combining the sample size of shallow phenotypes with the sensitivity and specificity of deep phenotypes.
Inactivated voltage-gated sodium channels are preferentially targeted in cinacalcet block of mouse neocortical action potentials
Authors: Lindner Jamie S. , Rajayer Salil R. , Smith Stephen M. 
Published: August 2022

AbstractVoltage-gated sodium channel (VGSC) activation is essential for action potential generation in the brain. Allosteric calcium-sensing receptor (CaSR) agonist, cinacalcet, strongly and ubiquitously inhibits VGSC currents in neocortical neurons via an unidentified, G-protein-dependent blocking molecule. The mechanisms by which VGSC characteristics influence cinacalcet-mediated inhibition are not well understood. Here, using whole-cell patch clamp methods, we investigated the voltage-dependence of cinacalcet-mediated inhibition of VGSCs and the channel state preference of cinacalcet. The rate of inhibition of VGSC currents was accelerated at more depolarized holding potentials. Cinacalcet shifted the voltage-dependence of both fast and slow inactivation of VGSCs in the hyperpolarizing direction. Utilizing a simple model, the voltage-dependence of VGSC current inhibition may be explained if the affinity of the blocking molecule to the channel states follows the sequence: fast-inactivated > slow-inactivated > resting. The state dependence of block contributes to the non-linearity of action potential block by cinacalcet. This dynamic and abundant signaling pathway by which G-proteins regulate VGSC currents provides an important voltage-dependent mechanism for modulating central neuronal excitability.Key points summaryVoltage-gated sodium channels are essential for the action potential generation and propagation that is central to physiological function in excitable cells. VGSC inhibitors are useful therapies to treat epilepsy, pain, and cardiac arrhythmias.Cinacalcet inhibits VGSC currents strongly and the underlying G-protein dependent signaling pathway occurs in the vast majority of neocortical and hippocampal neurons.Here we demonstrate that cinacalcet inhibits the VGSC current by activating a downstream blocking molecule that preferentially binds to the fast-inactivated state, that the blocking molecule stabilizes the inactivated states, and that cinacalcet impacts neuronal excitability in a non-linear manner.Characterization of the mechanism by which cinacalcet operates will facilitate the determination of its role in regulating neocortical excitability and the identification of new therapeutic targets for epilepsy, pain, and arrythmias.
Wastewater Influent Microbial Immigration and Contribution to Resource Consumption in Activated Sludge Using Taxon-Specific Mass-Flow Immigration Model
Authors: Guo Bing , Liu Chenxiao , Gibson Claire , Klai Nouha , Lin Xuan , Frigon Dominic 
Published: August 2022

AbstractWastewater influent microorganisms are part of the total chemical oxygen demand (COD) and affect the activated sludge (AS) microbial community. Precise modeling of AS processes requires accurate quantification of influent microorganisms, which is missing in many AS models (ASMs). In this study, influent microorganisms in COD unit were determined using a fast quantification method based on DNA yield and was compared with conventional respirometry method. The actively growing influent microorganisms were identified. A mass-flow immigration model was developed to quantify the influent-to-AS immigration efficiency (mi) of specific taxon i using mass balance and 16S rRNA gene high-throughput sequencing data. The modelled average m was 0.121-0.257 in site 1 (LaPrairie), and 0.050-0.126 in site 2 (Pincourt), which were corrected to 0.111-0.186 and 0.048-0.109 respectively using a constrain of mi ≤ 1. The model was further developed to calculate contributions to organic substrate consumption by specific taxa. Those genera with zero or negative net growth rates were not completely immigration dependent (mi < 1) and contributed to 2.4% - 5.4% of the substrate consumption. These results suggest that influent microbiome may be important contributors to AS microbiome assembly and system performance (substrate consumption), which may help to improve future AS process modelling and design.SynopsisInfluent microbial immigration lacks detailed taxon-specific quantification. This study presents quantitative methods and models for influent biomass, mass-flow immigration model, and resource consumption in activated sludge.Graphic Abstract
Single-cell RNA sequencing identifies regulators of differentiation and nutritional cues in Drosophila female germ cells
Authors: Sun Zhipeng , Nystul Todd G. , Zhong Guohua 
Published: August 2022

ABSTRACTDrosophila ovarian germline stem cells (GSCs) are powerful model for stem cell research. However, due to the scarcity of GSCs in ovarian tissue, it is difficult to obtain the transcriptional profile of GSCs and identify novel GSC markers. In this study, we took advantage of single cell RNA sequencing (scRNA-seq) to profile the germline cells and somatic cells in wild type Drosophila ovary. We then performed an in vivo RNAi screen and network analysis to identify genes that are involved in the early stages of germ cell differentiation. We identified 33 genes with limited expression during early germ cell development and identified 19 genes that potentially regulate germ cell differentiation. Among these, an uncharacterized gene, which we named eggplant (eggpl), is highly expressed in GSC and downregulated in early daughter cells. Upon RNAi knockdown of eggpl, we observed an increase in germ cell proliferation, an accumulation of cysts in the early mitotic (2- and 4-cell) stages and an increase in overall ovary size compared to control when flies were maintained on a standard diet. In flies fed a rich yeast diet, the expression of eggpl was significantly lower and the effects of eggpl RNAi were suppressed, suggesting that downregulation of eggpl may link nutritional status to germ cell proliferation and differentiation. We also found that the matrix metalloproteases, Mmp1 and Mmp2 as well as the tissue inhibitor of metalloproteases (Timp) are additional regulators of eggpl. Collectively, this study provides new insight into the signaling networks that regulate early germ cell development and identifies eggpl as a key player in this process.
On the hidden diversity and niche specialization of the microbial realm of subterranean estuaries
Authors: Calvo‐Martin Elisa , Teira Eva , Álvarez‐Salgado Xosé Antón , Rocha Carlos , Jiang Shan , Justel‐Díez Maider , Ibánhez Juan Severino Pino 
Published: August 2022

AbstractSubterranean estuaries (STEs) modulate the chemical composition of continental groundwater before it reaches the coast, but their microbial community is poorly known. Here, we explored the microbial ecology of two neighbouring, yet contrasting STEs (Panxón and Ladeira STEs; Ría de Vigo, NW Iberian Peninsula). We investigated microbial composition (16S rRNA gene sequencing), abundance, heterotrophic production and their geochemical drivers. A total of 10,150 OTUs and 59 phyla were retrieved from porewater sampled during four surveys covering each STE seepage face. In both STEs, we find a very diverse microbial community composed by abundant cosmopolitans and locally restricted rare taxa. Porewater oxygen and dissolved organic matter are the main environmental predictors of microbial community composition. More importantly, the high variety of benthic microbiota links to biogeochemical processes of different elements in STEs. The oxygen‐rich Panxón beach showed strong associations of the ammonium oxidizing archaea Nitrosopumilales with the heterotrophic community, thus acting as a net source of nitrogen to the coast. On the other hand, the prevailing anoxic conditions of Ladeira beach promoted the dominance of anaerobic heterotrophs related to the degradation of complex and aromatic compounds, such as Dehalococcoidia and Desulfatiglans, and the co‐occurrence of methane oxidizers and methanogens.
Yes We Cannibal Panel Discussion: Reading, Unearthing, and Eating Anthropocentrism with Cesar & Lois
Authors: Keel Mat , Lessner Liz 
Published: August 2022

AbstractThis panel discussion took place on June 26, 2021, as part of the programming for an exhibition by critical art collaborative Cesar & Lois at experimental art and research project space Yes We Cannibal (Baton Rouge, LA). The exhibition was entitled Eat the Anthropocene with Cesar & Lois, mycelia and friend entities and ran for six weeks. The panel discussion collected scholars from art, anthropology, literature, landscape architecture, and amateur Mycology to elucidate themes relevant to the artwork, which features a variety of experimental collaborations between codices and fungal life.
Overnight joint replacement surgery: a pilot Australian study
Authors: Qurashi Sol , Chinnappa Jason , Aktas Sam , Dabboussi Abdul Majid , Rahman Md Bayzidur 
Published: August 2022

AbstractBackgroundWith a stretched healthcare system and elective surgery backlog, measures to improve efficiency and decrease costs associated with surgical procedures need to be prioritized. This study compares the benefits of multi‐disciplinary involvement in an enhanced recovery after surgery (ERAS) protocol‐led overnight model following total hip replacement (THR) and total knee replacement (TKR).MethodsPatients in each of two private hospitals undergoing THR or TKR were prospectively enrolled. One hospital (Overnight) was fully committed to the ERAS protocol implementation on all levels and formed the treatment group while in the other hospital (control), patients only had the anaesthetic and operative procedure as part of the ERAS protocol but did not follow the perioperative measures of the protocol. Outcomes on hospital length of stay (LOS), inpatient rehabilitation, functional outcomes, satisfaction, adverse events and readmission rates were investigated.ResultsMedian LOS in the Overnight group was significantly smaller than in the control group (1 vs. 3 days, P < 0.0001). The Overnight group had lower rates of inpatient rehabilitation utilization (4% vs. 41.2%, P < 0.0001), similar improvements in functional hip and knee scores and no increased rate of adverse events or readmission. All patients in both groups were satisfied with their treatment.ConclusionOvernight THR and TKR can safely be performed in the majority of patients, with a multi‐disciplinary approach protocol and involvement of all perioperative stakeholders.
Use of GLP‐1 receptor agonists and subsequent risk of alcohol‐related events. A nationwide register‐based cohort and self‐controlled case series study
Authors: Wium‐Andersen Ida Kim , Wium‐Andersen Marie Kim , Fink‐Jensen Anders , Rungby Jørgen , Jørgensen Martin Balslev , Osler Merete 
Published: August 2022

AbstractAnimal studies have related glucagon‐like peptide 1 receptor agonists (GLP‐1) to lower alcohol intake. We examined whether GLP‐1 was associated with risk of alcohol‐related events in a nationwide cohort study and a self‐controlled case series analysis including all new users of GLP1 (n = 38 454) and dipeptidyl peptidase 4 inhibitors (DPP4) (n = 49 222) in Denmark 2009–2017. They were followed for hospital contacts with alcohol use disorder or purchase of drugs for treatment of alcohol dependence in nationwide registers from 2009 to 2018. Associations were examined using Cox proportional hazard and conditional Poisson regression. During follow‐up of median 4.1 years, 649 (0.7%) of participants were registered with an alcohol‐related event. Initiation of GLP‐1 treatment was associated with lower risk of an alcohol‐related event (Hazard ratio = 0.46 (95%CI: 0.24–0.86) compared with initiation of DPP4 during the first 3 months of follow‐up. Self‐controlled analysis showed the highest risk of alcohol‐related events in the 3‐month pretreatment period (incidence rate ratio [IRR] = 1.25 (1.00–1.58)), whereas the risk was lowest in the first 3‐month treatment period (IRR = 0.74 (0.56–0.97). In conclusion, compared with DPP4 users, individuals who start treatment with GLP‐1 had lower incidence of alcohol‐related events both in cohort and self‐controlled analyses. Thus, there might be a transient preventive effect of GLP1 on alcohol‐related events the first months after treatment initiation.
Short research article: COVID‐19 and its impact on child and youth mental health service demand in the community and emergency department
Authors: Tedja Amy M. , Shanmugam Meenakshi S. , Stathis Stephen , Middeldorp Christel M. 
Published: August 2022

BackgroundTo explore changes in child and youth mental health service (CYMHS) demand in Brisbane, Australia, following the COVID pandemic.MethodsThe number of monthly presentations and referrals to respectively the emergency department (ED) and community CYMHS were compared among 2018, 2019 and 2020.ResultsThe study shows a marked increase in referrals to ED starting from July and in the community from May 2020. In the population referred to as community teams, the proportions of Indigenous children and those from lower socio‐economic areas decreased.ConclusionsThe COVID‐19 pandemic has aggravated the supply and demand disparity in CYMHS, with the largest effect on the most vulnerable families.
Pronounced antiseizure activity of the subtype‐selective GABAA positive allosteric modulator darigabat in a mouse model of drug‐resistant focal epilepsy
Authors: Gurrell Rachel , Iredale Philip , Evrard Alexis , Duveau Venceslas , Ruggiero Céline , Roucard Corinne 
Published: August 2022

AbstractAimDarigabat is an α2/3/5 subunit‐selective positive allosteric modulator of GABAA receptors that has demonstrated broad‐spectrum activity in several preclinical models of epilepsy as well as in a clinical photoepilepsy trial. The objective here was to assess the acute antiseizure effect of darigabat in the mesial temporal lobe epilepsy (MTLE) mouse model of drug‐resistant focal seizures.MethodsThe MTLE model is generated by single unilateral intrahippocampal injection of low dose (1 nmole) kainic acid in adult mice, and subsequent epileptiform activity is recorded following implantation of a bipolar electrode under general anesthesia. After a period of epileptogenesis (~4 weeks), spontaneous and recurrent hippocampal paroxysmal discharges (HPD; focal seizures) are recorded using intracerebral electroencephalography. The number and cumulated duration of HPDs were recorded following administration of vehicle (PO), darigabat (0.3–10 mg kg−1, PO), and positive control diazepam (2 mg kg−1, IP).RESULTSDarigabat dose‐dependently reduced the expression of HPDs, demonstrating comparable efficacy profile to diazepam at doses of 3 and 10 mg kg−1.CONCLUSIONSDarigabat exhibited a robust efficacy profile in the MTLE model, a preclinical model of drug‐resistant focal epilepsy. A Phase II proof‐of‐concept placebo‐controlled, adjunctive‐therapy trial (NCT04244175) is ongoing to evaluate efficacy and safety of darigabat in patients with drug‐resistant focal seizures.
Management of treatment‐related sequelae following colorectal cancer
Authors: Haas Susanne , Mikkelsen Anette Højer , Kronborg Camilla Jensenius Skovhus , Oggesen Birthe T. , Møller Pia F. , Fassov Janne , Frederiksen Nina Abild , Krogsgaard Marianne , Graugaard‐Jensen Charlotte , Ventzel Lise , Christensen Peter , Emmertsen Katrine Jøssing 
Published: August 2022

AbstractAimColorectal cancer survivors are one of the most rapidly growing groups of patients living with and beyond cancer. In a national multidisciplinary setting, we have examined the extent of late treatment‐related sequelae in colorectal cancer survivors and present the scientific evidence for management of these conditions in this patient category with the aim of facilitating identification and treatment.MethodA systematic search for existing guidelines and relevant studies was performed across 16 and 4 databases, respectively, from inception to 2021. This yielded 13 guidelines and 886 abstracts, of which 188 were included in the finalized guideline (231 included for full text review). Secondarily, bibliographies were cross‐referenced and 53 additional articles were included.ResultsSymptoms have been divided into overall categories including psychosocial, bowel‐related, urinary, sexual (male and female), pain/neuropathy and fatigue symptoms or complaints that are examined individually. Merging and grading of data resulted in 22 recommendations and 42 management strategies across categories. Recommendations are of a more general character, whereas management strategies provide more practical advice suited for initiation on site before referral to specialized units.ConclusionTreatment‐related sequelae in colorectal cancer survivors are common and attention needs to be focused on identifying patients with unmet treatment needs and the development of evidence‐based treatment algorithms.