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In order to meet the ever-increasing demand for the throughput of 5G mobile communications, more and more frequency bands are defined for the LTE system. However, some parts of the bands have been used by satellite services. When an LTE system in one country is within the footprint of a satellite service owned by another country, to prevent the interference from the satellite services, the LTE system will avoid using the overlapped frequency bands. In order to make use of the overlapped LTE bands, a Downlink Only Frame Structure (DOFS) approach is proposed in this paper. It treats the interfered band as a secondary carrier of a licensed primary carrier and employs a standard frame structure to transmit only downlink traffic on the band. The feasibility of the proposed DOFS approach is evaluated by both considering practical implementation parameters and using a popular commercial simulation tool at an interfered spot. The results reveal that, for most part of the evaluated zone, the SINR is good enough for 64QAM modulation.

The COVID-pandemic has required changes to healthcare delivery and has been a stressful time for people with diabetes mellitus (DM) . Previous literature suggests that virtual health appointments for diabetes care can be effective and result in high patient satisfaction. However, it is unclear if patients with DM are satisfied with the widespread adoption of virtual care during the pandemic. The aim of this study was to evaluate the impact of virtual care during the pandemic on patient satisfaction in patients with type 1 and type 2 DM. The validated Patient Satisfaction Questionnaire (PSQ-III) was completed by 197 patients who had an in-person appointment in the six months before March 18, 2020 (pre-COVID) and a subsequent virtual appointment within six months after that date. For each form of healthcare delivery (i.e. in-person and virtual) , the satisfaction in six aspects of care was measured: general satisfaction, technical quality, interpersonal manner, communication, time spent with doctor, and accessibility of care. Both type 2 DM and age >55 years were associated with decreased general satisfaction with virtual care compared to in-person care. Both type 2 DM and female sex were associated with decreased technical quality of care. Accessibility of care decreased significantly in the overall study group. No significant differences in patient satisfaction were observed in the type 1 DM group. Despite our findings, 74% of respondents answered they would consider virtual health appointments in the future. Our data suggests that many patients welcome virtual health as an addition to their medical care. However, virtual health does not seem to deliver the same level of patient satisfaction as in-person appointments over the longer term. Future research on how fatigue with pandemic restrictions has affected patient satisfaction is needed to evaluate whether virtual health appointments are a viable option for long term diabetes care. Disclosure C.Chang: None. A.Dissanayake: None. M.Pawlowska: Advisory Panel; Novo Nordisk, Other Relationship; Medtronic. B.Schroeder: Advisory Panel; Novartis Canada, Novartis Canada, Novartis Canada, Novo Nordisk Canada Inc., Novo Nordisk Canada Inc., Novo Nordisk Canada Inc. J.Mackenzie-feder: Advisory Panel; Recordati S.p.A. A.White: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Canada Inc.

Promoting myelination capacity of endogenous oligodendrocyte precursor cells (OPCs) is a promising therapeutic approach for central nervous system demyelinating disorders such as Multiple Sclerosis (MS). To aid in the discovery of myelination promoting compounds, we generated an advanced, genome engineered, human pluripotent stem cell (hPSC) line that consist of three reporters (identification-and-purification tag, GFP, and secreted NanoLuc) driven by the endogenous PDGFRα, PLP1 and MBP genes, respectively. Based upon this line, we established a high-throughput drug screening platform and performed a small molecule screen with 2500 bioactive molecules. In addition to a number of previously known pathways, our screening effort identified new pathways whose inhibition enhance oligodendrocyte maturation and myelination. Although further genetic and molecular validation is required, the identified inhibitors could potentially be repurposed to develop remyelination therapy for MS and other demyelinating disorders.

Indeed, intelligent model is a sub-domain in computer science that its purposes utilized in numerous pieces of reality. Particularly in case of automotive industry, to select the most appropriate personal vehicle is challenging for the customers. The challenge was taken as a main problem of this study. In this research, the reasonableness is characterized by the customer parameters which portray the customer’s identity. By utilizing the mix technique for fuzzy-logic and Euclidean distance calculation, the customer’s identities are fitted into the personal-vehicle parameters. At long last, the constructed model for choosing personal vehicle plays several customer’s parameters; e.g., age, gender, education, income and job. The model designed thru utilizing the object-oriented methodology. The result of simulation of 66 purchasers and 44 conceivable vehicles are able to propose the most reasonable vehicle for every purchaser. As an extended version, the model successfully delivers the completed scheme due to added parameters and method. It is a truthful contribution provided by this research.

Data on the health and social determinants for Native Hawaiians and Pacific Islanders (NHPIs) in the United States are hidden, because data are often not collected or are reported in aggregate with other racial/ethnic groups despite decades of calls to disaggregate NHPI data. As a form of structural racism, data omissions contribute to systemic problems such as inability to advocate, lack of resources, and limitations on political power. The authors conducted a data audit to determine how US federal agencies are collecting and reporting disaggregated NHPI data. Using the COVID-19 pandemic as a case study, they reviewed how states are reporting NHPI cases and deaths. They then used California's neighborhood equity metric—the California Healthy Places Index (HPI)—to calculate the extent of NHPI underrepresentation in communities targeted for COVID-19 resources in that state. Their analysis shows that while collection and reporting of NHPI data nationally has improved, federal data gaps remain. States are vastly underreporting: more than half of states are not reporting NHPI COVID-19 case and death data. The HPI, used to inform political decisions about allocation of resources to combat COVID-19 in at-risk neighborhoods, underrepresents NHPIs. The authors make recommendations for improving NHPI data equity to achieve health equity and social justice.

As of March 2021, Native Hawaiians and Pacific Islanders (NHPIs) in the United States have lost more than 800 lives to COVID-19—the highest per capita death rate in 18 of 20 US states reporting NHPI deaths. However, NHPI risks are overlooked in policy discussions. We discuss the NHPI COVID-19 Data Policy Lab and dashboard, featuring the disproportionate COVID-19 mortality burden for NHPIs. The Lab democratized NHPI data, developed community infrastructure and resources, and informed testing site and outreach policies related to health equity.

Functional microgels are preferred stem cell carriers due to the ease of delivery through minimally invasive injection and seamless integration with the surrounding host tissue. We have previously developed a biostimulatory nanofiber-hydrogel composite (NHC) through covalently crosslinking a hyaluronic acid hydrogel network with surface-functionalized poly (ε-caprolactone) nanofibre fragments. The NHC mimics the microarchitecture of native soft tissue matrix, showing enhanced cell infiltration, immunomodulation, and proangiogenic properties. Here, we improved injectability of the pre-formed NHC by mechanical fragmentation, making it into micro-fragmented NHC (mfNHC) in a granular gel form as a stem cell carrier to deliver mesenchymal stem cells (MSCs) for soft tissue remodelling. The mfNHC showed similar storage modulus but a significantly reduced injection force, as compared with the corresponding bulk NHC. When injected subcutaneously in a rat model, mfNHC-MSC constructs initiated an elevated level of host macrophage infiltration, more pro-regenerative polarization and subsequently, improved angiogenesis and adipogenesis response when compared to mfNHC alone. A similar trend of host cell infiltration and pro-angiogenic response was detected in a swine model with a larger volume injection. These results suggest a strong potential for use of the mfNHC as an injectable carrier for cell delivery and soft tissue remodelling.

Injury and loss of oligodendrocytes can cause demyelinating diseases such as multiple sclerosis. To improve our understanding of human oligodendrocyte development, which could facilitate development of remyelination-based treatment strategies, here we describe time-course single-cell-transcriptomic analysis of developing human stem cell-derived oligodendrocyte-lineage-cells (hOLLCs). The study includes hOLLCs derived from both genome engineered embryonic stem cell (ESC) reporter cells containing an Identification-and-Purification tag driven by the endogenous PDGFRα promoter and from unmodified induced pluripotent (iPS) cells. Our analysis uncovers substantial transcriptional heterogeneity of PDGFRα-lineage hOLLCs. We discover sub-populations of human oligodendrocyte progenitor cells (hOPCs) including a potential cytokine-responsive hOPC subset, and identify candidate regulatory genes/networks that define the identity of these sub-populations. Pseudotime trajectory analysis defines developmental pathways of oligodendrocytes vs astrocytes from PDGFRα-expressing hOPCs and predicts differentially expressed genes between the two lineages. In addition, pathway enrichment analysis followed by pharmacological intervention of these pathways confirm that mTOR and cholesterol biosynthesis signaling pathways are involved in maturation of oligodendrocytes from hOPCs., Brain myelinating oligodendrocytes are rare and difficult to isolate, which has limited data on their development. Here the authors develop a reporter for scalable purification of human pluripotent stem cell derived oligodendrocyte lineage cells, and use this to map differentiation using single cell RNA-sequencing

Injury and loss of oligodendrocytes can cause demyelinating diseases such as multiple sclerosis. To improve our understanding of oligodendrocyte development, which could facilitate development of remyelination-based treatment strategies, we performed single-cell-transcriptomic-analysis of developing human oligodendrocyte-precursor-cells (hOPCs). We engineered knock-in hESC-reporter lines in which an Identification-and-Purification tag is expressed under control of the endogenous, OPC-specific,PDGFRαpromoter, and performed time-course single-cell-RNA-sequencing of purified hOPCs. Our analysis uncovered marked transcriptional heterogeneity of PDGFRα+ hOPCs and identified regulatory genes and networks that control their differentiation and myelination competence. Pseudotime trajectory analysis revealed two distinct trajectories for the development of oligodendrocytes vs astrocytes from hOPCs. We also identified novel transcription factors and other genes that developing hOPCs potentially use to choose between oligodendrocyte vs astrocyte lineages. In addition, pathway enrichment analysis followed by pharmacological intervention of those pathways confirm that mTOR and cholesterol biosynthesis signaling pathways are involved in maturation of oligodendrocytes from hOPCs.

To facilitate the development of large-scale transcriptional regulatory networks (TRNs) that may enable in-silico analyses of disease mechanisms, a reliable catalogue of experimentally verified direct transcriptional regulatory interactions (DTRIs) is needed for training and validation. There has been a long history of using low-throughput experiments to validate single DTRIs. Therefore, we reason that a reliable set of DTRIs could be produced by curating the published literature for such evidence. In our survey of previous curation efforts, we identified the lack of details about the quantity and the types of experimental evidence to be a major gap, despite the theoretical importance of such details for the identification of bona fide DTRIs. We developed a curation protocol to inspect the published literature for support of DTRIs at the experiment level, focusing on genes important to the development of the mammalian nervous system. We sought to record three types of low-throughput experiments: Transcription factor (TF) perturbation, TF-DNA binding, and TF-reporter assays. Using this protocol, we examined a total of 1,310 papers to assemble a collection of 1,499 unique DTRIs, involving 251 TFs and 825 target genes, many of which were not reported in any other DTRI resource. The majority of DTRIs (965; 64%) were supported by two or more types of experimental evidence and 27% were supported by all three. Of the DTRIs with all three types of evidence, 170 had been tested using primary tissues or cells and 44 had been tested directly in the central nervous system. We used our resource to document research biases among reports towards a small number of well-studied TFs. To demonstrate a use case for this resource, we compared our curation to a previously published high-throughput perturbation screen and found significant enrichment of the curated targets among genes differentially expressed in the developing brain in response to Pax6 deletion. This study demonstrates a proof-of-concept for the assembly of a high resolution DTRI resource to support the development of large-scale TRNs., Author summary The capacity to computationally reconstruct gene regulatory networks using large-scale biological data is currently limited by the absence of a high confidence set of one-to-one regulatory interactions. Given the lengthy history of using small scale experimental assays to investigate individual interactions, we reason that a reliable collection of gene regulatory interactions could be compiled by systematically inspecting the published literature. To this end, we developed a curation protocol to examine and record evidence of regulatory interactions at the individual experiment level. Focusing on the area of brain development, we applied our pipeline to 1,310 publications. We identified 3,601 individual experiments, providing detailed information about 1,499 regulatory interactions. Many of these interactions have verified activity specifically in the embryonic brain. By capturing reports of regulatory interactions at this level of detail, we equip the users with more granular information than other similar resources, enabling more informed assessments of reliability.

In Indonesia, the issue of waste is definitely challenging. This problem demands an exclusive and prudent treatment to implement; as a destructive consequence practically generated from incorrect strategy implementation in treating is wide-ranging, particularly for human’s life and health and also for environment. This paper offers a generic smart ecological decision support model (ecoDSM) for treating medical waste. The mathematical model based on fuzzy logic conception that combined with the other heuristic optimization method are functioned to measure and justify six alternatives of treating strategy decision. Based on empirical data of two types of medical waste (i.e. sharp and infectious) coming from private hospital; the model’s simulation result shows that the "mechanical processing and chemical disinfectant" treatment strategy is the most objective decision should be implemented by the hospital.

Licensed shared access (LSA) is one of the emerging modes of regulation for dynamic spectrum sharing management among incumbent wireless networks and secondary networks such as LTE mobile networks. This proof- of-concept demonstration of LSA exploits the Virtually Shared Spectrum Access (ViSSA) platform among various wireless networks and management entities. The ViSSA platform is an innovative integration of five parts by combining LTE small cells, emulators and management servers: i) a monitoring and management center with a spectrum repository that extends a license-exempt mode compliant geo-location database (GLDB/SR); ii) emulated incumbents that may register to GLDB/SR or directly access their spectrum; iii) a few LTE small cell networks of secondary accesses, each network having an LSA controller to communicate between GLDB/SR and its own network management; iv) feature-based sensing of incumbent signals emulated by a USRP; and v) implementation of LSRAI- and http-based communications among i) - iv) via Internet. On-site exhibition of ViSSA platform will demonstrate the novel LSA management of database-guided and sensing-based evacuation yielding to the incumbent. Demonstrations of re-activation of secondary LTE small cells in other available spectrum bands show the feasibility of completing evacuation and re-activation in 60 to 70 seconds.

This essay examines the importance of disaggregating Native Hawaiian and Pacific Islander data, issues currently faced by NHPI communities, and where NHPI communities could be in 2040. Projected demographic trends may exacerbate challenges faced by NHPIs in areas such as health, education, income, incarceration, housing, and immigration. The impact of climate change, technological innovations, and the United States’ shift towards a majority-minority status on NHPI communities are also analyzed. Three recommendations for improving the position of NHPIs in 2040 are provided: (1) Address the needs of an increasingly diverse NHPI community; (2) develop community capacity for civic engagement; and (3) invest in leadership development and NHPI youth.

Excessive poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) activation kills cells via a cell-death process designated "parthanatos" in which PAR induces the mitochondrial release and nuclear translocation of apoptosis-inducing factor to initiate chromatinolysis and cell death. Accompanying the formation of PAR are the reduction of cellular NAD(+) and energetic collapse, which have been thought to be caused by the consumption of cellular NAD(+) by PARP-1. Here we show that the bioenergetic collapse following PARP-1 activation is not dependent on NAD(+) depletion. Instead PARP-1 activation initiates glycolytic defects via PAR-dependent inhibition of hexokinase, which precedes the NAD(+) depletion in N-methyl-N-nitroso-N-nitroguanidine (MNNG)-treated cortical neurons. Mitochondrial defects are observed shortly after PARP-1 activation and are mediated largely through defective glycolysis, because supplementation of the mitochondrial substrates pyruvate and glutamine reverse the PARP-1-mediated mitochondrial dysfunction. Depleting neurons of NAD(+) with FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, does not alter glycolysis or mitochondrial function. Hexokinase, the first regulatory enzyme to initiate glycolysis by converting glucose to glucose-6-phosphate, contains a strong PAR-binding motif. PAR binds to hexokinase and inhibits hexokinase activity in MNNG-treated cortical neurons. Preventing PAR formation with PAR glycohydrolase prevents the PAR-dependent inhibition of hexokinase. These results indicate that bioenergetic collapse induced by overactivation of PARP-1 is caused by PAR-dependent inhibition of glycolysis through inhibition of hexokinase.

T cell therapies require the removal and culture of T cells ex vivo to expand several thousand-fold. However, these cells often lose the phenotype and cytotoxic functionality for mediating effective therapeutic responses. The extracellular matrix (ECM) has been used to preserve and augment cell phenotype; however, it has not been applied to cellular immunotherapies. Here, a hyaluronic acid (HA)-based hydrogel is engineered to present the two stimulatory signals required for T-cell activation—termed an artificial T-cell stimulating matrix (aTM). It is found that biophysical properties of the aTM—stimulatory ligand density, stiffness, and ECM proteins—potentiate T cell signaling and skew phenotype of both murine and human T cells. Importantly, the combination of the ECM environment and mechanically sensitive TCR signaling from the aTM results in a rapid and robust expansion of rare, antigen-specific CD8+ T cells. Adoptive transfer of these tumor-specific cells significantly suppresses tumor growth and improves animal survival compared with T cells stimulated by traditional methods. Beyond immediate immunotherapeutic applications, demonstrating the environment influences the cellular therapeutic product delineates the importance of the ECM and provides a case study of how to engineer ECM-mimetic materials for therapeutic immune stimulation in the future.

DNA damage-activated nuclease identified Cells that experience stresses and accumulate excessive damage to DNA undergo cell death mediated by a nuclear enzyme known as PARP-1. During this process, apoptosis-inducing factor (AIF) translocates to the nucleus and activates one or more nucleases to cleave DNA. Wang et al. found that macrophage migration inhibitory factor (MIF) is an AIF-associated endonuclease that contributes to PARP-1-induced DNA fragmentation (see the Perspective by Jonas). In mouse neurons in culture, loss of MIF protected neurons from cell death caused by excessive stimulation. Targeting MIF could thus provide a therapeutic strategy against diseases in which PARP-1 activation is excessive. Science , this issue p. 82 ; see also p. 36

Identification and validation of a drug discovery target is a prominent step in drug development. In the post-genomic era it is possible to reevaluate the association of a gene with a specific biological function to see if a homologous gene can subsume this role. This concept has special relevance to drug discovery in human infectious diseases, like malaria. A trophozoite cysteine protease (falcipain-1) from the papain family, thought to be responsible for the degradation of erythrocyte hemoglobin, has been considered a promising target for drug discovery efforts owing to the antimalarial activity of peptide based covalent cysteine protease inhibitors. This led to the development of non-peptidic non-covalent inhibitors of falcipain-1 and their characterization as antimalarials. It is now clear from sequencing efforts that the malaria genome contains more than one cysteine protease and that falcipain-1 is not the most important contributor to hemoglobin degradation. Rather, falcipain-2 and falcipain-3 appear to account for the majority of cysteine hemoglobinase activity in the plasmodium trophozoite. We have modeled the falcipain-2 cysteine protease from one of the major human malaria species, Plasmodium falciparum and compared it to our original work on falcipain-1. As with falcipain-1, computational screening of the falcipain-2 active site was conducted using DOCK. Using structural superpositions within the protease family and evolutionary analysis of substrate specificity sites, we focused on the commonalities and the protein specific features to direct our drug discovery effort. Since 1993, the size of the Available Chemicals Directory had increased from 55313 to 195419 unique chemical structures. For falcipain-2, eight inhibitors were identified with IC50’s against the enzyme between 1 and 7 µM. Application of three of these inhibitors to infected erythrocytes cured malaria in culture, but parasite death did not correlate with food vacuole abnormalities associated with the activity of mechanistic inhibitors of cysteine proteases like the epoxide E64. Using plasmodial falcipain proteases, we show how a protein family perspective can influence target discovery and inhibitor design. We suspect that parallel drug discovery programs where a family of targets is considered, rather than serial programs built on a single therapeutic focus, will become the dominant industrial paradigm. Economies of scale in assay development and in compound synthesis are expected owing to the functional and structural features of individual family members. One of the remaining challenges in post-genomic drug discovery is that inhibitors of one target are likely to show some activity against other family members. This lack of specificity may lead to difficulties in functional assignments and target validation as well as a complex side effect profile.

A splice form of IGF-1, IGF-1Eb, is upregulated after exercise or injury. Physiological responses have been ascribed to the 24-amino acid COOH-terminal peptide that is cleaved from the NH3-terminal 70-amino acid mature IGF-1 protein. This COOH-terminal peptide was termed “mechano-growth factor” (MGF). Activities claimed for the MGF peptide included enhancing muscle satellite cell proliferation and delaying myoblast fusion. As such, MGF could represent a promising strategy to improve muscle regeneration. Thus, at our two pharmaceutical companies, we attempted to reproduce the claimed effect of MGF peptides on human and mouse muscle myoblast proliferation and differentiation in vitro. Concentrations of peptide up to 500 ng/ml failed to increase the proliferation of C2C12 cells or primary human skeletal muscle myoblasts. In contrast, all cell types exhibited a proliferative response to mature IGF-1 or full-length IGF-1Eb. MGF also failed to inhibit the differentiation of myoblasts into myotubes. To address whether the response to MGF was lost in these tissue culture lines, we measured proliferation and differentiation of primary mouse skeletal muscle stem cells exposed to MGF. This, too, failed to demonstrate a significant effect. Finally, we tested whether MGF could alter a separate documented in vitro effect of the peptide, activation of p-ERK, but not p-Akt, in cardiac myocytes. Although a robust response to IGF-1 was observed, there were no demonstrated activating responses from the native or a stabilized MGF peptide. These results call in to question whether there is a physiological role for MGF.