bluuebunny/crossref_metadata_2025 huggingface dataset:
Selective Isolation of Multidrug-Resistant Pedobacter spp., Producers of Novel Antibacterial Peptides
Authors: Bjerketorp Joakim , Levenfors Jolanta J. , Nord Christina , Guss Bengt , Öberg Bo , Broberg Anders
Published: February 2021

Twenty-eight multidrug-resistant bacterial strains closely related or identical to Pedobacter cryoconitis, Pedobacter lusitanus and Pedobacter steynii were isolated from soil samples by selection for multidrug-resistance. Approximately 3–30% of the selected isolates were identified as Pedobacter, whereas isolation without antibiotics did not yield any isolates of this genus. Next generation sequencing data showed Pedobacter to be on 69th place among the bacterial genera (0.32% of bacterial sequences). The Pedobacter isolates produced a wide array of novel compounds when screened by UHPLC-MS/MSMS, and hierarchical cluster analysis resulted in several distinct clusters of compounds produced by specific isolates of Pedobacter, and most of these compounds were found to be peptides. The Pedobacter strain UP508 produced isopedopeptins, whereas another set of strains produced pedopeptins, which both are known cyclic lipodepsipeptides produced by Pedobacter sp. Other Pedobacter strains produced analogous peptides with a sequence variation. Further strains of Pedobacter produced additional novel antibacterial cyclic lipopeptides (ca 800 or 1400 Da in size) and/or linear lipopeptides (ca 700–960 Da in size). A 16S rRNA phylogenetic tree for the Pedobacter isolates revealed several distinct clades and subclades of isolates. One of the subclades comprised isolates producing isopedopeptin analogs, but the isopedopeptin producing isolate UP508 was clearly placed on a separate branch. We suggest that the non-ribosomal peptide synthases producing pedopeptins, isopedopeptins, and the analogous peptides, may derive from a common ancestral non-ribosomal peptide synthase gene cluster, which may have been subjected to a mutation leading to changed specificity in one of the modules and then to a modular rearrangement leading to the changed sequence found in the isopedopeptins produced by isolate UP508.
Evidence for Involvement of the Salmonella enterica Z-Ring Assembly Factors ZapA and ZapB in Resistance to Bile
Authors: Fernández-Fernández Rocío , Hernández Sara B. , Puerta-Fernández Elena , Sánchez-Romero María A. , Urdaneta Verónica , Casadesús Josep
Published: February 2021

Genes annotated asygfEandyiiUin the genome ofSalmonella entericaserovar Typhimurium encode proteins homologous toEscherichia colicell division factors ZapA and ZapB, respectively. ZapA−and ZapB−mutants ofS. entericaare bile-sensitive. The amount ofzapBmRNA increases in the presence of a sublethal concentration of sodium deoxycholate (DOC) whilezapAmRNA remains unaffected. IncreasedzapBmRNA level in the presence of DOC is not caused by upregulation ofzapBtranscription but by increased stability ofzapBmRNA. This increase is suppressed by anhfqmutation, suggesting the involvement of a small regulatory RNA. We provide evidence that such sRNA is MicA. The ZapB protein is degraded in the presence of DOC, and degradation appears to involve the Lon protease. We propose that increased stability ofzapBmRNA in the presence of DOC may counter degradation of bile-damaged ZapB, thereby providing sufficient level of functional ZapB protein to permit Z-ring assembly in the presence of bile.
The Listening Network and Cochlear Implant Benefits in Hearing-Impaired Adults
Authors: James Chris J. , Graham Petra L. , Betances Reinoso Frank A. , Breuning Silvia N. , Durko Marcin , Huarte Irujo Alicia , Royo López Juan , Müller Lida , Perenyi Adam , Jaramillo Saffon Rafael , Salinas Garcia Sandra , Schüssler Mark , Schwarz Langer Margarita J. , Skarzynski Piotr H. , Mecklenburg Dianne J.
Published: February 2021

Older adults with mild or no hearing loss make more errors and expend more effort listening to speech. Cochlear implants (CI) restore hearing to deaf patients but with limited fidelity. We hypothesized that patient-reported hearing and health-related quality of life in CI patients may similarly vary according to age. Speech Spatial Qualities (SSQ) of hearing scale and Health Utilities Index Mark III (HUI) questionnaires were administered to 543 unilaterally implanted adults across Europe, South Africa, and South America. Data were acquired before surgery and at 1, 2, and 3 years post-surgery. Data were analyzed using linear mixed models with visit, age group (18–34, 35–44, 45–54, 55–64, and 65+), and side of implant as main factors and adjusted for other covariates. Tinnitus and dizziness prevalence did not vary with age, but older groups had more preoperative hearing. Preoperatively and postoperatively, SSQ scores were significantly higher (Δ0.75–0.82) for those aged <45 compared with those 55+. However, gains in SSQ scores were equivalent across age groups, although postoperative SSQ scores were higher in right-ear implanted subjects. All age groups benefited equally in terms of HUI gain (0.18), with no decrease in scores with age. Overall, younger adults appeared to cope better with a degraded hearing before and after CI, leading to better subjective hearing performance.
Passive Immunization With a Novel Monoclonal Anti-PrP Antibody TW1 in an Alzheimer’s Mouse Model With Tau Pathology
Authors: Boutajangout Allal , Zhang Wei , Kim Justin , Abdali Wed Ali , Prelli Frances , Wisniewski Thomas
Published: February 2021

Neurofibrillary tangles (NFTs) are a major pathologic hallmark of Alzheimer’s disease (AD). Several studies have shown that amyloid β oligomers (Aβo) and tau oligomers mediate their toxicity, in part, via binding to cellular prion protein (PrPC) and that some anti-PrP antibodies can block this interaction. We have generated a novel monoclonal anti-PrP antibody (TW1) and assessed the efficacy of passive immunization with it in a mouse model of AD with extensive tau pathology: hTau/PS1 transgenic (Tg) mice. These mice were injected intraperitoneally once a week with TW1 starting at 5 months of age. Behavior was assessed at 8 months of age and brain tissue was subsequently harvested for analysis of treatment efficacy at 9 months. Mice treated with TW1 did not show any significant difference in sensorimotor testing including traverse beam, rotarod, and locomotor activity compared to controls. Significant cognitive benefits were observed with the novel object recognition test (ORT) in the immunized mice (two-tailed, t-test p = 0.0019). Immunized mice also showed cognitive benefits on the closed field symmetrical maze (day 1 two-tailed t-test p = 0.0001; day 2 two-tailed t-test p = 0.0015; day 3 two-tailed t-test p = 0.0002). Reduction of tau pathology was observed with PHF-1 immunohistochemistry in the piriform cortex by 60% (two-tailed t-test p = 0.01) and in the dentate gyrus by 50% (two-tailed t-test p = 0.02) in animals treated with TW1 compared to controls. There were no significant differences in astrogliosis or microgliosis observed between treated and control mice. As assessed by Western blots using PHF-1, the TW1 therapy reduced phosphorylated tau pathology (two-tailed t-test p = 0.03) and improved the ratio of pathological soluble tau to tubulin (PHF1/tubulin; two-tailed t-test p = 0.0006). Reduction of tau pathology also was observed using the CP13 antibody (two-tailed t-test p = 0.0007). These results indicate that passive immunization with the TW1 antibody can significantly decrease tau pathology as assessed by immunohistochemical and biochemical methods, resulting in improved cognitive function in a tau transgenic mouse model of AD.
Thalamic Structural Connectivity Abnormalities in Minimal Hepatic Encephalopathy
Authors: Chen Hua-Jun , Zhang Xiao-Hong , Shi Jia-Yan , Jiang Shao-Fan , Sun Yi-Fan , Zhang Ling , Li Dan , Chen Rong
Published: February 2021

Background and Aims: Numerous studies have demonstrated thalamus-related structural, functional, and metabolic abnormalities in minimal hepatic encephalopathy (MHE). We conducted the first study to investigate thalamic structural connectivity alterations in MHE.

Methods

Diffusion tensor imaging (DTI)-based probabilistic tractography was employed to determine the structural linkage between the thalamus and cortical/subcortical regions in 52 cirrhotic patients [22 with MHE; 30 without MHE (NHE)] and 30 controls. We measured these thalamic connections, which included connectivity strength (CS), fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), and then compared these among the three groups. Neurocognitive assessment was also performed. Correlation analysis was conducted to investigate the relationship between neurocognitive performance and the above measurements. Classification analysis was performed to determine whether thalamic connection measurements can distinguish MHE from NHE.

Results

The probabilistic tractography revealed thalamic structural connections, which were disrupted in cirrhotic patients (as reflected by a decrease in CS/FA and an increase in MD/AD/RD). Abnormal thalamic connections primarily involved the prefrontal cortex, sensorimotor cortex, parietal cortex, medial temporal cortex and hippocampus, and striatum. Thalamic connectivity abnormalities deteriorated from NHE to MHE, and they were correlated with patients’ neurocognitive performance. The moderate classification accuracy was obtained using CS and MD as discriminating indexes.

Conclusion

Our results demonstrated the altered thalamic structural connectivity involving both cortical and subcortical regions in MHE, which could be regarded as representative of MHE-related widespread impairments in white matter pathways. The disturbed thalamic connectivity may underlie the mechanism of cognitive deficits in MHE and may potentially be utilized as a biomarker for diagnosing MHE and in monitoring disease progression. In addition to thalamic–cortical/subcortical connections, further studies are recommended to explore the structural alterations in other white matter pathways in MHE.
Monosynaptic Retrograde Tracing From Prelimbic Neuron Subpopulations Projecting to Either Nucleus Accumbens Core or Rostromedial Tegmental Nucleus
Authors: Cruz Adelis M. , Kim Tabitha H. , Smith Rachel J.
Published: February 2021

The prelimbic (PL) region of the medial prefrontal cortex (mPFC) has been implicated in both driving and suppressing motivated behaviors, including cocaine-seeking in rats. These seemingly opposing functions may be mediated by different efferent targets of PL projections, such as the nucleus accumbens (NAc) core and rostromedial tegmental nucleus (RMTg), which have contrasting roles in reward-seeking behaviors. We sought to characterize the anatomical connectivity differences between PL neurons projecting to NAc core and RMTg. We used conventional retrograde tracers to reveal distinct subpopulations of PL neurons projecting to NAc core vs. RMTg in rats, with very little overlap. To examine potential differences in input specificity for these two PL subpopulations, we then used Cre-dependent rabies virus (EnvA-RV-EGFP) as a monosynaptic retrograde tracer and targeted specific PL neurons via injections of retrograde CAV2-Cre in either NAc core or RMTg. We observed a similar catalog of cortical, thalamic, and limbic afferents for both NAc- and RMTg-projecting populations, with the primary source of afferent information arising from neighboring prefrontal neurons in ipsilateral PL and infralimbic cortex (IL). However, when the two subpopulations were directly compared, we found that RMTg-projecting PL neurons received a greater proportion of input from ipsilateral PL and IL, whereas NAc-projecting PL neurons received a greater proportion of input from most other cortical areas, mediodorsal thalamic nucleus, and several other subcortical areas. NAc-projecting PL neurons also received a greater proportion of contralateral cortical input. Our findings reveal that PL subpopulations differ not only in their efferent target but also in the input specificity from afferent structures. These differences in connectivity are likely to be critical to functional differences of PL subpopulations.
Comparison of Longitudinal Changes of Cerebral Small Vessel Disease Markers and Cognitive Function Between Subcortical Vascular Mild Cognitive Impairment With and Without NOTCH3 Variant: A 5-Year Follow-Up Study
Authors: Yoon Cindy W. , Kim Young-Eun , Kim Hee Jin , Ki Chang-Seok , Lee Hyejoo , Rha Joung-Ho , Na Duk L. , Seo Sang Won
Published: February 2021

No study yet has compared the longitudinal course and prognosis between subcortical vascular cognitive impairment patients with and without genetic component. In this study, we compared the longitudinal changes in cerebral small vessel disease markers and cognitive function between subcortical vascular mild cognitive impairment (svMCI) patients with and without NOTCH3 variant [NOTCH3(+) svMCI vs. NOTCH3(–) svMCI]. We prospectively recruited patients with svMCI and screened for NOTCH3 variants by sequence analysis for mutational hotspots in the NOTCH3 gene. Patients were annually followed-up for 5 years through clinical interviews, neuropsychological tests, and brain magnetic resonance imaging. Among 63 svMCI patients, 9 (14.3%) had either known mutations or possible pathogenic variants. The linear mixed effect models showed that the NOTCH3(+) svMCI group had much greater increases in the lacune and cerebral microbleed counts than the NOTCH3(–) svMCI group. However, there were no significant differences between the two groups regarding dementia conversion rate and neuropsychological score changes over 5 years.
Sleep Spindle Characteristics in Obstructive Sleep Apnea Syndrome (OSAS)
Authors: Mohammadi Hiwa , Aarabi Ardalan , Rezaei Mohammad , Khazaie Habibolah , Brand Serge
Published: February 2021

Background:We compared the density and duration of sleep spindles topographically in stage 2 and 3 of non-rapid eye movement sleep (N2 and N3) among adults diagnosed with Obstructive Sleep Apnea Syndrome (OSAS) and healthy controls.

Materials and Methods:Thirty-one individuals with OSAS (mean age: 48.50 years) and 23 healthy controls took part in the study. All participants underwent a whole night polysomnography. Additionally, those with OSAS were divided into mild, moderate and severe cases of OSAS.

Results:For N2, sleep spindle density did not significantly differ between participants with and without OSAS, or among those with mild, moderate and severe OSAS. For N3,post-hocanalyses revealed significantly higher spindle densities in healthy controls and individuals with mild OSAS than in those with moderate or severe OSAS. Last, in N2 a higher AHI was associated with a shorter sleep spindle duration.

Conclusion:OSAS is associated with a significantly lower spindle density in N3 and a shorter spindle duration in N2. Our results also revealed that, in contrast to moderate and severe OSAS, the sleep spindle characteristics of individuals with mild OSAS were very similar to those of healthy controls.
Creutzfeldt-Jakob and Vascular Brain Diseases: Their Overlap and Relationships
Authors: Balash Yacov , Korczyn Amos D. , Khmelev Nadejda , Eilam Anda , Adi Meital , Gilad Ronit
Published: February 2021

Only a few case reports of stroke-like onset of Creutzfeldt-Jakob disease (CJD) have previously been published. We aimed to analyze the neurological, imaging, electroencephalographic (EEG), and laboratory features of patients with this very rare phenomenon. Here, we review the clinical characteristics, onset features, and clinical course variants of stroke-like CJD in 23 such patients. The median age of the patients was 71 years (range: 56–84 years); 12 were women. In 20 patients, CJD was sporadic. Thirteen patients developed apoplexy-like onset of symptoms, whereas the others had prodromal non-specific complaints. Most often the patients manifested with pyramidal signs (n = 13), ataxia (n = 9), and aphasia (n = 8). On MRI DWI sequence, all subjects had abnormal hyperintensities in various parts of the cerebral cortex, striatum, or thalamus, while EEG detected periodic triphasic waves only in 11. CSF 14-3-3 protein and total τ-protein were abnormal in 17 of 23 cases. All patients died, median lifespan being 2 months (range: 19 days−14 months). In conclusion, a complex of clinical, radiological, and laboratory manifestations of stroke-like onset of CJD is outlined. The clinical relationships between CJD and stroke are considered, in an attempt to highlight this rare presentation of an uncommon disease.
Neurotransmitters, Cell Types, and Circuit Mechanisms of Motor Skill Learning and Clinical Applications
Authors: Tian Wotu , Chen Shengdi
Published: February 2021

Animals acquire motor skills to better survive and adapt to a changing environment. The ability to learn novel motor actions without disturbing learned ones is essential to maintaining a broad motor repertoire. During motor learning, the brain makes a series of adjustments to build novel sensory–motor relationships that are stored within specific circuits for long-term retention. The neural mechanism of learning novel motor actions and transforming them into long-term memory still remains unclear. Here we review the latest findings with regard to the contributions of various brain subregions, cell types, and neurotransmitters to motor learning. Aiming to seek therapeutic strategies to restore the motor memory in relative neurodegenerative disorders, we also briefly describe the common experimental tests and manipulations for motor memory in rodents.
Promising Biomarker Candidates for Cardioembolic Stroke Etiology. A Brief Narrative Review and Current Opinion
Authors: Markus Arnold , Valerie Schütz , Mira Katan
Published: February 2021

Determining the cause of stroke is considered one of the main objectives in evaluating a stroke patient in clinical practice. However, ischemic stroke is a heterogeneous disorder and numerous underlying disorders are implicated in its pathogenesis. Although progress has been made in identifying individual stroke etiology, in many cases underlying mechanisms still remain elusive. Since secondary prevention strategies are tailored toward individual stroke mechanisms, patients whose stroke etiology is unknown may not receive optimal preventive treatment. Cardioembolic stroke is commonly defined as cerebral vessel occlusion by distant embolization arising from thrombus formation in the heart. It accounts for the main proportion of ischemic strokes, and its share to stroke etiology is likely to rise even further in future decades. However, it can be challenging to distinguish cardioembolism from other possible etiologies. As personalized medicine advances, stroke researchers' focus is increasingly drawn to etiology-associated biomarkers. They can provide deeper insight regarding specific stroke mechanisms and can help to unravel previously undetected pathologies. Furthermore, etiology-associated biomarkers could play an important role in guiding future stroke prevention strategies. To achieve this, broad validation of promising candidate biomarkers as well as their implementation in well-designed randomized clinical trials is necessary. This review focuses on the most-promising candidates for diagnosis of cardioembolic stroke. It discusses existing evidence for possible clinical applications of these biomarkers, addresses current challenges, and outlines future perspectives.
Antiplatelet Therapy in the Secondary Prevention of Non-cardioembolic Ischemic Stroke and Transient Ischemic Attack: A Mini-Review
Authors: Vališ Martin , Klímová Blanka , Novotný Michal , Herzig Roman
Published: February 2021

The aim of this mini-review is to discuss the main antiplatelet agents that have been successfully used in the secondary prevention of non-cardioembolic ischemic stroke and transient ischemic attacks (TIA). The methodology is based on a literature review of available peer-reviewed English studies listed in PubMed. The findings reveal that aspirin remains a reliable antiplatelet agent in the secondary prevention of acute non-cardioembolic ischemic stroke and TIA. Nevertheless, currently, there are also other agents, i.e., ticagrelor, clopidogrel, and cilostazol, that can be applied. In addition, the results indicate that time is significant not only in severe stroke but also in non-severe stroke and TIA, which suggests that antiplatelet therapy should be applied within 24 h after the first symptoms because early treatment can lead to an improvement in neurological outcomes and reduce the chance of an early subsequent stroke.
Endothelial Shear Stress and Platelet FcγRIIa Expression in Intracranial Atherosclerotic Disease
Authors: Liebeskind David S. , Hinman Jason D. , Kaneko Naoki , Kitajima Hiroaki , Honda Tristan , De Havenon Adam H. , Feldmann Edward , Nogueira Raul G. , Prabhakaran Shyam , Romano Jose G. , Callas Peter W. , Schneider David J.
Published: February 2021

Intracranial atherosclerotic disease (ICAD) has been characterized by the degree of arterial stenosis and downstream hypoperfusion, yet microscopic derangements of endothelial shear stress at the luminal wall may be key determinants of plaque growth, vascular remodeling and thrombosis that culminate in recurrent stroke. Platelet interactions have similarly been a principal focus of treatment, however, the mechanistic basis of anti-platelet strategies is largely extrapolated rather than directly investigated in ICAD. Platelet FcγRIIa expression has been identified as a potent risk factor in cardiovascular disease, as elevated expression markedly increases the risk of recurrent events. Differential activation of the platelet FcγRIIa receptor may also explain the variable response of individual patients to anti-platelet medications. We review existing data on endothelial shear stress and potential interactions with the platelet FcγRIIa receptor that may alter the evolving impact of ICAD, based on local pathophysiology at the site of arterial stenosis. Current methods for quantification of endothelial shear stress and platelet activation are described, including tools that may be readily adapted to the clinical realm for further understanding of ICAD.
Multimodal Assessment of Precentral Anodal TDCS: Individual Rise in Supplementary Motor Activity Scales With Increase in Corticospinal Excitability
Authors: Karabanov Anke Ninija , Shindo Keiichiro , Shindo Yuko , Raffin Estelle , Siebner Hartwig Roman
Published: February 2021

Background

Transcranial direct current stimulation (TDCS) targeting the primary motor hand area (M1-HAND) may induce lasting shifts in corticospinal excitability, but after-effects show substantial inter-individual variability. Functional magnetic resonance imaging (fMRI) can probe after-effects of TDCS on regional neural activity on a whole-brain level.

Objective

Using a double-blinded cross-over design, we investigated whether the individual change in corticospinal excitability after TDCS of M1-HAND is associated with changes in task-related regional activity in cortical motor areas.

Methods

Seventeen healthy volunteers (10 women) received 20 min of real (0.75 mA) or sham TDCS on separate days in randomized order. Real and sham TDCS used the classic bipolar set-up with the anode placed over right M1-HAND. Before and after each TDCS session, we recorded motor evoked potentials (MEP) from the relaxed left first dorsal interosseus muscle after single-pulse transcranial magnetic stimulation(TMS) of left M1-HAND and performed whole-brain fMRI at 3 Tesla while participants completed a visuomotor tracking task with their left hand. We also assessed the difference in MEP latency when applying anterior-posterior and latero-medial TMS pulses to the precentral hand knob (AP-LM MEP latency).

Results

Real TDCS had no consistent aftereffects on mean MEP amplitude, task-related activity or motor performance. Individual changes in MEP amplitude, measured directly after real TDCS showed a positive linear relationship with individual changes in task-related activity in the supplementary motor area and AP-LM MEP latency.

Conclusion

Functional aftereffects of classical bipolar anodal TDCS of M1-HAND on the motor system vary substantially across individuals. Physiological features upstream from the primary motor cortex may determine how anodal TDCS changes corticospinal excitability.
Wnt/β-Catenin Signaling Promotes Differentiation of Ischemia-Activated Adult Neural Stem/Progenitor Cells to Neuronal Precursors
Authors: Kriska Jan , Janeckova Lucie , Kirdajova Denisa , Honsa Pavel , Knotek Tomas , Dzamba David , Kolenicova Denisa , Butenko Olena , Vojtechova Martina , Capek Martin , Kozmik Zbynek , Taketo Makoto Mark , Korinek Vladimir , Anderova Miroslava
Published: February 2021

Modulating endogenous regenerative processes may represent a suitable treatment for central nervous system (CNS) injuries, such as stroke or trauma. Neural stem/progenitor cells (NS/PCs), which naturally reside in the subventricular zone (SVZ) of the adult brain, proliferate and differentiate to other cell types, and therefore may compensate the negative consequences of ischemic injury. The fate of NS/PCs in the developing brain is largely influenced by Wingless/Integrated (Wnt) signaling; however, its role in the differentiation of adult NS/PCs under ischemic conditions is still enigmatic. In our previous study, we identified the Wnt/β-catenin signaling pathway as a factor promoting neurogenesis at the expense of gliogenesis in neonatal mice. In this study, we used adult transgenic mice in order to assess the impact of the canonical Wnt pathway modulation (inhibition or hyper-activation) on NS/PCs derived from the SVZ, and combined it with the middle cerebral artery occlusion (MCAO) to disclose the effect of focal cerebral ischemia (FCI). Based on the electrophysiological properties of cultured cells, we first identified three cell types that represented in vitro differentiated NS/PCs – astrocytes, neuron-like cells, and precursor cells. Following FCI, we detected fewer neuron-like cells after Wnt signaling inhibition. Furthermore, the immunohistochemical analysis revealed an overall higher expression of cell-type-specific proteins after FCI, indicating increased proliferation and differentiation rates of NS/PCs in the SVZ. Remarkably, Wnt signaling hyper-activation increased the abundance of proliferating and neuron-like cells, while Wnt pathway inhibition had the opposite effect. Finally, the expression profiling at the single cell level revealed an increased proportion of neural stem cells and neuroblasts after FCI. These observations indicate that Wnt signaling enhances NS/PCs-based regeneration in the adult mouse brain following FCI, and supports neuronal differentiation in the SVZ.
A Functional Spiking Neural Network of Ultra Compact Neurons
Authors: Stoliar Pablo , Schneegans Olivier , Rozenberg Marcelo J.
Published: February 2021

We demonstrate that recently introduced ultra-compact neurons (UCN) with a minimal number of components can be interconnected to implement a functional spiking neural network. For concreteness we focus on the Jeffress model, which is a classic neuro-computational model proposed in the 40’s to explain the sound directionality detection by animals and humans. In addition, we introduce a long-axon neuron, whose architecture is inspired by the Hodgkin-Huxley axon delay-line and where the UCNs implement the nodes of Ranvier. We then interconnect two of those neurons to an output layer of UCNs, which detect coincidences between spikes propagating down the long-axons. This functional spiking neural neuron circuit with biological relevance is built from identical UCN blocks, which are simple enough to be made with off-the-shelf electronic components. Our work realizes a new, accessible and affordable physical model platform, where neuroscientists can construct arbitrary mid-size spiking neuronal networks in a lego-block like fashion that work in continuous time. This should enable them to address in a novel experimental manner fundamental questions about the nature of the neural code and to test predictions from mathematical models and algorithms of basic neurobiology research. The present work aims at opening a new experimental field of basic research in Spiking Neural Networks to a potentially large community, which is at the crossroads of neurobiology, dynamical systems, theoretical neuroscience, condensed matter physics, neuromorphic engineering, artificial intelligence, and complex systems.
Predicting Metastasis Risk in Pancreatic Neuroendocrine Tumors Using Deep Learning Image Analysis
Authors: Klimov Sergey , Xue Yue , Gertych Arkadiusz , Graham Rondell P. , Jiang Yi , Bhattarai Shristi , Pandol Stephen J. , Rakha Emad A. , Reid Michelle D. , Aneja Ritu
Published: February 2021

Background

The prognosis of patients with pancreatic neuroendocrine tumors (PanNET), the second most common type of pancreatic cancer, varies significantly, and up to 15% of patients develop metastasis. Although certain morphological characteristics of PanNETs have been associated with patient outcome, there are no available morphology-based prognostic markers. Given that current clinical histopathology markers are unable to identify high-risk PanNET patients, the development of accurate prognostic biomarkers is needed. Here, we describe a novel machine learning, multiclassification pipeline to predict the risk of metastasis using morphological information from whole tissue slides.

Methods

Digital images from surgically resected tissues from 89 PanNET patients were used. Pathologist-annotated regions were extracted to train a convolutional neural network (CNN) to identify tiles consisting of PanNET, stroma, normal pancreas parenchyma, and fat. Computationally annotated cancer or stroma tiles and patient metastasis status were used to train CNN to calculate a region based metastatic risk score. Aggregation of the metastatic probability scores across the slide was performed to predict the risk of metastasis.

Results

The ability of CNN to discriminate different tissues was high (per-tile accuracy >95%; whole slide cancer regions Jaccard index = 79%). Cancer and stromal tiles with high evaluated probability provided F1 scores of 0.82 and 0.69, respectively, when we compared tissues from patients who developed metastasis and those who did not. The final model identified low-risk (n = 76) and high-risk (n = 13) patients, as well as predicted metastasis-free survival (hazard ratio: 4.71) after adjusting for common clinicopathological variables, especially in grade I/II patients.

Conclusion

Using slides from surgically resected PanNETs, our novel, multiclassification, deep learning pipeline was able to predict the risk of metastasis in PanNET patients. Our results suggest the presence of prognostic morphological patterns in PanNET tissues, and that these patterns may help guide clinical decision making.
Quantitative Proteomic Profiling Identifies a Potential Novel Chaperone Marker in Resistant Breast Cancer
Authors: Gallegos Karen M. , Patel Jankiben R. , Llopis Shawn D. , Walker Rashidra R. , Davidson A. Michael , Zhang Wensheng , Zhang Kun , Tilghman Syreeta L.
Published: February 2021

Development of aromatase inhibitor resistant breast cancer among postmenopausal women continues to be a major clinical obstacle. Previously, our group demonstrated that as breast cancer cells transition from hormone-dependent to hormone-independent, they are associated with increased growth factor signaling, enhanced cellular motility, and the epithelial to mesenchymal transition (EMT). Given the complexity of cancer stem cells (CSC) and their implications on endocrine resistance and EMT, we sought to understand their contribution towards the development of aromatase inhibitor resistant breast cancer. Cells cultured three dimensionally as mammospheres are enriched for CSCs and more accurately recapitulates tumorsin vivo. Therefore, a global proteomic analysis was conducted using letrozole resistant breast cancer cells (LTLT-Ca) mammospheres and compared to their adherent counterparts. Results demonstrated over 1000 proteins with quantitative abundance ratios were identified. Among the quantified proteins, 359 were significantly altered (p< 0.05), where 173 were upregulated and 186 downregulated (p< 0.05, fold change >1.20). Notably, midasin, a chaperone protein required for maturation and nuclear export of the pre-60S ribosome was increased 35-fold. Protein expression analyses confirmed midasin is ubiquitously expressed in normal tissue but is overexpressed in lobular and ductal breast carcinoma tissue as well as ER+ and ER- breast cancer cell lines. Functional enrichment analyses indicated that 19 gene ontology terms and one KEGG pathway were over-represented by the down-regulated proteins and both were associated with protein synthesis. Increased midasin was strongly correlated with decreased relapse free survival in hormone independent breast cancer. For the first time, we characterized the global proteomic signature of CSC-enriched letrozole-resistant cells associated with protein synthesis, which may implicate a role for midasin in endocrine resistance.
Computed Tomography-Based Radiomics Model for Predicting the WHO/ISUP Grade of Clear Cell Renal Cell Carcinoma Preoperatively: A Multicenter Study
Authors: Wang Ruihui , Hu Zhengyu , Shen Xiaoyong , Wang Qidong , Zhang Liang , Wang Minhong , Feng Zhan , Chen Feng
Published: February 2021

Purpose

To examine the ability of computed tomography radiomic features in multivariate analysis and construct radiomic model for identification of the the WHO/ISUP pathological grade of clear cell renal cell carcinoma (ccRCC).

Methods

This was a retrospective study using data of four hospitals from January 2018 to August 2019. There were 197 patients with a definitive diagnosis of ccRCC by post-surgery pathology or biopsy. These subjects were divided into the training set (n = 122) and the independent external validation set (n = 75). Two phases of Enhanced CT images (corticomedullary phase, nephrographic phase) of ccRCC were used for whole tumor Volume of interest (VOI) plots. The IBEX radiomic software package in Matlab was used to extract the radiomic features of whole tumor VOI images. Next, the Mann–Whitney U test and minimum redundancy-maximum relevance algorithm(mRMR) was used for feature dimensionality reduction. Next, logistic regression combined with Akaike information criterion was used to select the best prediction model. The performance of the prediction model was assessed in the independent external validation cohorts. Receiver Operating Characteristic curve (ROC) was used to evaluate the discrimination of ccRCC in the training and independent external validation sets.

Results

The logistic regression prediction model constructed with seven radiomic features showed the best performance in identification for WHO/ISUP pathological grades. The Area Under Curve (AUC) of the training set was 0.89, the sensitivity comes to 0.85 and specificity was 0.84. In the independent external validation set, the AUC of the prediction model was 0.81, the sensitivity comes to 0.58, and specificity was 0.95.

Conclusion

A radiological model constructed from CT radiomic features can effectively predict the WHO/ISUP pathological grade of CCRCC tumors and has a certain clinical generalization ability, which provides an effective value for patient prognosis and treatment.
A Weighted Gene Co-Expression Network Analysis–Derived Prognostic Model for Predicting Prognosis and Immune Infiltration in Gastric Cancer
Authors: Chen Qingchuan , Tan Yuen , Zhang Chao , Zhang Zhe , Pan Siwei , An Wen , Xu Huimian
Published: February 2021

Background

Gastric cancer (GC) is a major public health problem worldwide. In recent decades, the treatment of gastric cancer has improved greatly, but basic research and clinical application of gastric cancer remain challenges due to the high heterogeneity. Here, we provide new insights for identifying prognostic models of GC.

Methods

We obtained the gene expression profiles of GSE62254 containing 300 samples for training. GSE15459 and TCGA-STAD for validation, which contain 200 and 375 samples, respectively. Weighted gene co-expression network analysis (WGCNA) was used to identify gene modules. We performed Lasso regression and Cox regression analyses to identify the most significant five genes to develop a novel prognostic model. And we selected two representative genes within the model for immunohistochemistry staining with 105 GC specimens from our hospital to verify the prediction efficiency. Moreover, we estimated the correlation coefficient between our model and immune infiltration using the CIBERSORT algorithm. The data from GSE15459 and TCGA cohort validated the robustness and predictive accuracy of this prognostic model.

Results

Of the 12 gene modules identified, 1,198 green-yellow module genes were selected for further analysis. Multivariate Cox analysis was performed on genes from univariate Cox regression and Lasso regression analysis using the Cox proportional hazards regression model. Finally, we constructed a five gene prognostic model: Risk Score = [(-0.7547) * Expression (ARHGAP32)] + [(-0.8272) * Expression (KLF5)] + [1.09 * Expression (MAMLD1)] + [0.5174 * Expression (MATN3)] + [1.66 * Expression (NES)]. The prognosis of samples in the high-risk group was significantly poorer than that of samples in the low-risk group (p = 6.503e-11). The risk model was also regarded as an independent predictor of prognosis (HR, 1.678, p < 0.001). The observed correlation with immune cells suggested that this risk model could potentially predict immune infiltration.

Conclusion

This study identified a potential risk model for prognosis and immune infiltration prediction in GC using WGCNA and Cox regression analysis.
Glycemic Control as an Early Prognostic Marker in Advanced Pancreatic Cancer
Authors: Alpertunga Ipek , Sadiq Rabail , Pandya Deep , Lo Tammy , Dulgher Maxim , Evans Sarah , Bennett Bridget , Rennert Nancy , Frank Richard C.
Published: February 2021

Purpose

Impaired glucose metabolism is present in most patients with pancreatic ductal adenocarcinoma (PDAC). Whereas previous studies have focused on pre-treatment glycemic indices and prognosis in those with concomitant diabetes, the effects of glycemic control during chemotherapy treatment on prognosis, in patients with and without diabetes, have not been well characterized. We examined the relationship between early glycemic control and overall survival (OS) in a cohort of patients with advanced PDAC treated in a community setting.

Patients and Methods

Seventy-three patients with advanced PDAC (38% with diabetes) receiving chemotherapy while participating in a biobanking clinical trial were included. Clinical characteristics and laboratory results during 1 year were obtained from the electronic medical record. Kaplan-Meier estimate, log-rank test and hazard ratios were computed to assess the effect of glycemic control on OS. The Cox proportional hazards regression model was applied to ascertain the significance of glycemic control with other survival variables.

Results

One thousand four hundred eighteen random blood glucose (RBG) values were analyzed. In accord with previous findings, a 50% decline in the serum tumor marker CA 19-9 at any time was predictive of survival (P=0.0002). In univariate analysis, an elevated pre-treatment average RBG, 3-month average RBG (RBG-3) and the FOLFIRINOX regimen were associated with longer survival. Based on ROC analysis (AUC=0.82), an RBG-3 of 120 mg/dl was determined to be the optimal cutoff to predict 12-month survival. In multivariate analysis that included age, stage, BMI, performance status, presence of diabetes, and chemotherapy regimen, only RBG-3 maintained significance: an RBG-3 ≤120 mg/dl predicted for improved OS compared to >120 mg/dl (19 vs. 9 months; HR=0.37, P=0.002). In contrast, an early decline in CA 19-9 could not predict OS.

Conclusion

Lower glucose levels during the first 3 months of treatment for advanced PDAC predict for improved OS in patients both with and without diabetes. These results suggest that RBG-3 may be a novel prognostic biomarker worthy of confirmation in a larger patient cohort and that studies exploring a possible cause and effect of this novel survival-linked relationship are warranted.
MicroRNA-320a Promotes Epithelial Ovarian Cancer Cell Proliferation and Invasion by Targeting RASSF8
Authors: Zhang Lili , Chen Huixiao , He Fengxi , Zhang Shiqian , Li Aihua , Zhang Aifeng , Zhang Anqi
Published: February 2021

MicroRNAs (miRNAs) play important roles in tumorigenesis by controlling target gene expression. With opposing roles as a tumor suppressor or oncogene, microRNA-320a (miR-320a) was found to participate in tumor genesis and progression and also identified as a potentially useful marker in cancer diagnosis, treatment, and prognosis. To better understand the role of miR-320a in ovarian cancer, we investigated miR-320a expression in epithelial ovarian cancer (EOC) specimens as well as EOC cell lines and analyzed correlations between miR-320a expression and processes associated with EOC progression. The miR-320a level in EOC specimens was found to be associated with ovarian cancer progression and infiltration. Through in vitro and in vivo studies, we found that miR-320a significantly promoted the proliferation, migration, and invasion of EOC cells, and we identified RASSF8 as a target gene of miR-320a that was downregulated in EOC tissues and cell lines. In vitro downregulation of RASSF8 promoted the growth, migration, and invasion of EOC cells. Together these findings indicate that RASSF8 is a direct target of miR-320a, through which miR-320a promotes the progression of EOC.
Rab12 Promotes Radioresistance of HPV-Positive Cervical Cancer Cells by Increasing G2/M Arrest
Authors: Huang Yujie , Tian Yonghao , Zhang Wenhao , Liu Ruijuan , Zhang Weifang
Published: February 2021

Background

HPV-positive (HPV+) cervical cancer cells are more radioresistant compared with HPV-negative (HPV-) cervical cancer cells, but the underlying mechanism is not fully illuminated. Our previous mass spectrometry data showed that Ras-associated binding protein Rab12 was up-regulated by HPV, and this study is to investigate the role of Rab12 in the radioresistance of HPV-positive cervical cancer cells.

Methods

CCK-8 assay, colony formation assay, flow cytometry, and Western blot were performed to determine cell proliferation, apoptosis, cell cycle distribution, and protein expressions. DNA damage and repair levels were measured by comet assays and detection of γ-H2AX, XRCC4, and pBRCA1 protein expressions.

Results

Rab12 mRNA and protein expressions were up-regulated in cervical cancer tissues and HPV+ cervical cancer cells. Knockdown of Rab12 enhanced radiosensitivity while overexpression of Rab12 promotes radioresistance. Knockdown of Rab12 alleviated G2/M arrest by decreasing p-Cdc2(Tyr15) after radiation, which was a result of the reduction of p-Cdc25C(Ser216). Rab12 knockdown caused more DNA double-strand breaks (DSBs) and inhibited DNA homologous recombination repair (HRR) after radiation. Instead, overexpression of Rab12 enhanced radioresistance by increasing G2/M arrest, which provided more time for DNA HRR.

Conclusions

Rab12 may serve as a potential therapeutic target to improve clinical treatment outcome of cervical cancer.
Nomograms to Predict the Density of Tumor-Infiltrating Lymphocytes in Patients With High-Grade Serous Ovarian Cancer
Authors: Dai Danian , Liu Lili , Huang He , Chen Shangqiu , Chen Bo , Cao Junya , Luo Xiaolin , Wang Feng , Luo Rongzhen , Liu Jihong
Published: February 2021

Background

Tumor-infiltrating lymphocytes (TILs) have important roles in predicting tumor therapeutic responses and progression, however, the method of evaluating TILs is complicated. We attempted to explore the association of TILs with clinicopathological characteristics and blood indicators, and to develop nomograms to predict the density of TILs in patients with high-grade serous ovarian cancer (HGSOC).

Methods

The clinical profiles of 197 consecutive postoperative HGSOC patients were retrospectively analyzed. Tumor tissues and matched normal fallopian tubes were immunostained for CD3+, CD8+, and CD4+ T cells on corresponding tissue microarrays and the numbers of TILs were counted using the NIH ImageJ software. The patients were classified into low- or high-density groups for each marker (CD3, CD4, CD8). The associations of the investigated TILs to clinicopathological characteristics and blood indicators were assessed and the related predictors for densities of TILs were used to develop nomograms; which were then further evaluated using the C-index, receiver operating characteristic (ROC) curves and calibration plots.

Results

Menopausal status, estrogen receptor (ER), Ki-67 index, white blood cell (WBC), platelets (PLT), lactate dehydrogenase (LDH), and carbohydrate antigen 153 (CA153) had significant association with densities of tumor-infiltrating CD3+, CD8+, or CD4+ T cells. The calibration curves of the CD3+ (C-index = 0.748), CD8+ (C-index = 0.683) and CD4+ TILs nomogram (C-index = 0.759) demonstrated excellent agreement between predictions and actual observations. ROC curves of internal validation indicated good discrimination for the CD8+ TILs nomogram [area under the curve (AUC) = 0.659, 95% CI 0.582–0.736] and encouraging performance for the CD3+ (AUC= 0.708, 95% CI 0.636–0.781) and CD4+ TILs nomogram (AUC = 0.730, 95% CI 0.659–0.801).

Conclusion

Menopausal status, ER, Ki-67 index, WBC, PLT, LDH, and CA153 could reflect the densities of T cells in the tumor microenvironment. Novel nomograms are conducive to monitor the immune status of patients with HGSOC and help doctors to formulate the appropriate treatment strategies.
Hepatic Arterial Infusion Chemotherapy Combined With PD-1 Inhibitors Plus Lenvatinib Versus PD-1 Inhibitors Plus Lenvatinib for Advanced Hepatocellular Carcinoma
Authors: Mei Jie , Tang Yu-Hao , Wei Wei , Shi Ming , Zheng Lie , Li Shao-Hua , Guo Rong-Ping
Published: February 2021

Background

Lenvatinib combined with programmed cell death protein-1 (PD-1) inhibitors has resulted in good survival outcomes in the treatment of unresectable hepatocellular carcinoma (HCC). Hepatic artery infusion chemotherapy (HAIC) has also attracted attention due to its high response rates and favorable survival for advanced HCC patients. The present study aimed to compare the efficacy of HAIC combined with PD-1 inhibitors plus lenvatinib (HPL) and PD-1 inhibitors plus lenvatinib (PL) in patients with advanced HCC.

Methods

Between July 2018 and December 2019, patients diagnosed with advanced HCC who initially received HPL or PL treatment were reviewed for eligibility. Efficacy was evaluated according to tumor response and survival.

Results

In total, 70 patients met the criteria and were included in the present study, and they were divided into the HPL group (n = 45) and PL group (n = 25). The overall response rate (40.0 vs. 16.0%, respectively; p = 0.038) and disease control rate (77.6 vs. 44.0%, respectively; p < 0.001) were higher in the HPL group than in the PL group. The median overall survival was 15.9 months in the HPL group and 8.6 months in the PL group (p = 0.0015; HR = 0.6; 95% CI 0.43–0.83). The median progression-free survival was 8.8 months in the HPL group and 5.4 months in the PL group (p = 0.0320; HR = 0.74; 95% CI 0.55–0.98).

Conclusion

Compared to PL, HPL was associated with a significantly better treatment response and survival benefits for patients with advanced HCC.