Miracle-dz/UniFAR-FTUs huggingface dataset:
Physiological aging at striatal synapses

Mike Levine's body of work guides thinking on how the basal ganglia process information to create coordinated movements and skill learning throughout the life span and in disease. This special issue is a nod to Mike's career and a well‐deserved gesture by the neuroscience community thanking him for the impact he has made on many people's careers and the field of basal ganglia physiology. This paper reviews how aging impacts basal ganglia processing with a focus on single cell and synaptic physiology. This review begins with the work Mike did with his collaborators Nat Buchwald, Chester Hull and Jay Schneider. These early studies paved the way for subsequent studies on changes in synaptic processing that occur with aging in the basal ganglia. The primary focus of this review is aging at corticostriatal synapses. Corticostriatal synapses show reduced expression of both short‐term and long‐term synaptic potentiation. The roles of age‐related changes in calcium homeostasis, vesicle cycling, dopamine modulation, and NMDA receptor function in aging's effect on synaptic plasticity are discussed. The article ends with a review of mitochondrial aging theory as it applies to age‐induced changes in corticostriatal synaptic function.
Organization of motor pools depends on the combined function of N-cadherin and type II cadherins

ABSTRACT Type I and type II classical cadherins constitute a family of cell adhesion molecules expressed in complex combinatorial profiles in the nervous system, suggesting that a cadherin code implements specific adhesive recognition events that control the development of neural circuits. In the spinal cord, classical cadherins define at a molecular level the positional organization of motor neuron subtypes into discrete nuclear structures termed motor pools. However, the roles and contributions of different members of the family in defining motor neuron spatial organization are not yet clear. By combining mouse genetics with quantitative positional analysis, we found that motor neuron organization into pools depends on type II cadherins. Type II cadherin function, however, does not strictly reflect the predictions arising from binding specificities at a molecular level, but instead relies on N-cadherin, a type I cadherin whose elimination is required to reveal type II contributions. Summary: In mouse, type II cadherins control the organization of motor neurons into pools by functional interaction with N-cadherin rather than via the implementation of an adhesive code.
The Purinergic System as a Pharmacological Target for the Treatment of Immune-Mediated Inflammatory Diseases

Immune-mediated inflammatory diseases (IMIDs) encompass a wide range of seemingly unrelated conditions, such as multiple sclerosis, rheumatoid arthritis, psoriasis, inflammatory bowel diseases, asthma, chronic obstructive pulmonary disease, and systemic lupus erythematosus. Despite differing etiologies, these diseases share common inflammatory pathways, which lead to damage in primary target organs and frequently to a plethora of systemic effects as well. The purinergic signaling complex comprising extracellular nucleotides and nucleosides and their receptors, the P2 and P1 purinergic receptors, respectively, as well as catabolic enzymes and nucleoside transporters is a major regulatory system in the body. The purinergic signaling complex can regulate the development and course of IMIDs. Here we provide a comprehensive review on the role of purinergic signaling in controlling immunity, inflammation, and organ function in IMIDs. In addition, we discuss the possible therapeutic applications of drugs acting on purinergic pathways, which have been entering clinical development, to manage patients suffering from IMIDs.
Mammillothalamic Disconnection Alters Hippocampocortical Oscillatory Activity and Microstructure: Implications for Diencephalic Amnesia

Diencephalic amnesia can be as debilitating as the more commonly known temporal lobe amnesia, yet the precise contribution of diencephalic structures to memory processes remains elusive. Across four cohorts of male rats, we used discrete lesions of the mammillothalamic tract to model aspects of diencephalic amnesia and assessed the impact of these lesions on multiple measures of activity and plasticity within the hippocampus and retrosplenial cortex. Lesions of the mammillothalamic tract had widespread indirect effects on hippocampocortical oscillatory activity within both theta and gamma bands. Both within-region oscillatory activity and cross-regional synchrony were altered. The network changes were state-dependent, displaying different profiles during locomotion and paradoxical sleep. Consistent with the associations between oscillatory activity and plasticity, complementary analyses using several convergent approaches revealed microstructural changes, which appeared to reflect a suppression of learning-induced plasticity in lesioned animals. Together, these combined findings suggest a mechanism by which damage to the medial diencephalon can impact upon learning and memory processes, highlighting an important role for the mammillary bodies in the coordination of hippocampocortical activity. SIGNIFICANCE STATEMENT Information flow within the Papez circuit is critical to memory. Damage to ascending mammillothalamic projections has consistently been linked to amnesia in humans and spatial memory deficits in animal models. Here we report on the changes in hippocampocortical oscillatory dynamics that result from chronic lesions of the mammillothalamic tract and demonstrate, for the first time, that the mammillary bodies, independently of the supramammillary region, contribute to frequency modulation of hippocampocortical theta oscillations. Consistent with the associations between oscillatory activity and plasticity, the lesions also result in a suppression of learning-induced plasticity. Together, these data support new functional models whereby mammillary bodies are important for coordinating hippocampocortical activity rather than simply being a relay of hippocampal information as previously assumed.
Intentional cranial modification from the Houtaomuga Site in Jilin, China: Earliest evidence and longest in situ practice during the Neolithic Age.

OBJECTIVES Intentional cranial modification (ICM) was a long-established tradition used to reshape the head. Unfortunately, motivation of the act is unclear. It has been found in recent and contemporary human populations throughout the Old and New Worlds, yet the drawback of the quest into the origin, diffusion, and meanings of ICM is the lack of early materials for scientific examination. This study reports the discovery of ICM from the Neolithic Houtaomuga Site in Northeast China and the importance in deepening our knowledge of this intriguing tradition. MATERIALS AND METHODS Twenty-five skeletons unearthed from the Neolithic cultural Phases 1-4 in the Houtaomuga Site were visually screened for ICM features. Cranial measurements were conducted to quantify the degree of variation in the modified skulls and typical ones were computer tomography (CT) scanned to obtain a diploë structure and 3D model. RESULTS Eleven skulls carrying signs of ICM from both sexes varying in age from juveniles to full adults were identified ranging from 12,000 BP to 5,000 BP. Three types of modification patterns were observed and most of them were of typical fronto-occipital modification pattern. In particular, there were remarkable variations in the curvature of the crania along the sagittal direction. DISCUSSION Overall, the antiquity as well as the cultural and genetic continuity of the population in Houtaomuga Site demonstrated the earliest confirmed ICM cases from the easternmost Old World, and the longest in situ duration of ICM practice at one single Neolithic site. This circumstance largely contributes to our understanding of the origins and distribution of ICM in Eurasia and the American continent.
Standing on the Shoulders of Dwarfs.

N o technical innovation in the last 2 decades has had more impact on the practice of interventional pulmonology than endobronchial ultrasound (EBUS). EBUS has been particularly impactful in the diagnosis and staging of non–small cell lung cancer (NSCLC). The recommended treatment of NSCLC is determined in large part by the presence or absence of mediastinal nodal metastases, so accurate mediastinal staging is of crucial importance. Current guidelines recommend the use of a needle-based technique—EBUS, endoscopic ultrasound, or a combined procedure—as the initial test of choice for patients with NSCLC who require invasive mediastinal staging because they are at high or intermediate risk of N2/N3 disease.1 Guidelines currently suggest that preoperative mediastinal staging of patients with peripheral stage IA tumors without radiographic evidence of N1 or N2 adenopathy, who are undergoing surgery, is not required.1 A number of previous studies have evaluated the performance of EBUS in mediastinal staging of NSCLC. The majority have included primarily patients with radiologic evidence of mediastinal nodal involvement and a correspondingly higher prevalence of N2/N3 disease.1,2 Meta-analyses and systematic reviews of these studies have yielded an impressively high sensitivity and negative predictive value in this population.1–3 However, subgroup analyses have suggested that EBUS has a better sensitivity in those patients with selected radiographic evidence of mediastinal involvement than in unselected patients or in those with a lower prevalence of N2/N3 disease.1,2 This inconsistency has raised doubts about the role of EBUS for mediastinal staging in low-prevalence groups of patients. In this issue, Leong et al4 attempt to clarify this issue with a systematic review and meta-analysis of studies evaluating EBUS for preoperative mediastinal staging in patients with radiographic N0/N1 lung cancer. The authors qualitatively reviewed 13 articles, of which 9 papers reporting data from 1146 patients had sufficient information to be included in a quantitative meta-analysis. The mean prevalence of occult N2/N3 metastasis was 15%, and EBUS had a pooled sensitivity of 49% with a negative predictive value of 91% for the unsuspected N2/N3 disease. The sensitivities of the included studies showed moderate heterogeneity in the authors’ analysis, and one potential source of heterogeneity identified was the study methodological quality. The authors conclude that even with a pooled sensitivity of 49% for occult N2/N3 disease, preoperative EBUS staging can significantly reduce the frequency of postoperative upstaging, but still recommending surgical confirmation of negative EBUS results.4
uORF-mediated translational control: recently elucidated mechanisms and implications in cancer

ABSTRACT Protein synthesis is tightly regulated, and its dysregulation can contribute to the pathology of various diseases, including cancer. Increased or selective translation of mRNAs can promote cancer cell proliferation, metastasis and tumor expansion. Translational control is one of the most important means for cells to quickly adapt to environmental stresses. Adaptive translation involves various alternative mechanisms of translation initiation. Upstream open reading frames (uORFs) serve as a major regulator of stress-responsive translational control. Since recent advances in omics technologies including ribo-seq have expanded our knowledge of translation, we discuss emerging mechanisms for uORF-mediated translation regulation and its impact on cancer cell biology. A better understanding of dysregulated translational control of uORFs in cancer would facilitate the development of new strategies for cancer therapy.
Characterization and Phylogenetic Analysis of Campylobacter Species Isolated from Paediatric Stool and Water Samples in the Northwest Province, South Africa

Antibiotic-resistant Campylobacter could adversely affect treatment outcomes, especially in children. We investigated the antibiotic susceptibility profiles, virulence potentials and genetic relatedness of Campylobacter spp. from paediatric and water samples in the North West Province, South Africa. Overall, 237 human and 20 water isolates were identified using culture and real-time polymerase chain reaction (PCR). The antibiotic susceptibility profiles were determined using the disk diffusion method. Gradient strips were used to determine the minimum inhibitory concentration of each antibiotic. Antibiotic resistance (gryA, tetO and 23S rRNA 2075G and 2074C) and virulence (cadF and ciaB) genes were also investigated using PCR. A phylogenetic tree to ascertain the clonality between water and clinical isolates was constructed using MEGA 7. Overall, 95% (water) and 64.7% (human) of the isolates were resistant to at least one antibiotic tested. The highest resistance was against clarithromycin (95%) for water and ampicillin (60.7%) for human isolates. The 23S rRNA 2075G/2074C mutation was the most expressed resistance gene. Phylogenetic reconstruction revealed eight intermixed clades within water and human Campylobacter isolates. This study suggests the possible circulation of potentially pathogenic antibiotic-resistant Campylobacter in the Northwest Province, South Africa with drinking water being a possible vector for disease transmission in this area.
Design and Synthesis of CNS-targeted Flavones and Analogues with Neuroprotective Potential Against H2O2- and Aβ1-42-Induced Toxicity in SH-SY5Y Human Neuroblastoma Cells

With the lack of available drugs able to prevent the progression of Alzheimer’s disease (AD), the discovery of new neuroprotective treatments able to rescue neurons from cell injury is presently a matter of extreme importance and urgency. Here, we were inspired by the widely reported potential of natural flavonoids to build a library of novel flavones, chromen-4-ones and their C-glucosyl derivatives, and to explore their ability as neuroprotective agents with suitable pharmacokinetic profiles. All compounds were firstly evaluated in a parallel artificial membrane permeability assay (PAMPA) to assess their effective permeability across biological membranes, namely the blood-brain barrier (BBB). With this test, we aimed not only at assessing if our candidates would be well-distributed, but also at rationalizing the influence of the sugar moiety on the physicochemical properties. To complement our analysis, logD7.4 was determined. From all screened compounds, the p-morpholinyl flavones stood out for their ability to fully rescue SH-SY5Y human neuroblastoma cells against both H2O2- and Aβ1-42-induced cell death. Cholinesterase inhibition was also evaluated, and modest inhibitory activities were found. This work highlights the potential of C-glucosylflavones as neuroprotective agents, and presents the p-morpholinyl C-glucosylflavone 37, which did not show any cytotoxicity towards HepG2 and Caco-2 cells at 100 μM, as a new lead structure for further development against AD.
Regulation of sclerostin in glucocorticoid-induced osteoporosis (GIO) in mice and humans

Glucocorticoids (GC) are used for the treatment of inflammatory diseases, including various forms of arthritis. However, their use is limited, amongst others, by adverse effects on bone. The Wnt and bone formation inhibitor sclerostin was recently implicated in the pathogenesis of GC-induced osteoporosis. However, data are ambiguous. The aim of this study was to assess the regulation of sclerostin by GC using several mouse models with high GC levels and two independent cohorts of patients treated with GC. Male 24-week-old C57BL/6 and 18-week-old DBA/1 mice exposed to GC and 12-week-old mice with endogenous hypercortisolism displayed reduced bone formation as indicated by reduced levels of P1NP and increased serum sclerostin levels. The expression of sclerostin in femoral bone tissue and GC-treated bone marrow stromal cells, however, was not consistently altered. In contrast, GC dose- and time-dependently suppressed sclerostin at mRNA and protein levels in human mesenchymal stromal cells, and this effect was GC receptor dependent. In line with the human cell culture data, patients with rheumatoid arthritis (RA, n = 101) and polymyalgia rheumatica (PMR, n = 21) who were exposed to GC had lower serum levels of sclerostin than healthy age- and sex-matched controls (−40%, P < 0.01 and −26.5%, P < 0.001, respectively). In summary, sclerostin appears to be differentially regulated by GC in mice and humans as it is suppressed by GCs in humans but is not consistently altered in mice. Further studies are required to delineate the differences between GC regulation of sclerostin in mice and humans and assess whether sclerostin mediates GC-induced osteoporosis in humans.
Incidence of infections associated with oral glucocorticoid dose in people diagnosed with polymyalgia rheumatica or giant cell arteritis: a cohort study in England

BACKGROUND: Most patients with polymyalgia rheumatica or giant cell arteritis are treated with glucocorticoid therapy in primary care. We estimated dose–response risks of infection for this population in England. METHODS: We conducted a retrospective record-linkage study involving a cohort of people with polymyalgia rheumatica or giant cell arteritis registered in family practices across England (1998–2017). Estimates of first occurring infection per level of time-variant current and cumulative dose were obtained using Kaplan–Meier methods and multilevel proportional-hazards Cox models. RESULTS: Of 39 938 patients attending 389 family practices, 22 234 (55.7%) had at least 1 infection over a median follow-up period of 4.8 years, with 5937 (26.7%) requiring hospital admission and 1616 (7.3%) dying within 7 days of diagnosis. Cumulative risks of all-cause infection were 18.3% (95% confidence interval [CI] 17.9%–18.7%) at 1 year, 54.7% (95% CI 54.1%–55.2%) at 5 years and 76.9% (95% CI 76.2%–77.5%) at 10 years. Lower respiratory tract infections, conjunctivitis and herpes zoster were the most commonly diagnosed infections. The increases in adjusted hazard ratios (HRs) for all-cause infection per 5 mg prednisolone-equivalent daily dose increase and per 1000 mg cumulative dose increase in the last year from the patient’s end date of follow-up were 1.13 (95% CI 1.12–1.14) and 1.50 (95% CI 1.49–1.52), respectively. Adjusted HRs associated with periods of current glucocorticoid versus no glucocorticoid use ranged from 1.48 (95% CI 1.39–1.57) for fungal to 1.70 (95% CI 1.60–1.80) for bacterial infection. Stepwise dose-related associations were found for bacterial, viral, parasitic and fungal infections, irrespective of patient age, duration of underlying chronic disease and baseline vaccination status. INTERPRETATION: We quantified the excess risk of all-cause, bacterial, viral, parasitic and fungal infection conferred by oral glucocorticoids in people with polymyalgia rheumatica or giant cell arteritis and found strong dose responses for all types, even at daily doses of less than 5 mg prednisolone.
Treatment of Multidrug-Resistant Vancomycin-Resistant Enterococcus faecium Hardware-Associated Vertebral Osteomyelitis with Oritavancin plus Ampicillin

Weekly oritavancin plus ampicillin continuous infusion combination therapy was used to successfully treat a deep spine vancomycin-resistant Enterococcus faecium infection associated with hardware. Checkerboard and time-kill assays confirmed synergy between these two antibiotics. ABSTRACT Weekly oritavancin plus ampicillin continuous infusion combination therapy was used to successfully treat a deep spine vancomycin-resistant Enterococcus faecium infection associated with hardware. Checkerboard and time-kill assays confirmed synergy between these two antibiotics. Further synergies of oritavancin and ampicillin with rifampin or the endogenous human antimicrobial peptide cathelicidin LL-37 were demonstrated.
Protein Nanotubes: From Bionanotech towards Medical Applications

Nanobiotechnology involves the study of structures found in nature to construct nanodevices for biological and medical applications with the ultimate goal of commercialization. Within a cell most biochemical processes are driven by proteins and associated macromolecular complexes. Evolution has optimized these protein-based nanosystems within living organisms over millions of years. Among these are flagellin and pilin-based systems from bacteria, viral-based capsids, and eukaryotic microtubules and amyloids. While carbon nanotubes (CNTs), and protein/peptide-CNT composites, remain one of the most researched nanosystems due to their electrical and mechanical properties, there are many concerns regarding CNT toxicity and biodegradability. Therefore, proteins have emerged as useful biotemplates for nanomaterials due to their assembly under physiologically relevant conditions and ease of manipulation via protein engineering. This review aims to highlight some of the current research employing protein nanotubes (PNTs) for the development of molecular imaging biosensors, conducting wires for microelectronics, fuel cells, and drug delivery systems. The translational potential of PNTs is highlighted.
Structured, uncertainty-driven exploration in real-world consumer choice

Significance We study how people make choices among a large number of options when they have limited experience. In a large dataset of online food delivery purchases, we find evidence for sophisticated exploration strategies predicted by contemporary theories. People actively seek to reduce their uncertainty about restaurants and use similarity-based generalization to guide their selections. Our findings suggest that theories of exploratory choice have real-world validity. Making good decisions requires people to appropriately explore their available options and generalize what they have learned. While computational models can explain exploratory behavior in constrained laboratory tasks, it is unclear to what extent these models generalize to real-world choice problems. We investigate the factors guiding exploratory behavior in a dataset consisting of 195,333 customers placing 1,613,967 orders from a large online food delivery service. We find important hallmarks of adaptive exploration and generalization, which we analyze using computational models. In particular, customers seem to engage in uncertainty-directed exploration and use feature-based generalization to guide their exploration. Our results provide evidence that people use sophisticated strategies to explore complex, real-world environments.
Tensile and Interfacial Loading Characteristics of Boron Nitride-Carbon Nanosheet Reinforced Polymer Nanocomposites

The discovery of hybrid boron nitride–carbon (BN–C) nanostructures has triggered enormous research interest in the design and fabrication of new generation nanocomposites. The robust design of these nanocomposites for target applications requires their mechanical strength to be characterized with a wide range of factors. This article presents a comprehensive study, with the aid of molecular dynamics analysis, of the tensile loading mechanics of BN–C nanosheet reinforced polyethylene (PE) nanocomposites. It is observed that the geometry and lattice arrangement of the BN–C nanosheet influences the tensile loading characteristics of the nanocomposites. Furthermore, defects in the nanosheet can severely impact the tensile loading resistance, the extent of which is determined by the defect’s location. This study also found that the tensile loading resistance of nanocomposites tends to weaken at elevated temperatures. The interfacial mechanics of the BN–C nanocomposites are also investigated. This analysis revealed a strong dependency with the carbon concentration in the BN–C nanosheet.