Miracle-dz/UniFAR-FTUs huggingface dataset:
Lysine 63-linked polyubiquitin potentially partners with p62 to promote the clearance of protein inclusions by autophagy

Although protein inclusions associated with neurodegenerative diseases are typically enriched with ubiquitin, it is currently unclear whether the topology of ubiquitin linkage plays a role in their biogenesis. In an attempt to clarify this, our recent work identified K63-linked polyubiquitin as a key regulator of inclusion dynamics. We found in the setting of ectopic overexpression of different ubiquitin species in cultured cells that K63-linked ubiquitination promotes the formation and autophagic clearance of protein inclusions linked to several major neurodegenerative diseases. Further supporting this, we report here a similar phenomenon in cells co-expressing Ubc13 and Uev1a but not those expressing UbcH7 or UbcH8. Notably, Ubc13 in association with Uev1a is known to promote K63-linked ubiquitination. In exploring how K63-linked ubiquitination could promote the clearance of inclusions by autophagy, we also found in our current study that K63-linked polyubiquitin interacts with p62, a ubiquitin-binding protein previously demonstrated by others to facilitate autophagy-mediated clearance of inclusions. Further, K63 ubiquitin-positive inclusions were found to be enriched with p62. Given the observed intimate relationship between p62 and K63 polyubiquitin, our results suggest that p62 and K63-linked polyubiquitin may function as key partners involved in directing clearance of protein inclusions by autophagy. Addendum to: Tan JMM, Wong ESP, Kirkpatrick DS, Pletnikova O, Ko HS, Tay S-P, Ho M.W. L. , Troncoso J, Gygi SP, Lee MK, Dawson VL, Dawson TM, Lim K-L. Lysine 63-linked ubiquitination promotes the formation and autophagic clearance of protein inclusions associated with neurodegenerative diseases. Human Mol Genet; In press.
Generation of imidazolinone herbicide resistant trait in Arabidopsis

Recently-emerged base editing technologies could create single base mutations at precise genomic positions without generation DNA double strand breaks. Herbicide resistant mutations have been successfully introduced to different plant species, including Arabidopsis, watermelon, wheat, potato and tomato via C to T (or G to A on the complementary strand) base editors (CBE) at the P197 position of endogenous acetolactate synthase (ALS) genes. Additionally, G to A conversion to another conserved amino acid S653 on ALS gene could confer tolerance to imidazolinone herbicides. However, no such mutation was successfully generated via CBE, likely due to the target C base is outside of the classic base editing window. Since CBE driven by egg cell (EC) specific promoter would re-edit the wild type alleles in egg cells and early embryos, we hypothesized the diversity of base editing outcomes could be largely increased at later generations to allow selection of desired herbicide resistant mutants. To test this hypothesis, we aimed to introduce C to T conversion to the complement strand of S653 codon at ALS gene, hosting a C at the 10th position within the 20-nt spacer sequence outside of the classic base editing window. While we did not detect base-edited T1 plants, efficient and diverse base edits emerged at later generations. Herbicide resistant mutants with different editing outcomes were recovered when T3 and T4 seeds were subject to herbicide selection. As expected, most herbicide resistant plants contained S653N mutation as a result of G10 to A10. Our results showed that CBE could create imidazolinone herbicide resistant trait in Arabidopsis and be potentially applied to crops to facilitate weed control.
Early-Life Programming and Reprogramming of Adult Kidney Disease and Hypertension: The Interplay between Maternal Nutrition and Oxidative Stress

Kidney disease and hypertension both have attained the status of a global pandemic. Altered renal programming resulting in kidney disease and hypertension can begin in utero. Maternal suboptimal nutrition and oxidative stress have important implications in renal programming, while specific antioxidant nutrient supplementations may serve as reprogramming strategies to prevent kidney disease and hypertension of developmental origins. This review aims to summarize current knowledge on the interplay of maternal nutrition and oxidative stress in response to early-life insults and its impact on developmental programming of kidney disease and hypertension, covering two aspects. Firstly, we present the evidence from animal models supporting the implication of oxidative stress on adult kidney disease and hypertension programmed by suboptimal maternal nutrition. In the second part, we document data on specific antioxidant nutrients as reprogramming strategies to protect adult offspring against kidney disease and hypertension from developmental origins. Research into the prevention of kidney disease and hypertension that begin early in life will have profound implications for future health.
ASC Modulates CTL Cytotoxicity and Transplant Outcome Independent of the Inflammasome

The adaptor protein ASC is a key component of the inflammasome complex. ASC-deficient CD8+ T cells have impaired capacity to induce graft-versus-host disease and graft rejection and can control leukemia burden over time. The adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) is known to facilitate caspase-1 activation, which is essential for innate host immunity via the formation of the inflammasome complex, a multiprotein structure responsible for processing IL1β and IL18 into their active moieties. Here, we demonstrated that ASC-deficient CD8+ T cells failed to induce severe graft-versus-host disease (GVHD) and had impaired capacity for graft rejection and graft-versus-leukemia (GVL) activity. These effects were inflammasome independent because GVHD lethality was not altered in recipients of caspase-1/11–deficient T cells. We also demonstrated that ASC deficiency resulted in a decrease in cytolytic function, with a reduction in granzyme B secretion and CD107a expression by CD8+ T cells. Altogether, our findings highlight that ASC represents an attractive therapeutic target for improving outcomes of clinical transplantation.
CMOS-Compatible and Low-Cost Thin Film MACE Approach for Light-Emitting Si NWs Fabrication

Silicon nanowires (Si NWs) are emerging as an innovative building block in several fields, such as microelectronics, energetics, photonics, and sensing. The interest in Si NWs is related to the high surface to volume ratio and the simpler coupling with the industrial flat architecture. In particular, Si NWs emerge as a very promising material to couple the light to silicon. However, with the standard synthesis methods, the realization of quantum-confined Si NWs is very complex and often requires expensive equipment. Metal-Assisted Chemical Etching (MACE) is gaining more and more attention as a novel approach able to guarantee high-quality Si NWs and high density with a cost-effective approach. Our group has recently modified the traditional MACE approach through the use of thin metal films, obtaining a strong control on the optical and structural properties of the Si NWs as a function of the etching process. This method is Complementary Metal-Oxide-Semiconductors (CMOS)-technology compatible, low-cost, and permits us to obtain a high density, and room temperature light-emitting Si NWs due to the quantum confinement effect. A strong control on the Si NWs characteristics may pave the way to a real industrial transfer of this fabrication methodology for both microelectronics and optoelectronics applications.
Controlled Vasoregulation of Postischemic Liver Microcirculation - A Therapeutic Approach

One of the changes produced by ischemia and reperfusion is endothelin (ET)-mediated constriction of the hepatic vascular bed. This leads to microcirculatory disturbances and reduced blood flow, thereby causing local hypoxia and liver damage. Our aim was to induce stepwise changes of microvascular vessel diameters so as to define the best protective vessel width that could be produced by drug therapy and thereby to minimize ischemia/reperfusion injury. The mixed ET receptor antagonist bosentan was used in different dosages in a rat liver ischemia/reperfusion model with splenocaval shunt. In vivo microscopy was performed 30-90 min after reperfusion and local hepatic tissue pO2
Zygotic Vsx1 Plays a Key Role in Defining V2a Interneuron Sub-Lineage by Directly Repressing tal1 Transcription in Zebrafish

In the spinal cord, excitatory V2a and inhibitory V2b interneurons are produced together by the final division of common P2 progenitors. During V2a and V2b diversification, Tal1 is necessary and sufficient to promote V2b differentiation and Vsx2 suppresses the expression of motor neuron genes to consolidate V2a interneuron identity. The expression program of Tal1 is triggered by a Foxn4-driven regulatory network in the common P2 progenitors. Why the expression of Tal1 is inhibited in V2a interneurons at the onset of V2a and V2b sub-lineage diversification remains unclear. Since transcription repressor Vsx1 is expressed in the P2 progenitors and newborn V2a cells in zebrafish, we investigated the role of Vsx1 in V2a fate specification during V2a and V2b interneuron diversification in this species by loss and gain-of-function experiments. In vsx1 knockdown embryos or knockout Go chimeric embryos, tal1 was ectopically expressed in the presumptive V2a cells, while the generation of V2a interneurons was significantly suppressed. By contrast, in vsx1 overexpression embryos, normal expression of tal1 in the presumptive V2b cells was suppressed, while the generation of V2a interneuron was expanded. Chromatin immunoprecipitation and electrophoretic mobility shift assays in combination with core consensus sequence mutation analysis further revealed that Vsx1 can directly bind to tal1 promoter and repress tal1 transcription. These results indicate that Vsx1 can directly repress tal1 transcription and plays an essential role in defining V2a interneuron sub-lineage during V2a and V2b sub-lineage diversification in zebrafish.
Genetic Diversity of 10 Indigenous Pig Breeds in China by Using Microsatellite Markers

The genetic diversities of 10 Chinese pig populations were analyzed by using microsatellite DNA polymorphisms. The results showed that the mean heterozygosities of the 10 populations were between 0.4561 and 0.6446, the mean polymorphism information contents were 0.4241-0.6184 and the mean effective number of alleles were 2.4295-3.7573. These indicated that the genetic diversity of local Chinese pigs was high. The clustering of the 10 populations was nearly inaccordance with their geographical distributions.
Effects of life‐state on detectability in a demographic study of the terrestrial orchid Cleistes bifaria

1 Most plant demographic studies follow marked individuals in permanent plots. Plots tend to be small, so detectability is assumed to be one for every individual. However, detectability could be affected by factors such as plant traits, time, space, observer, previous detection, biotic interactions, and especially by life‐state. 2 We used a double‐observer survey and closed population capture–recapture modelling to estimate state‐specific detectability of the orchid Cleistes bifaria in a long‐term study plot of 41.2 m2. Based on AICc model selection, detectability was different for each life‐state and for tagged vs. previously untagged plants. There were no differences in detectability between the two observers. 3 Detectability estimates (SE) for one‐leaf vegetative, two‐leaf vegetative, and flowering/fruiting states correlated with mean size of these states and were 0.76 (0.05), 0.92 (0.06), and 1 (0.00), respectively, for previously tagged plants, and 0.84 (0.08), 0.75 (0.22), and 0 (0.00), respectively, for previously untagged plants. (We had insufficient data to obtain a satisfactory estimate of previously untagged flowering plants). 4 Our estimates are for a medium‐sized plant in a small and intensively surveyed plot. It is possible that detectability is even lower for larger plots and smaller plants or smaller life‐states (e.g. seedlings) and that detectabilities < 1 are widespread in plant demographic studies. 5 State‐dependent detectabilities are especially worrying since they will lead to a size‐ or state‐biased sample from the study plot. Failure to incorporate detectability into demographic estimation methods introduces a bias into most estimates of population parameters such as fecundity, recruitment, mortality, and transition rates between life‐states. We illustrate this by a simple example using a matrix model, where a hypothetical population was stable but, due to imperfect detection, wrongly projected to be declining at a rate of 8% per year. 6 Almost all plant demographic studies are based on models for discrete states. State and size are important predictors both for demographic rates and detectability. We suggest that even in studies based on small plots, state‐ or size‐specific detectability should be estimated at least at some point to avoid biased inference about the dynamics of the population sampled.
Technical Metrics Used to Evaluate Health Care Chatbots: Scoping Review

Background Dialog agents (chatbots) have a long history of application in health care, where they have been used for tasks such as supporting patient self-management and providing counseling. Their use is expected to grow with increasing demands on health systems and improving artificial intelligence (AI) capability. Approaches to the evaluation of health care chatbots, however, appear to be diverse and haphazard, resulting in a potential barrier to the advancement of the field. Objective This study aims to identify the technical (nonclinical) metrics used by previous studies to evaluate health care chatbots. Methods Studies were identified by searching 7 bibliographic databases (eg, MEDLINE and PsycINFO) in addition to conducting backward and forward reference list checking of the included studies and relevant reviews. The studies were independently selected by two reviewers who then extracted data from the included studies. Extracted data were synthesized narratively by grouping the identified metrics into categories based on the aspect of chatbots that the metrics evaluated. Results Of the 1498 citations retrieved, 65 studies were included in this review. Chatbots were evaluated using 27 technical metrics, which were related to chatbots as a whole (eg, usability, classifier performance, speed), response generation (eg, comprehensibility, realism, repetitiveness), response understanding (eg, chatbot understanding as assessed by users, word error rate, concept error rate), and esthetics (eg, appearance of the virtual agent, background color, and content). Conclusions The technical metrics of health chatbot studies were diverse, with survey designs and global usability metrics dominating. The lack of standardization and paucity of objective measures make it difficult to compare the performance of health chatbots and could inhibit advancement of the field. We suggest that researchers more frequently include metrics computed from conversation logs. In addition, we recommend the development of a framework of technical metrics with recommendations for specific circumstances for their inclusion in chatbot studies.
Targeted PET Imaging of Chemokine Receptor 2–Positive Monocytes and Macrophages in the Injured Heart

Proinflammatory macrophages are important mediators of inflammation after myocardial infarction and of allograft injury after heart transplantation. The aim of this study was to image the recruitment of proinflammatory chemokine receptor 2–positive (CCR2+) cells in multiple heart injury models. Methods: 64Cu-DOTA-extracellular loop 1 inverso (ECL1i) PET was used to image CCR2+ monocytes and macrophages in a heart transplantation mouse model. Flow cytometry was performed to characterize CCR2+ cells. Autoradiography on a human heart specimen was conducted to confirm binding specificity. 64Cu- and 68Ga-DOTA-ECL1i were compared in an ischemia–reperfusion injury mouse model. Results: 64Cu-DOTA-ECL1i showed sensitive and specific detection of CCR2+ cells in all tested mouse models, with efficacy comparable to that of 68Ga-DOTA-ECL1i. Flow cytometry demonstrated specific expression of CCR2 on monocytes and macrophages. The tracer binds to human CCR2. Conclusion: This work establishes the utility of 64Cu-DOTA-ECL1i to image CCR2+ monocytes and macrophages in mouse models and provides the requisite preclinical information to translate the targeted clinical-grade CCR2 imaging probe for clinical investigation of heart diseases.
Pediatric Leigh Syndrome: Neuroimaging Features and Genetic Correlations

The neurodiagnostic criteria of Leigh syndrome have not yet been clearly redefined based on the expanding of molecular etiologies. We aimed to analyze 20 years of clinical, genetic, and magnetic resonance studies from our Leigh syndrome cohort to provide a detailed description of central nervous system lesions in Leigh syndrome and their biological evolution in view of their genetic and clinical findings. Our study adds new neurodiagnostic insights to the current knowledge of Leigh syndrome, including association with overlapping syndromes, and the correlation of pathogenic genetic variants with neuroimaging phenotypes. ANN NEUROL 2020;88:218–232.
A Design of Experiment Approach for Surface Roughness Comparisons of Foam Injection-Moulding Methods

The pursuit of polymer parts produced through foam injection moulding (FIM) that have a comparable surface roughness to conventionally processed components are of major relevance to expand the application of FIM. Within this study, 22% talc-filled copolymer polypropylene (PP) parts were produced through FIM using both a physical and chemical blowing agent. A design of experiments (DoE) was performed whereby the processing parameters of mould temperatures, injection speeds, back-pressure, melt temperature and holding time were varied to determine their effect on surface roughness, Young’s modulus and tensile strength. The results showed that mechanical performance can be improved when processing with higher mould temperatures and longer holding times. Also, it was observed that when utilising chemical foaming agents (CBA) at low-pressure, surface roughness comparable to that obtained from conventionally processed components can be achieved. This research demonstrates the potential of FIM to expand to applications whereby weight saving can be achieved without introducing surface defects, which has previously been witnessed within FIM.
Plasma Oxalate as a Predictor of Kidney Function Decline in a Primary Hyperoxaluria Cohort

This retrospective analysis investigated plasma oxalate (POx) as a potential predictor of end-stage kidney disease (ESKD) among primary hyperoxaluria (PH) patients. PH patients with type 1, 2, and 3, age 2 or older, were identified in the Rare Kidney Stone Consortium (RKSC) PH Registry. Since POx increased with falling estimated glomerular filtration rate (eGFR), patients were stratified by chronic kidney disease (CKD) subgroups (stages 1, 2, 3a, and 3b). POx values were categorized into quartiles for analysis. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for risk of ESKD were estimated using the Cox proportional hazards model with a time-dependent covariate. There were 118 patients in the CKD1 group (nine ESKD events during follow-up), 135 in the CKD 2 (29 events), 72 in CKD3a (34 events), and 45 patients in CKD 3b (31 events). During follow-up, POx Q4 was a significant predictor of ESKD compared to Q1 across CKD2 (HR 14.2, 95% CI 1.8–115), 3a (HR 13.7, 95% CI 3.0–62), and 3b stages (HR 5.2, 95% CI 1.1–25), p < 0.05 for all. Within each POx quartile, the ESKD rate was higher in Q4 compared to Q1–Q3. In conclusion, among patients with PH, higher POx concentration was a risk factor for ESKD, particularly in advanced CKD stages.
Observer differences in the North American Breeding Bird Survey

Because count data collected in many bird surveys are only an index to pop- ulation size, factors that can influence the counts must be identified and incorporated into analyses. Observer quality is often ignored in analyses of population changes from survey data, but observers differ in methods and capabilities and, hence, tend to count different numbers of birds. We assess the consequences of between-observer differences in counts for estimation of population trends in the North American Breeding Bird Survey. Observer differences in numbers of birds counted were found in 50% of the 369 species we examined. For many species, observers in later years tended to count more birds than observers in earlier years, suggesting an increase in observer quality over time. Analysis of population trends from 1966 through 1991 indicates that failure to include observers as covariables in the analysis results in an overly optimistic view of population trends. Received 8 March 1993, accepted 24 October 1993.
The Zinc-Finger Domain Containing Protein ZC4H2 Interacts with TRPV4, Enhancing Channel Activity and Turnover at the Plasma Membrane

The Ca2+-permeable Transient Receptor Potential channel vanilloid subfamily member 4 (TRPV4) is involved in a broad range of physiological processes, including the regulation of systemic osmotic pressure, bone resorption, vascular tone, and bladder function. Mutations in the TRPV4 gene are the cause of a spectrum of inherited diseases (or TRPV4-pathies), which include skeletal dysplasias, arthropathies, and neuropathies. There is little understanding of the pathophysiological mechanisms underlying these variable disease phenotypes, but it has been hypothesized that disease-causing mutations affect interaction with regulatory proteins. Here, we performed a mammalian protein–protein interaction trap (MAPPIT) screen to identify proteins that interact with the cytosolic N terminus of human TRPV4, a region containing the majority of disease-causing mutations. We discovered the zinc-finger domain-containing protein ZC4H2 as a TRPV4-interacting protein. In heterologous expression experiments, we found that ZC4H2 increases both the basal activity of human TRPV4 as well as Ca2+ responses evoked by ligands or hypotonic cell swelling. Using total internal reflection fluorescence (TIRF) microscopy, we further showed that ZC4H2 accelerates TRPV4 turnover at the plasma membrane. Overall, these data demonstrate that ZC4H2 is a positive modulator of TRPV4, and suggest a link between TRPV4 and ZC4H2-associated rare disorders, which have several neuromuscular symptoms in common with TRPV4-pathies.
Trends in wheelchair recommendations in a dedicated seating department

ABSTRACT Introduction In the early 2000 s, investigators at the federal government noted growing Medicare expenditures for power mobility devices, which were related to high profit margins and fraudulent activity. Medicare responded with policy and program changes, and stakeholders in wheelchair service delivery have noticed an impact on their services and changes in wheelchair user access to needed equipment. Methods This study examined 4,252 wheelchair clinical recommendations made by full-time wheelchair seating department therapists between 2007 and 2017 through a retrospective chart review. Demographic counts and percentages were examined in relationship with equipment over time. Results The number of recommendations increased over time in all age groups, but most for people aged 19–64. Fifty percent of people with Medicare were younger than 65, and 63% of Medicare recommendations were for complex wheelchair bases. Overall, decreased recommendations were noted in 2008, consistent with the economic recession. An increase in recommendations occurred from 2014 to 2017, consistent with the onset of the Affordable Care Act. Conclusions Most change occurred for middle and older age groups, complex manual wheelchairs, and standard power mobility devices. This study supports the need for a separate Medicare category of Complex Rehabilitation Technology for those with severe disabilities.