Miracle-dz/UniFAR-FTUs huggingface dataset:
Investigation of Recessed Gate AlGaN/GaN MIS-HEMTs with Double AlGaN Barrier Designs toward an Enhancement-Mode Characteristic

In this work, recessed gate AlGaN/GaN metal-insulator-semiconductor high-electron-mobility transistors (MIS-HEMTs) with double AlGaN barrier designs are fabricated and investigated. Two different recessed depths are designed, leading to a 5 nm and a 3 nm remaining bottom AlGaN barrier under the gate region, and two different Al% (15% and 20%) in the bottom AlGaN barriers are designed. First of all, a double hump trans-conductance (gm)–gate voltage (VG) characteristic is observed in a recessed gate AlGaN/GaN MIS-HEMT with a 5 nm remaining bottom Al0.2Ga0. 8N barrier under the gate region. Secondly, a physical model is proposed to explain this double channel characteristic by means of a formation of a top channel below the gate dielectric under a positive VG. Finally, the impacts of Al% content (15% and 20%) in the bottom AlGaN barrier and 5 nm/3 nm remaining bottom AlGaN barriers under the gate region are studied in detail, indicating that lowering Al% content in the bottom can increase the threshold voltage (VTH) toward an enhancement-mode characteristic.
Methanogenic response to long-term permafrost thaw is determined by paleoenvironment

ABSTRACT Methane production in thawing permafrost can be substantial, yet often evolves after long lag phases or is even lacking. A central question is to which extent the production of methane after permafrost thaw is determined by the initial methanogenic community. We quantified the production of methane relative to carbon dioxide (CO2) and enumerated methanogenic (mcrA) gene copies in long-term (2–7 years) anoxic incubations at 4 °C using interglacial and glacial permafrost samples of Holocene and Pleistocene, including Eemian, origin. Changes in archaeal community composition were determined by sequencing of the archaeal 16S rRNA gene. Long-term thaw stimulated methanogenesis where methanogens initially dominated the archaeal community. Deposits of interstadial and interglacial (Eemian) origin, formed under higher temperatures and precipitation, displayed the greatest response to thaw. At the end of the incubations, a substantial shift in methanogenic community composition and a relative increase in hydrogenotrophic methanogens had occurred except for Eemian deposits in which a high abundance of potential acetoclastic methanogens were present. This study shows that only anaerobic CO2 production but not methane production correlates significantly with carbon and nitrogen content and that the methanogenic response to permafrost thaw is mainly constrained by the paleoenvironmental conditions during soil formation.
Targeting Root Ion Uptake Kinetics to Increase Plant Productivity and Nutrient Use Efficiency1[OPEN]

Root ion uptake kinetics is a promising target for boosting nutrient acquisition by addressing knowledge gaps and meta-analysis of kinetics across species, and for providing future prospects. Root system architecture has received increased attention in recent years; however, significant knowledge gaps remain for physiological phenes, or units of phenotype, that have been relatively less studied. Ion uptake kinetics studies have been invaluable in uncovering distinct nutrient uptake systems in plants with the use of Michaelis-Menten kinetic modeling. This review outlines the theoretical framework behind ion uptake kinetics, provides a meta-analysis for macronutrient uptake parameters, and proposes new strategies for using uptake kinetics parameters as selection criteria for breeding crops with improved resource acquisition capability. Presumably, variation in uptake kinetics is caused by variation in type and number of transporters, assimilation machinery, and anatomical features that can vary greatly within and among species. Critically, little is known about what determines transporter properties at the molecular level or how transporter properties scale to the entire root system. A meta-analysis of literature containing measures of crop nutrient uptake kinetics provides insights about the need for standardization of reporting, the differences among crop species, and the relationships among various uptake parameters and experimental conditions. Therefore, uptake kinetics parameters are proposed as promising target phenes that integrate several processes for functional phenomics and genetic analysis, which will lead to a greater understanding of this fundamental plant process. Exploiting this genetic and phenotypic variation has the potential to greatly advance breeding efforts for improved nutrient use efficiency in crops.
Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis

Metastasis: A matter of translation? Solid tumors shed a small number of cancer cells into the bloodstream, some of which are believed to contribute to metastasis. The molecular features that confer these circulating tumor cells (CTCs) with metastatic potential are poorly understood. Ebright et al. studied CTCs from breast cancer patients and found that cells with increased expression levels of certain ribosomal proteins and regulators of translation had greater metastatic capacity in a mouse model (see the Perspective by Ma and Jeffrey). Consistent with this finding, patients with higher levels of this subset of CTCs tended to have a poorer prognosis. Science, this issue p. 1468; see also p. 1424 Circulating breast cancer cells that overexpress certain ribosomal proteins show enhanced metastatic potential in mice. Circulating tumor cells (CTCs) are shed into the bloodstream from primary tumors, but only a small subset of these cells generates metastases. We conducted an in vivo genome-wide CRISPR activation screen in CTCs from breast cancer patients to identify genes that promote distant metastasis in mice. Genes coding for ribosomal proteins and regulators of translation were enriched in this screen. Overexpression of RPL15, which encodes a component of the large ribosomal subunit, increased metastatic growth in multiple organs and selectively enhanced translation of other ribosomal proteins and cell cycle regulators. RNA sequencing of freshly isolated CTCs from breast cancer patients revealed a subset with strong ribosome and protein synthesis signatures; these CTCs expressed proliferation and epithelial markers and correlated with poor clinical outcome. Therapies targeting this aggressive subset of CTCs may merit exploration as potential suppressors of metastatic progression.
Change is Good for the Brain: Activity Diversity and Cognitive Functioning Across Adulthood.

OBJECTIVES Participating in a variety of daily activities (i.e., activity diversity) requires people to adjust to a variety of situations and engage in a greater diversity of behaviors. These experiences may, in turn, enhance cognitive functioning. This study examined associations between activity diversity and cognitive functioning across adulthood. METHOD Activity diversity was defined as the breadth and evenness of participation in seven common daily activity domains (e.g., paid work, time with children, leisure, physical activities, volunteering). Participants from the National Survey of Daily Experiences (NSDE: N=732, Mage=56) provided activity data during eight consecutive days at Wave 1 (W1) and Wave 2 (W2) ten years apart. They also provided cognitive data at W2. RESULTS Greater activity diversity at W2 was associated with higher overall cognitive functioning and higher executive functioning at W2. Individuals who increased activity diversity from W1 to W2 also exhibited higher scores in overall cognitive functioning and executive functioning at W2. Overall cognitive functioning, executive functioning, and episodic memory were better in those who had higher activity diversity at both waves, or increased activity diversity from W1 to W2, compared to those who had lower activity diversity or decreased activity diversity over time. DISCUSSION Activity diversity is important for cognitive health in adulthood. Future work can study the directionality between activity diversity and cognitive functioning and underlying social and neurological mechanisms for these associations.
Factors related to white blood cell elevation in acute type A aortic dissection

Aortic dissection may induce a systemic inflammatory reaction. The etiological backgrounds for elevation of the white blood cell count remain to be clarified. In 466 patients with acute type A aortic dissection treated surgically within 48 hours of symptom onset, the etiologic background of an elevated admission white blood cell count and the effect of such elevation on outcomes were assessed retrospectively. Patients’ white blood cell count differed significantly in relation to the extent of dissection, with a median (25th, 75th percentile) white blood cell count of 10.4 (8.1, 13.9) x 103/μL for dissection confined to the ascending aorta, 10.5 (8.2,13.) 103/μL for dissection extending to the aortic arch/descending aorta, 11.1 (8.2, 13.7) x 103/μL for extension to the abdominal aorta, and 13.3 (9.8, 15.9) x 103/μL for extension to the iliac artery (p<0.001). With 11.0 x 103/μL used as the cut-off value for white blood cell count elevation, multivariable analysis showed current smoking (p<0.001; odds ratio, 2.79), dissection extending to the iliac artery (p = 0.006; odds ratio, 1.79), age (p = 0.007, odds ratio, 0.98), and no coronary ischemia (p = 0.027, odds ratio, 2.22) to be factors related to the elevated white blood cell count. Mean age differed significantly between patients with and without an elevated white blood cell count (62.3 vs. 68.3 years, p <0.001). Although in-hospital mortality was similar (7.5% vs.10.9%, p = 0.19), 5-year survival was lower in patients without an elevated count (85.7% vs. 78.6%, p = 0.019), reflecting their more advanced age. In conclusion, our data suggest that dissection morphology and patient age influence the acute phase systemic inflammatory response associated with an elevated white blood cell count in patients with ATAAD. A better understanding of this relation may help optimize diagnosis and perioperative care.
The mirogabalin ALDAY phase 3 program in pain associated with fibromyalgia: the lessons learned

Abstract Aims The main aim of this work was to identify and to share the lessons learned from the negative outcome of the mirogabalin ALDAY phase 3 clinical program in pain associated with fibromyalgia. These lessons are important to improve planning and design of future phase 3 programs in fibromyalgia. Methods A systematic review from Cochrane Library, Medline, Embase, clinicaltrials.gov, pharmaceutical companies, and regulatory agencies’ websites, was carried out starting from the development of gabapentin, the first α2δ ligand studied for the treatment of neuropathic pain and ending with the mirogabalin program. Results Based on the outcome of the main fibromyalgia programs, several differences in design, primary endpoint choice, magnitude of placebo response, presence of an active comparator, and size of the entire clinical program were identified. This analysis focused on the negative primary results of the mirogabalin ALDAY program and found several contributing factors. Above all, the magnitude of placebo response and the unprecedented size of the program were identified. The number of study visits and procedures was also high and highly demanding on all subjects involved in ALDAY. Outcome In terms of main lessons learned from ALDAY, the first was the need for a comprehensive patient-focused strategy to preliminarily identify the challenges of fibromyalgia based on patient perspective and study complexity. Second, there was a need for a harmonized, truly patient-centric, global regulatory guidance accepted by regulatory agencies. Third, ALDAY proved that a phase 2 proof of concept, dose ranging study is necessary before commencing any phase 3 program in fibromyalgia.
Identification of Data Injection Attacks in Networked Control Systems Using Noise Impulse Integration †

The benefits of using Networked Control Systems (NCS) in the growing Industry 4.0 are numerous, including better management and operational capabilities, as well as costs reduction. However, despite these benefits, the use of NCSs can also expose physical plants to new threats originated in the cyber domain—such as data injection attacks in NCS links through which sensors and controllers transmit signals. In this sense, this work proposes a link monitoring strategy to identify linear time-invariant (LTI) functions executed during controlled data injection attacks by a Man-in-the-Middle hosted in an NCS link. The countermeasure is based on a bioinspired metaheuristic, called Backtracking Search Optimization Algorithm (BSA), and uses white Gaussian noise to excite the attack function. To increase the accuracy of this countermeasure, it is proposed the Noise Impulse Integration (NII) technique, which is developed using the radar pulse integration technique as inspiration. The results demonstrate that the proposed countermeasure is able to accurately identify LTI attack functions, here executed to impair measurements transmitted by the plant sensor, without interfering with the NCS behavior when the system is in its normal operation. Moreover, the results indicate that the NII technique can increase the accuracy of the attack identification.
Exosomes mediate sensory hair cell protection in the inner ear.

Hair cells are the mechanosensory receptors of the inner ear, responsible for hearing and balance. Hair cell death and consequent hearing loss are common results of treatment with ototoxic drugs, including the widely-used aminoglycoside antibiotics. Induction of heat shock proteins (HSPs) confers protection against aminoglycoside-induced hair cell death via paracrine signaling that requires extracellular HSP70 (Heat Shock 70 kDa Protein). We investigated the mechanisms underlying this non-cell-autonomous protective signaling in the inner ear. In response to heat stress, inner ear tissue releases exosomes that carry HSP70 in addition to canonical exosome markers and other proteins. Isolated exosomes from heat-shocked utricles were sufficient to improve survival of hair cells exposed to the aminoglycoside antibiotic neomycin, while inhibition or depletion of exosomes from the extracellular environment abolished the protective effect of heat shock. Hair-cell specific expression of the known HSP70 receptor, Toll-like receptor 4 (TLR4), was required for the protective effect of exosomes, and exosomal HSP70 interacted with TLR4 on hair cells. Our results indicate that exosomes are a previously undescribed mechanism of intercellular communication in the inner ear that can mediate non-autonomous hair cell survival. Exosomes may represent a novel class of nano-carriers for delivery of therapeutics against hearing loss.
Mass Spectrometry for Identification, Monitoring, and Minimal Residual Disease Detection of M-Proteins.

BACKGROUND Monoclonal gammopathies (MGs) are plasma cell disorders defined by the clonal expansion of plasma cells, resulting in the characteristic excretion of a monoclonal immunoglobulin (M-protein). M-protein detection and quantification are integral parts of the diagnosis and monitoring of MGs. Novel treatment modalities impose new challenges on the traditional electrophoretic and immunochemical methods that are routinely used for M-protein diagnostics, such as interferences from therapeutic monoclonal antibodies and the need for increased analytical sensitivity to measure minimal residual disease. CONTENT Mass spectrometry (MS) is ideally suited to accurate mass measurements or targeted measurement of unique clonotypic peptide fragments. Based on these features, MS-based methods allow for the analytically sensitive measurement of the patient-specific M-protein. SUMMARY This review provides a comprehensive overview of the MS methods that have been developed recently to detect, characterize, and quantify M-proteins. The advantages and disadvantages of using these techniques in clinical practice and the impact they will have on the management of patients with MGs are discussed.
Linking Genes to Molecules in Eukaryotic Sources: An Endeavor to Expand Our Biosynthetic Repertoire

The discovery of natural products continues to interest chemists and biologists for their utility in medicine as well as facilitating our understanding of signaling, pathogenesis, and evolution. Despite an attenuation in the discovery rate of new molecules, the current genomics and transcriptomics revolution has illuminated the untapped biosynthetic potential of many diverse organisms. Today, natural product discovery can be driven by biosynthetic gene cluster (BGC) analysis, which is capable of predicting enzymes that catalyze novel reactions and organisms that synthesize new chemical structures. This approach has been particularly effective in mining bacterial and fungal genomes where it has facilitated the discovery of new molecules, increased the understanding of metabolite assembly, and in some instances uncovered enzymes with intriguing synthetic utility. While relatively less is known about the biosynthetic potential of non-fungal eukaryotes, there is compelling evidence to suggest many encode biosynthetic enzymes that produce molecules with unique bioactivities. In this review, we highlight how the advances in genomics and transcriptomics have aided natural product discovery in sources from eukaryotic lineages. We summarize work that has successfully connected genes to previously identified molecules and how advancing these techniques can lead to genetics-guided discovery of novel chemical structures and reactions distributed throughout the tree of life. Ultimately, we discuss the advantage of increasing the known biosynthetic space to ease access to complex natural and non-natural small molecules.
Pathogenetic Potential Relating to Metabolic Activity in a Mouse Model of Infection with the Chikungunya Virus East/Central/South African Genotype

Epidemics of the Chikungunya virus (CHIKV) from 2004 onwards were caused by the East/Central/South African (ECSA) genotype. However, the pathogenesis of the genotype infection has not been fully explained. In this study, we examined the pathogenic potential of CHIKV ECSA genotype M-30 (M-30) by comparing it with that of African genotype S-27 (S-27) in mice. Following low titer infections in type-I IFN receptor KO (A129) mice, we found that the M-30 infection caused high and acute fatality compared with the S-27 infection. M-30-infected A129 mice showed higher viral loads in their central nervous systems and peripheral organs, and increased levels of IFN-γ responses in their brains. Interestingly, M-30-infected mice did not show the hypophagia and reductions in weight which were observed in S-27-infected mice. Our observations provide a novel explanation of the pathogenic mechanisms attributed to virus proliferation, anti-type-II IFN response and metabolic activity in the CHIKV ECSA virus in mice.
Implications of immune-inflammatory responses in smooth muscle dysfunction and disease

In the past few decades, solid evidence has been accumulated for the pivotal significance of immunoinflammatory processes in the initiation, progression, and exacerbation of many diseases and disorders. This groundbreaking view came from original works by Ross who first described that excessive inflammatory-fibroproliferative response to various forms of insult to the endothelium and smooth muscle of the artery wall is essential for the pathogenesis of atherosclerosis (Ross, Nature 1993; 362(6423): 801–9). It is now widely recognized that both innate and adaptive immune reactions are avidly involved in the inflammation-related remodeling of many tissues and organs. When this state persists, irreversible fibrogenic changes would occur often culminating in fatal insufficiencies of many vital parenchymal organs such as liver, lung, heart, kidney and intestines. Thus, inflammatory diseases are becoming the common life-threatening risk for and urgent concern about the public health in developed countries (Wynn et al., Nature Medicine 2012; 18(7): 1028–40). Considering this timeliness, we organized a special symposium entitled “Implications of immune/inflammatory responses in smooth muscle dysfunction and disease” in the 58th annual meeting of the Japan Society of Smooth Muscle Research. This symposium report will provide detailed synopses of topics presented in this symposium; (1) the role of inflammasome in atherosclerosis and abdominal aortic aneurysms by Fumitake Usui-Kawanishi and Masafumi Takahashi; (2) Mechanisms underlying the pathogenesis of hyper-contractility of bronchial smooth muscle in allergic asthma by Hiroyasu Sakai, Wataru Suto, Yuki Kai and Yoshihiko Chiba; (3) Vascular remodeling in pulmonary arterial hypertension by Keizo Hiraishi, Lin Hai Kurahara and Ryuji Inoue.
Transmission dynamics and evolutionary history of 2019‐nCoV

To investigate the time origin, genetic diversity, and transmission dynamics of the recent 2019‐nCoV outbreak in China and beyond, a total of 32 genomes of virus strains sampled from China, Thailand, and the USA with sampling dates between 24 December 2019 and 23 January 2020 were analyzed. Phylogenetic, transmission network, and likelihood‐mapping analyses of the genome sequences were performed. On the basis of the likelihood‐mapping analysis, the increasing tree‐like signals (from 0% to 8.2%, 18.2%, and 25.4%) over time may be indicative of increasing genetic diversity of 2019‐nCoV in human hosts. We identified three phylogenetic clusters using the Bayesian inference framework and three transmission clusters using transmission network analysis, with only one cluster identified by both methods using the above genome sequences of 2019‐nCoV strains. The estimated mean evolutionary rate for 2019‐nCoV ranged from 1.7926 × 10−3 to 1.8266 × 10−3 substitutions per site per year. On the basis of our study, undertaking epidemiological investigations and genomic data surveillance could positively impact public health in terms of guiding prevention efforts to reduce 2019‐nCOV transmission in real‐time.
Influence of More Than 5 Years of Continuous Exposure to Antipsychotics on Cerebral Functional Connectivity of Chronic Schizophrenia

Objective: To explore the effect of long-term antipsychotics use on the strength of functional connectivity (FC) in the brains of patients with chronic schizophrenia. Method: We collected resting-state functional magnetic resonance imaging from 15 patients with continuously treated chronic schizophrenia (TCS), 19 patients with minimally TCS (MTCS), and 20 healthy controls (HCs). Then, we evaluated and compared the whole-brain FC strength (FCS; including full-range, short-range, and long-range FCS) among patients with TCS, MTCS, and HCs. Results: Patients with TCS and MTCS showed reduced full-/short-range FC compared with the HCs. No significant differences in the whole-brain FCS (including full-range, short-range, and long-range FCS) or clinical characteristics were identified between patients with TCS and MTCS. Additionally, the FCS in the right fusiform gyrus, right inferior temporal gyrus, and right inferior occipital gyrus negatively correlated with the duration of illness and positively correlated with onset age across all patients with chronic schizophrenia. Conclusions: Regardless of the long-term use of antipsychotics, patients with chronic schizophrenia show decreased FC compared with healthy individuals. For some patients with chronic schizophrenia, the influence of long-term and minimal/short-term antipsychotic exposure on resting-state FC was similar. The decreased full- and short-range FCS in the right fusiform gyrus, right inferior temporal gyrus, and right inferior occipital gyrus may be an ongoing pathological process that is not altered by antipsychotic interventions in patients with chronic schizophrenia. Large-sample, long-term follow-up studies are still needed for further exploration.