Miracle-dz/UniFAR-FTUs huggingface dataset:
PGC-1α Signaling Increases GABA(A) Receptor Subunit α2 Expression, GABAergic Neurotransmission and Anxiety-Like Behavior in Mice

Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master regulator of mitochondria biogenesis and cell stress playing a role in metabolic and degenerative diseases. In the brain PGC-1α expression has been localized mainly to GABAergic interneurons but its overall role is not fully understood. We observed here that the protein levels of γ-aminobutyric acid (GABA) type A receptor-α2 subunit (GABARα2) were increased in hippocampus and brain cortex in transgenic (Tg) mice overexpressing PGC-1α in neurons. Along with this, GABARα2 expression was enhanced in the hippocampus of the PGC-1α Tg mice, as shown by quantitative PCR. Double immunostaining revealed that GABARα2 co-localized with the synaptic protein gephyrin in higher amounts in the striatum radiatum layer of the hippocampal CA1 region in the Tg compared with Wt mice. Electrophysiology revealed that the frequency of spontaneous and miniature inhibitory postsynaptic currents (mIPSCs) was increased in the CA1 region in the Tg mice, indicative of an augmented GABAergic transmission. Behavioral tests revealed an increase for anxiety-like behavior in the PGC-1α Tg mice compared with controls. To study whether drugs acting on PPARγ can affect GABARα2, we employed pioglitazone that elevated GABARα2 expression in primary cultured neurons. Similar results were obtained using the specific PPARγ agonist, N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino) ethyl]-L-tyrosine hydrate (GW1929). These results demonstrate that PGC-1α regulates GABARα2 subunits and GABAergic neurotransmission in the hippocampus with behavioral consequences. This indicates further that drugs like pioglitazone, widely used in the treatment of type 2 diabetes, can influence GABARα2 expression via the PPARγ/PGC-1α system.
Early Visual Processing and Perception Processes in Object Discrimination Learning

A brief image presentation is sufficient to discriminate and individuate objects of expertise. Although perceptual expertise is acquired through extensive practice that increases the resolution of representations and reduces the latency of image decoding and coarse and fine information extraction, it is not known how the stages of visual processing impact object discrimination learning (ODL). Here, we compared object discrimination with brief (100 ms) and long (1,000 ms) perceptual encoding times to test if the early and late visual processes are required for ODL. Moreover, we evaluated whether encoding time and discrimination practice shape perception and recognition memory processes during ODL. During practice of a sequential matching task with initially unfamiliar complex stimuli, we find greater discrimination with greater encoding times regardless of the extent of practice, suggesting that the fine information extraction during late visual processing is necessary for discrimination. Interestingly, the overall discrimination learning was similar for brief and long stimuli, suggesting that early stages of visual processing are sufficient for ODL. In addition, discrimination practice enhances perceive and know for brief and long stimuli and both processes are associated with performance, suggesting that early stage information extraction is sufficient for modulating the perceptual processes, likely reflecting an increase in the resolution of the representations and an early availability of information. Conversely, practice elicited an increase of familiarity which was not associated with discrimination sensitivity, revealing the acquisition of a general recognition memory. Finally, the recall is likely enhanced by practice and is associated with discrimination sensitivity for long encoding times, suggesting the engagement of recognition memory in a practice independent manner. These findings contribute to unveiling the function of early stages of visual processing in ODL, and provide evidence on the modulation of the perception and recognition memory processes during discrimination practice and its relationship with ODL and perceptual expertise acquisition.
Allelic Dropout Is a Common Phenomenon That Reduces the Diagnostic Yield of PCR-Based Sequencing of Targeted Gene Panels

Primary cardiomyopathies (CMPs) are monogenic but multi-allelic disorders with dozens of genes involved in pathogenesis. The implementation of next-generation sequencing (NGS) approaches has resulted in more time- and cost-efficient DNA diagnostics of cardiomyopathies. However, the diagnostic yield of genetic testing for each subtype of CMP fails to exceed 60%. The aim of this study was to demonstrate that allelic dropout (ADO) is a common phenomenon that reduces the diagnostic yield in primary cardiomyopathy genetic testing based on targeted gene panels assayed on the Ion Torrent platform. We performed mutational screening with three custom targeted gene panels based on sets of oligoprimers designed automatically using AmpliSeq Designer® containing 1049 primer pairs for 37 genes with a total length of 153 kb. DNA samples from 232 patients were screened with at least one of these targeted gene panels. We detected six ADO events in both IonTorrent PGM (three cases) and capillary Sanger sequencing (three cases) data, identifying ADO-causing variants in all cases. All ADO events occurred due to common or rare single nucleotide variants (SNVs) in the oligoprimer binding sites and were detected because of the presence of “marker” SNVs in the target DNA fragment. We ultimately identified that PCR-based NGS involves a risk of ADO that necessitates the use of Sanger sequencing to validate NGS results. We assume that oligoprimer design without ADO data affects the amplification efficiency of up to 0.77% of amplicons.
Developing Innolysins Against Campylobacter jejuni Using a Novel Prophage Receptor-Binding Protein

Campylobacter contaminated poultry remains the major cause of foodborne gastroenteritis worldwide, calling for novel antibacterials. We previously developed the concept of Innolysin composed of an endolysin fused to a phage receptor binding protein (RBP) and provided the proof-of-concept that Innolysins exert bactericidal activity against Escherichia coli. Here, we have expanded the Innolysin concept to target Campylobacter jejuni. As no C. jejuni phage RBP had been identified so far, we first showed that the H-fiber originating from a CJIE1-like prophage of C. jejuni CAMSA2147 functions as a novel RBP. By fusing this H-fiber to phage T5 endolysin, we constructed Innolysins targeting C. jejuni (Innolysins Cj). Innolysin Cj1 exerts antibacterial activity against diverse C. jejuni strains after in vitro exposure for 45 min at 20°C, reaching up to 1.30 ± 0.21 log reduction in CAMSA2147 cell counts. Screening of a library of Innolysins Cj composed of distinct endolysins for growth inhibition, allowed us to select Innolysin Cj5 as an additional promising antibacterial candidate. Application of either Innolysin Cj1 or Innolysin Cj5 on chicken skin refrigerated to 5°C and contaminated with C. jejuni CAMSA2147 led to 1.63 ± 0.46 and 1.18 ± 0.10 log reduction of cells, respectively, confirming that Innolysins Cj can kill C. jejuni in situ. The receptor of Innolysins Cj remains to be identified, however, the RBP component (H-fiber) recognizes a novel receptor compared to lytic phages binding to capsular polysaccharide or flagella. Identification of other unexplored Campylobacter phage RBPs may further increase the repertoire of new Innolysins Cj targeting distinct receptors and working as antibacterials against Campylobacter.
Pituitary Remodeling Throughout Life: Are Resident Stem Cells Involved?

The pituitary gland has the primordial ability to dynamically adapt its cell composition to changing hormonal needs of the organism throughout life. During the first weeks after birth, an impressive growth and maturation phase is occurring in the gland during which the distinct hormonal cell populations expand. During pubertal growth and development, growth hormone (GH) levels need to peak which requires an adaptive enterprise in the GH-producing somatotrope population. At aging, pituitary function wanes which is associated with organismal decay including the somatopause in which GH levels drop. In addition to these key time points of life, the pituitary’s endocrine cell landscape plastically adapts during specific (patho-)physiological conditions such as lactation (need for PRL) and stress (engagement of ACTH). Particular resilience is witnessed after physical injury in the (murine) gland, culminating in regeneration of destroyed cell populations. In many other tissues, adaptive and regenerative processes involve the local stem cells. Over the last 15 years, evidence has accumulated that the pituitary gland houses a resident stem cell compartment. Recent studies propose their involvement in at least some of the cell remodeling processes that occur in the postnatal pituitary but support is still fragmentary and not unequivocal. Many questions remain unsolved such as whether the stem cells are key players in the vivid neonatal growth phase and whether the decline in pituitary function at old age is associated with decreased stem cell fitness. Furthermore, the underlying molecular mechanisms of pituitary plasticity, in particular the stem cell-linked ones, are still largely unknown. Pituitary research heavily relies on transgenic in vivo mouse models. While having proven their value, answers to pituitary stem cell-focused questions may more diligently come from a novel powerful in vitro research model, termed organoids, which grow from pituitary stem cells and recapitulate stem cell phenotype and activation status. In this review, we describe pituitary plasticity conditions and summarize what is known on the involvement and phenotype of pituitary stem cells during these pituitary remodeling events.
The Kinase Specificity of Protein Kinase Inhibitor Peptide

G-protein-coupled-receptor (GPCR) signaling is exquisitely controlled to achieve spatial and temporal specificity. The endogenous protein kinase inhibitor peptide (PKI) confines the spatial and temporal spread of the activity of protein kinase A (PKA), which integrates inputs from three major types of GPCRs. Despite its wide usage as a pharmaceutical inhibitor of PKA, it was unclear whether PKI only inhibits PKA activity. Here, the effects of PKI on 55 mouse kinases were tested in in vitro assays. We found that in addition to inhibiting PKA activity, both PKI (6–22) amide and full-length PKIα facilitated the activation of multiple isoforms of protein kinase C (PKC), albeit at much higher concentrations than necessary to inhibit PKA. Thus, our results call for appropriate interpretation of experimental results using PKI as a pharmaceutical agent. Furthermore, our study lays the foundation to explore the potential functions of PKI in regulating PKC activity and in coordinating PKC and PKA activities.
Helicobacter and the Potential Role in Neurological Disorders: There Is More Than Helicobacter pylori

Trillions of symbiotic microbial cells colonize our body, of which the larger part is present in the human gut. These microbes play an essential role in our health and a shift in the microbiome is linked to several diseases. Recent studies also suggest a link between changes in gut microbiota and neurological disorders. Gut microbiota can communicate with the brain via several routes, together called the microbiome–gut–brain axis: the neuronal route, the endocrine route, the metabolic route and the immunological route. Helicobacter is a genus of Gram-negative bacteria colonizing the stomach, intestine and liver. Several papers show the role of H. pylori in the development and progression of neurological disorders, while hardly anything is known about other Helicobacter species and the brain. We recently reported a high prevalence of H. suis in patients with Parkinson’s disease and showed an effect of a gastric H. suis infection on the mouse brain homeostasis. Here, we discuss the potential role of H. suis in neurological disorders and how it may affect the brain via the microbiome–gut–brain axis.
Modeling Complex Orthopedic Trauma in Rodents: Bone, Muscle and Nerve Injury and Healing

Orthopedic injury can occur from a variety of causes including motor vehicle collision, battlefield injuries or even falls from standing. Persistent limb pain is common after orthopedic injury or surgery and presents a unique challenge, as the initiating event may result in polytrauma to bone, muscle, and peripheral nerves. It is imperative that we understand the tissue-specific and multicellular response to this unique type of injury in order to best develop targeted treatments that improve healing and regeneration. In this Mini Review we will first discuss current rodent models of orthopedic trauma/complex orthotrauma. In the second section, we will focus on bone-specific outcomes including imaging modalities, biomechanical testing and immunostaining for markers of bone healing/turnover. In the third section, we will discuss muscle-related pathology including outcome measures of fibrosis, muscle regeneration and tensile strength measurements. In the fourth section, we will discuss nervous system-related pathology including outcome measures of pain-like responses, both reflexive and non-reflexive. In all sections we will consider parallels between preclinical outcome measures and the functional and mechanistic findings of the human condition.
Insulin Therapy Is Associated With an Increased Risk of Carotid Plaque in Type 2 Diabetes: A Real-World Study

Background: Controversies concerning the association between insulin therapy and atherosclerotic lesions in type 2 diabetes mellitus (T2DM) remain to exist. The purpose of this study was to investigate whether insulin therapy in T2DM patients is linked with the increased risk of carotid atherosclerosis in real-world settings. Methods: We retrospectively enrolled 2,356 hospitalized patients with T2DM, including 1,716 subjects receiving insulin therapy and 640 subjects without receiving insulin therapy. Carotid atherosclerotic lesions including carotid intima-media thickness (CIMT), carotid plaque and carotid stenosis were assessed by Doppler ultrasonography and were compared between T2DM patients treated with and without insulin. Results: After adjusting for age and duration of diabetes, there was a significant increase in the prevalence of carotid plaque in both men (52.0 vs. 41.7%, p = 0.007) and women (49.6 vs. 39.7%, p = 0.003) receiving insulin therapy than in those without receiving insulin therapy. After further controlling for other confounding factors, compared with the patients without receiving insulin therapy, the risk of carotid plaque was still significantly increased not only in women treated with insulin (OR: 1.810; 95% CI: 1.155–2.837, p = 0.010), but also in men treated with insulin (OR: 1.867; 95% CI: 1.307–2.666; p = 0.001). Additionally, HOMA2-B% was higher in both women and men without receiving insulin therapy compared with those receiving insulin therapy (p < 0.001 in both men and women), but HOMA-IR was significantly higher in patients treated with insulin than in those without receiving insulin therapy (p < 0.001 in both men and women). Conclusions: Insulin therapy is associated with markedly increased risk of carotid atherosclerotic lesions in type 2 diabetes, which partly attribute to the more serious insulin resistance in T2DM patients receiving insulin therapy.
Impacts of Postfire Management Are Unjustified in Spotted Owl Habitat

In mixed-conifer forests inhabited by California spotted owls, land managers hypothesize that without human intervention natural conifer regeneration will take many decades or longer to begin within interior areas of large high-severity fire patches, due to long distances from live tree seed sources. As a result, widespread post-fire logging, followed by sprayed application of herbicides and planting of conifer seedlings, are used to create tree plantations. These are activities routinely conducted in spotted owl territories following fires, despite current data that indicate this approach has adverse impacts on spotted owl occupancy. Land managers acknowledge such impacts, but continue these forest management practices, assuming they are a necessary harm, one that is warranted to ensure the later return of mature conifer forests used by spotted owls for nesting and roosting. However, few data have been gathered to test this hypothesis. At 5 years post-fire, we surveyed field plots on a grid within large high-severity fire patches in spotted owl habitat within the Rim fire of 2013 in the Sierra Nevada, California. In our analysis the percentage of plots lacking conifer regeneration decreased significantly with larger plot sizes, a finding contrary to previous studies which assumed vast “deforested” areas in wildland fires, a bias created by small plot size. We found higher conifer regeneration closer to live-tree edges, but we consistently found natural post-fire conifer regeneration at all distances into interior spaces of large high-severity fire patches, including >300 m from the nearest live trees. Distance from live-tree edges did not affect pine dominance in post-fire regeneration. The post-fire natural conifer regeneration reported in our results suggests that the adverse effects of current post-fire management in spotted owl habitat are not necessary practices that can be justified.
Phosphazenes with (2-Pyridylmethylamino) Groups, I. Syntheses and Crystal Structures of Pentaphenoxy(2-pyridylmethylamino)-cyclotriphosphazene and Its Copper(II) Nitrate, Platinum (II) Chloride, and Cobalt(II) Nitrate Complexes

The reaction of the (2-pyridylmethylamino)-substituted cyclotriphosphazene N3P3(OC6H5)5(NHCH2(C5H4N)-2) (1) with copper(II) nitrate, platinum(II) chloride, and cobalt(II) nitrate yields the stable complexes [Cu(NO3)2·(1)2] (1a), [PtCl2·(1)] (1b), [Co(NO3)2 · (1)] (1c). The X-ray crystallographic studies of these metal complexes revealed the different coordination behavior of the multifunctional ligand.
Deep Brain Stimulation Initiative: Toward Innovative Technology, New Disease Indications, and Approaches to Current and Future Clinical Challenges in Neuromodulation Therapy

Deep brain stimulation (DBS) is one of the most important clinical therapies for neurological disorders. DBS also has great potential to become a great tool for clinical neuroscience research. Recently, the National Engineering Laboratory for Neuromodulation at Tsinghua University held an international Deep Brain Stimulation Initiative workshop to discuss the cutting-edge technological achievements and clinical applications of DBS. We specifically addressed new clinical approaches and challenges in DBS for movement disorders (Parkinson's disease and dystonia), clinical application toward neurorehabilitation for stroke, and the progress and challenges toward DBS for neuropsychiatric disorders. This review highlighted key developments in (1) neuroimaging, with advancements in 3-Tesla magnetic resonance imaging DBS compatibility for exploration of brain network mechanisms; (2) novel DBS recording capabilities for uncovering disease pathophysiology; and (3) overcoming global healthcare burdens with online-based DBS programming technology for connecting patient communities. The successful event marks a milestone for global collaborative opportunities in clinical development of neuromodulation to treat major neurological disorders.
The Predictive Value of Tumor Volume and Its Change on Short-Term Outcome for Esophageal Squamous Cell Carcinoma Treated With Radiotherapy or Chemoradiotherapy

Objectives To investigate the tumor volume and its change on short-term outcome in esophageal squamous cell carcinoma (ESCC) patients who underwent definitive radiotherapy or chemoradiotherapy. Methods and Materials All data were retrospectively collected from 418 ESCC patients who received radiotherapy or chemoradiotherapy at our institution between 2015 and 2019. Short-term outcome using the treatment response evaluation was assessed according to the RECIST 1.1. The tumor volume change rate (TVCR) was defined as follows: TVCR = {1 − [gross tumor volume (GTV) at shrinking irradiation field planning)]/(GTV at the initial treatment planning)} ×100%. Chi square test was used to compare the clinic characteristics in different TVCR groups, and the difference between initial GTV (GTVi) and shrinking GTV (GTVs) was compared using Wilcoxon’s sign rank test. Logistic regression analysis and Spearman correlation was performed. Results There was a significant decrease in GTVi compared to GTVs (P < 0.001). In univariate analysis, age, cT-stage, TNM stage, treatment modality, GTVi, and TVCR were associated with short-term outcome (all P < 0.05). In multivariate analysis, gender and TVCR were statistically significant (P = 0.010, <0.001) with short-term outcome, and the combined predictive value of gender and TVCR exceeded that of TVCR (AUC, 0.876 vs 0.855). Conclusions TVCR could serve to forecast short-term outcome of radiotherapy or chemoradiotherapy in ESCC. It was of great significance to guide the individualized treatment of ESCC.
Study on Measure Approach of Void Fraction in Narrow Channel Based on Fully Convolutional Neural Network

Void fraction is one of the key parameters for gas-liquid study and detection of nuclear power system state. Based on fully convolutional neural network (FCN) and high-speed photography, an indirect void fraction measure approach for flow boiling condition in narrow channels is developed in this paper. Deep learning technique is applied to extract image features and can better realize the identification of gas and liquid phase in channels of complicated flow pattern and high void fraction, and can obtain the instantaneous value of void fraction for analyzing and monitoring. This paper verified the FCN method with visual boiling experiment data. Compared with the time-averaged experimental results calculated by the energy conservation method and the empirical formula, the relative deviations are within 11%, which verifies the reliability of this method. Moreover, the recognition results show that the FCN method has promising improvement in the scope of application compared with the traditional morphological method, and meanwhile saves the design cost. In the future, it can be applied to void fraction measurement and flow state monitoring of narrow channels under complex working conditions.
Shedding of Klotho: Functional Implications in Chronic Kidney Disease and Associated Vascular Disease

α-Klotho (Klotho) exists in two different forms, a membrane-bound and soluble form, which are highly expressed in the kidney. Both forms play an important role in various physiological and pathophysiological processes. Recently, it has been identified that soluble Klotho arises exclusively from shedding or proteolytic cleavage. In this review, we will highlight the mechanisms underlying the shedding of Klotho and the functional effects of soluble Klotho, especially in CKD and the associated cardiovascular complications. Klotho can be cleaved by a process called shedding, releasing the ectodomain of the transmembrane protein. A disintegrin and metalloproteases ADAM10 and ADAM17 have been demonstrated to be mainly responsible for this shedding, resulting in either full-length fragments or sub-fragments called KL1 and KL2. Reduced levels of soluble Klotho have been associated with kidney disease, especially chronic kidney disease (CKD). In line with a protective effect of soluble Klotho in vascular function and calcification, CKD and the reduced levels of soluble Klotho herein are associated with cardiovascular complications. Interestingly, although it has been demonstrated that soluble Klotho has a multitude of effects its direct impact on vascular cells and the exact underlying mechanisms remain largely unknown and should therefore be a major focus of further research. Moreover, functional implications of the cleavage process resulting in KL1 and KL2 fragments remain to be elucidated.