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Multipotent human mesenchymal stromal cells (MSCs) from multiple organs including the bone marrow (BM) and placenta harbor clinically relevant immunomodulation best demonstrated toward T lymphocytes. Surprisingly, there is limited knowledge on interactions with B lymphocytes, which originate from the BM where there is a resident MSC. With increasing data demonstrating MSC tissue‐specific propensities impacting therapeutic outcome, we therefore investigated the interactions of BM‐MSCs—its resident and “niche” MSC—and placental MSCs (P‐MSCs), another source of MSCs with well‐characterized immunomodulatory properties, on the global functional outcomes of pan‐peripheral B cell populations. We found that P‐MSCs but not BM‐MSCs significantly inhibit proliferation and further differentiation of stimulated human peripheral B populations in vitro. Moreover, although BM‐MSCs preserve multiple IL‐10‐producing regulatory B cell (Breg) subsets, P‐MSCs significantly increase all subsets. To corroborate these in vitro findings in vivo, we used a mouse model of B‐cell activation and found that adoptive transfer of P‐MSCs but not BM‐MSCs significantly decreased activated B220+ B cells. Moreover, adoptive transfer of P‐MSCs but not BM‐MSCs significantly decreased the overall B220+ B‐cell proliferation and further differentiation, similar to the in vitro findings. P‐MSCs also increased two populations of IL‐10‐producing murine Bregs more strongly than BM‐MSCs. Transcriptome analyses demonstrated multifactorial differences between BM‐ and P‐MSCs in the profile of relevant factors involved in B lymphocyte proliferation and differentiation. Our results highlight the divergent outcomes of tissue‐specific MSCs interactions with peripheral B cells, and demonstrate the importance of understanding tissue‐specific differences to achieve more efficacious outcome with MSC therapy., Multipotent bone marrow mesenchymal stromal cells (BM‐MSCs)—the resident MSC for B lymphocyte development—support stimulated peripheral B‐cell proliferation/differentiation, whereas placental MSCs (P‐MSCs) suppress proliferation/differentiation and more significantly increased multiple populations of IL‐10‐expressing regulatory B cells (Bregs). These divergent outcomes are likely due to multifactorial differences in the expression of relevant factors by the two MSC sources.

Human mesenchymal stem cells (MSCs) remain one of the best cell sources for cartilage, a tissue without regenerative capacity. However, MSC chondrogenesis is commonly induced through TGFβ, a pleomorphic growth factor without specificity for this lineage. Using tissue- and induced pluripotent stem cell-derived MSCs, we demonstrate an efficient and precise approach to induce chondrogenesis through Wnt/β-catenin antagonism alone without TGFβ. Compared to TGFβ, Wnt/β-catenin antagonism more rapidly induced MSC chondrogenesis without eliciting off-target lineage specification toward smooth muscle or hypertrophy; this was mediated through increasing N-cadherin levels and β-catenin interactions-key components of the adherens junctions (AJ)-and increasing cytoskeleton-mediated condensation. Validation with transcriptomic analysis of human chondrocytes compared to MSCs and osteoblasts showed significant downregulation of Wnt/β-catenin and TGFβ signaling along with upregulation of α-catenin as an upstream regulator. Our findings underscore the importance of understanding developmental pathways and structural modifications in achieving efficient MSC chondrogenesis for translational application.

Background: Little is known regarding the impact of socioeconomic factors on the use of evidence-based therapies and outcomes in patients with heart failure with reduced ejection fraction across Asia. Methods: We investigated the association of both patient-level (household income, education levels) and country-level (regional income level by World Bank classification, income disparity by Gini index) socioeconomic indicators on use of guideline-directed therapy and clinical outcomes (composite of 1-year mortality or HF hospitalization, quality of life) in the prospective multinational ASIAN-HF study (Asian Sudden Cardiac Death in Heart Failure). Results: Among 4540 patients (mean age: 60±13 years, 23% women) with heart failure with reduced ejection fraction, 39% lived in low-income regions; 34% in regions with high-income disparity (Gini ≥42.8%); 64.4% had low monthly household income (P interaction Conclusions: These findings highlight the importance of socioeconomic determinants among patients with heart failure in Asia and suggest that attention should be paid to address disparities in access to care among the poor and less educated, including those from wealthy regions. Registration: URL: https://clinicaltrials.gov ; Unique Identifier: NCT01633398.

We propose an optical cavity with spiral phase defect for particular vortex laser generation. Utilizing a reflective spatial light modulator that creates variable spiral phase defect, vortex beams with controllable topological charges are demonstrated.

The rapid aging of worldwide populations had led to epidemic increases in the incidence of osteoporosis (OP), but while treatments are available, high cost, adverse effects, and poor compliance continue to be significant problems. Naturally occurring plant-based compounds including phytoestrogens can be good and safe candidates to treat OP, but screening for osteogenic capacity has been difficult to achieve, largely due to the requirement of using primary osteoblasts or mesenchymal stem cells (MSCs), the progenitors of osteoblasts, to conduct time-consuming in vitro and in vivo osteogenic assay. Taking advantage of MSC osteogenic capacity and utilizing a promoter reporter assay for Runx2, the master osteogenesis transcription factor, we developed a rapid in vitro screening platform to screen osteogenic small molecules including natural plant-based compounds. We screened eight plant-derived compounds from different families including flavonoids, polyphenolic compounds, alkaloids, and isothiocyanates for osteogenic capacity using the human RUNX2-promoter luciferase reporter (hRUNX2-luc) transduced into the mouse MSC line, C3H10T1/2, with daidzein—a well-studied osteogenic phytoestrogen—as a positive control. Classical in vitro and in vivo osteogenesis assays were performed using primary murine and human bone marrow MSCs (BMMSCs) to validate the accuracy of this rapid screening platform. Using the MSC/hRUNX2-luc screening platform, we were able not only to shorten the selection process for osteogenic compounds from 3∼4 weeks to just a few days but also simultaneously perform comparisons between multiple compounds to assess relative osteogenic potency. Predictive analyses revealed nearly absolute correlation of the MSC/hRUNX2-luc reporter platform to the in vitro classical functional assay of mineralization using murine BMMSCs. Validation using human BMMSCs with in vitro mineralization and in vivo osteogenesis assays also demonstrated nearly absolute correlation to the MSC/hRUNX2-luc reporter results. Our findings therefore demonstrate that the MSC/hRUNX2 reporter platform can accurately, rapidly, and robustly screen for candidate osteogenic compounds and thus be relevant for therapeutic application in OP.

Admission committees use multiple sources of information to select residents. However, the way in which faculty members use each data source remains unclear and highly context-specific. The present study seeks to understand how faculty members use various sources of information about candidates to make admission decisions to a National Psychiatry Residency Program. The theory of core competencies was used as a foundation for this qualitative study. Framework analysis was used to structure the project and data presentation. Twenty key informants from the faculty were purposefully sampled in accordance with the initial theory. Open-ended semi-structured interviews were conducted to obtain their views about the essential competencies of psychiatrists and the ways in which these competencies could be reliably gauged. Participants described numerous competencies that they believed were essential to becoming competent psychiatrists. These competencies fell within the six core competencies of the Accreditation Council for Graduate Medical Education framework. However, several non-competency attributes (such as perseverance, empathy, and compassion) were also relevant in the selection process. To reduce the impact of self-presentation bias, to which these attributes were vulnerable, the faculty relied heavily on sources of information obtained from third parties, such as feedback from co-workers with first-hand experience of the candidate during their clinical placements. Faculty members place importance on informal informant-derived information about a candidate’s non-competency attributes in addition to core competencies when deciding whether or not to select a candidate for admission into a residency training program.

Background Data comparing outcomes in heart failure ( HF ) across Asia are limited. We examined regional variation in mortality among patients with HF enrolled in the ASIAN ‐HF (Asian Sudden Cardiac Death in Heart Failure) registry with separate analyses for those with reduced ejection fraction ( EF ; Methods and Results The ASIAN ‐ HF registry is a prospective longitudinal study. Participants with symptomatic HF were recruited from 46 secondary care centers in 3 Asian regions: South Asia (India), Southeast Asia (Thailand, Malaysia, Philippines, Indonesia, Singapore), and Northeast Asia (South Korea, Japan, Taiwan, Hong Kong, China). Overall, 6480 patients aged >18 years with symptomatic HF were recruited (mean age: 61.6±13.3 years; 27% women; 81% with HF and reduced r EF ). The primary outcome was 1‐year all‐cause mortality. Striking regional variations in baseline characteristics and outcomes were observed. Regardless of HF type, Southeast Asians had the highest burden of comorbidities, particularly diabetes mellitus and chronic kidney disease, despite being younger than Northeast Asian participants. One‐year, crude, all‐cause mortality for the whole population was 9.6%, higher in patients with HF and reduced EF (10.6%) than in those with HF and preserved EF (5.4%). One‐year, all‐cause mortality was significantly higher in Southeast Asian patients (13.0%), compared with South Asian (7.5%) and Northeast Asian patients (7.4%; P Conclusions This first multinational prospective study shows that the outcomes in Asian patients with both HF and reduced or preserved EF are poor overall and worst in Southeast Asian patients. Region‐specific risk factors and gaps in guideline‐directed therapy should be addressed to potentially improve outcomes. Clinical Trial Registration URL : https://www.clinicaltrials.gov/ . Unique identifier: NCT 01633398.

To evaluate the development and implementation of clinical practice guidelines for the management of depression globally.We conducted a systematic review of existing guidelines for the management of depression in adults with major depressive or bipolar disorder. For each identified guideline, we assessed compliance with measures of guideline development quality (such as transparency in guideline development processes and funding, multidisciplinary author group composition, systematic review of comparative efficacy research) and implementation (such as quality indicators). We compared guidelines from low- and middle-income countries with those from high-income countries.We identified 82 national and 13 international clinical practice guidelines from 83 countries in 27 languages. Guideline development processes and funding sources were explicitly specified in a smaller proportion of guidelines from low- and middle-income countries (8/29; 28%) relative to high-income countries (35/58; 60%). Fewer guidelines (2/29; 7%) from low- and middle-income countries, relative to high-income countries (22/58; 38%), were authored by a multidisciplinary development group. A systematic review of comparative effectiveness was conducted in 31% (9/29) of low- and middle-income country guidelines versus 71% (41/58) of high-income country guidelines. Only 10% (3/29) of low- and middle-income country and 19% (11/58) of high-income country guidelines described plans to assess quality indicators or recommendation adherence.Globally, guideline implementation is inadequately planned, reported and measured. Narrowing disparities in the development and implementation of guidelines in low- and middle-income countries is a priority. Future guidelines should present strategies to implement recommendations and measure feasibility, cost-effectiveness and impact on health outcomes.Évaluer le développement et la mise en œuvre des directives de pratique clinique pour la gestion de la dépression dans le monde.Nous avons effectué une revue systématique des directives existantes en matière de gestion de la dépression chez les adultes souffrant de troubles dépressifs majeurs ou de troubles bipolaires. Pour chaque directive identifiée, nous avons vérifié le degré de conformité vis-à-vis des mesures de qualité du développement des directives (transparence des processus d'élaboration des directives et de leur financement, composition multidisciplinaire du groupe d'auteurs, revue systématique des études d'efficacité comparative) ainsi que de la mise en œuvre (indicateurs de qualité). Nous avons confronté les directives des pays à faible et moyen revenu avec celles des pays à haut revenu.Nous avons identifié 82 directives de pratique clinique nationales et 13 directives de pratique clinique internationales dans 83 pays et en 27 langues. Les processus d'élaboration des directives et les sources de financement étaient explicitement indiquées dans une moindre proportion chez les pays à faible et moyen revenu (8/29; 28%) par rapport aux pays à haut revenu (35/58; 60%). Le nombre de directives rédigées par un groupe d'auteurs multidisciplinaire était moins élevé dans les pays à faible et moyen revenu (2/29; 7%) que dans les pays à haut revenu (22/58; 38%). Une revue systématique de l'efficacité comparative a été menée pour 31% (9/29) des directives dans les pays à faible et moyen revenu, contre 71% (41/58) des directives dans les pays à haut revenu. Seulement 10% (3/29) des directives émises par les pays à faible et moyen revenu et 19% (11/58) de celles émises par les pays à haut revenu comprenaient un programme d'évaluation des indicateurs de qualité ou de l'adhérence aux recommandations.La mise en œuvre des directives est mal planifiée, mal analysée et mal mesurée. Réduire les disparités de développement et de mise en œuvre des directives dans les pays à faible et moyen revenu est une priorité. À l'avenir, ces directives devraient prévoir des stratégies d'exécution des recommandations, mais aussi d'évaluation de la faisabilité, de la rentabilité et de l'impact sur l'état de santé.Evaluar la elaboración e implementación de las directrices de práctica clínica para el tratamiento de la depresión a nivel mundial.Se realizó una revisión sistemática de las directrices existentes para el tratamiento de la depresión en adultos con trastorno depresivo mayor o bipolar. Por cada directriz identificada, se evaluó el cumplimiento de las medidas de calidad de elaboración de directrices (como la transparencia en los procesos de elaboración de directrices y su financiamiento, la composición del grupo multidisciplinario de autores, la revisión sistemática del estudio de eficacia comparativo) y la implementación (como los indicadores de calidad). En este contexto, se compararon las directrices de los países de ingresos bajos y medios con las de los países de ingresos altos.Se identificaron las directrices de práctica clínica a nivel nacional (82) y a nivel internacional (13) de 83 países en 27 idiomas. Los procesos de elaboración de directrices y las fuentes de financiamiento se especificaron de manera explícita en un porcentaje menor de directrices de los países de ingresos bajos y medios (8/29; 28 %) en relación con las de los países de ingresos altos (35/58; 60 %). Un grupo de desarrollo multidisciplinario elaboró menos directrices (2/29; 7 %) para los países de ingresos bajos y medios, en relación con las de los países de ingresos altos (22/58; 38 %). Además, se realizó una revisión sistemática sobre la efectividad comparativa en el 31 % (9/29) de las directrices de los países de ingresos bajos y medios, frente al 71 % (41/58) de las directrices de los países de ingresos altos. Solo el 10 % (3/29) de las directrices de los países de ingresos bajos y medios y el 19 % (11/58) de las directrices de los países de ingresos altos describieron planes para evaluar los indicadores de calidad o el cumplimiento de las recomendaciones.La implementación de las directrices no se planifica, notifica ni evalúa de manera adecuada a nivel mundial. Es prioritario reducir las desigualdades en la elaboración y la implementación de las directrices en los países de ingresos bajos y medios. Las directrices que se elaboren en el futuro deberán presentar estrategias para implementar las recomendaciones y evaluar la viabilidad, la rentabilidad y el impacto en los resultados sanitarios.تقييم عملية وضع المبادئ التوجيهية للممارسة السريرية للتعامل مع الاكتئاب وتنفيذها على مستوى العالم.لقد أجرينا مراجعة منهجية للمبادئ التوجيهية الحالية الخاصة بالتعامل مع الاكتئاب لدى البالغين المصابين بحالات الاضطراب الاكتئابي أو الاضطراب ثنائي القطب. وفيما يتعلق بكل مبدأ توجيهي محدد، قمنا بتقييم الامتثال لمقاييس جودة وضع المبدأ التوجيهي (كالشفافية في عمليات وضع المبدأ التوجيهي والتمويل، وتكوين مجموعة من المؤلفين متعددي التخصصات، وكذلك المراجعة المنهجية لأبحاث الفعالية النسبية)، وتنفيذها (مثل مؤشرات الجودة). كما قمنا بمقارنة المبادئ التوجيهية الموجودة في البلدان منخفضة الدخل ومتوسطة الدخل، مع مثيلاتها الموجودة في البلدان مرتفعة الدخل.لقد حددنا 82 مبدأً توجيهيًا وطنيًا، و13 مبدأً توجيهيًا دوليًا من المبادئ التوجيهية الخاصة بالممارسات السريرية، من 83 بلدًا بـ 27 لغة. ولقد تم تحديد عمليات وضع المبدأ التوجيهي، ومصادر التمويل بشكل واضح في نسبة أصغر من المبادئ التوجيهية، الواردة من البلدان منخفضة الدخل ومتوسطة الدخل (8/29؛ 28%)، مقارنة بالبلدان مرتفعة الدخل (35/58؛ 60%). وتم وضع عدد أقل من المبادئ التوجيهية (2/29؛ 7%) الواردة من البلدان منخفضة الدخل ومتوسطة الدخل، بواسطة إحدى مجموعات التطوير متعددة التخصصات، مقارنة بالبلدان مرتفعة الدخل (22/58؛ 38%). وقد تم إجراء مراجعة منهجية للفعالية النسبية في 31% (9/29) من المبادئ التوجيهية للبلدان منخفضة الدخل ومتوسطة الدخل، مقابل 71% (41/58) من المبادئ التوجيهية للبلدان ذات الدخل المرتفع. ولم يتم وصف خطط لتقييم مؤشرات الجودة أو الالتزام بالتوصيات إلا في 10% من المبادئ التوجيهية فقط (3/29) الواردة من البلدان منخفضة الدخل ومتوسطة الدخل، و19% فقط (11/58) من المبادئ التوجيهية للبلدان عالية الدخل.لم يتم التخطيط لعملية تنفيذ المبدأ التوجيهي، والإبلاغ عنها وتقييمها، بشكل مناسب على الصعيد العالمي. إذ يعد تضييق الفوارق في عملية وضع المبادئ التوجيهية وتنفيذها في البلدان منخفضة الدخل ومتوسطة الدخل، إحدى الأولويات. ويجب أن تقدم المبادئ التوجيهية المستقبلية إستراتيجيات لتنفيذ التوصيات، وقياس الجدوى، وفعالية التكلفة، والتأثير على النتائج الصحية.评估全球抑郁症治疗临床实践指南的制定和实施情况。.我们系统评价了现有的成人重度抑郁或双相情感障碍的抑郁治疗指南。针对每份符合纳入标准的指南，我们评估其是否达到指南制定的质量标准（如制定过程和资金的透明度、多学科编著成员、比较疗效研究的系统评价），实施（如质量指标）是否合规。我们对比了中低收入国家和高收入国家的治疗指南。.我们最终确定了 82 份国家级和 13 份国际级的临床实践指南，涉及 83 个国家 27 种语言。与高收入国家相比，中低收入国家指南中明确说明其制定过程和资金来源的比例略低，29 份中仅 8 份给予明确说明，占比 28%，而高收入国家则达 60%，58 份中有 35 份。中低收入国家由多学科编撰成员编著的指南（29 份中仅有 2 份，占比 7%）相较于高收入国家也较少（58 份中有 22 份，占比 38%）。中低收入国家的指南中，有 31% (9/29) 对比较疗效展开系统审查，而高收入国家则达 71% (41/58)。中低收入国家仅有 10% (3/29) 的指南论述了评估质量指标的计划或随附了相关建议，而高收入国家则达 19% (11/58)。.全球范围内，指南的实施均缺乏充分的计划、报道和衡量。缩小中低收入国家在指南制定和实施方面的差距是当务之急。未来制定指南时，应提出实施策略建议，并衡量其可行性、成本效益及对健康结果的影响。.Оценить разработку и внедрениепрактических клинических рекомендаций по лечению депрессии во всем мире.Авторы выполнили систематический обзор существующих клинических рекомендаций по лечению депрессии у взрослых с клинической депрессией или биполярным расстройством. Всем идентифицированным клиническим рекомендациям была дана оценка по соответствию критериям качества разработки клинических рекомендаций (таким как прозрачность процессов разработки клинических рекомендаций и финансирования, мультидисциплинарный состав группы авторов, систематический обзор сравнительных исследований эффективности) и реализации (например, показатели качества). Авторы сравнили клинические рекомендации из стран с низким и средним уровнем доходов и из стран с высоким уровнем доходов.Было выявлено 82 национальных и 13 международных клинических рекомендации из 83 стран на 27 языках. Процессы разработки клинических рекомендаций и источники финансирования были четко указаны в меньшем количестве клинических рекомендаций из стран с низким и средним уровнем доходов (8/29; 28%) по сравнению со странами с высоким уровнем доходов (35/58; 60%). Меньшее количество клинических рекомендаций (2/29; 7%) из стран с низким и средним уровнем доходов по сравнению со странами с высоким уровнем доходов (22/58; 38%) было разработано мультидисциплинарной группой авторов. Систематический обзор сравнительной эффективности был выполнен в 31% (9/29) клинических рекомендаций из стран с низким и средним уровнем доходов по сравнению с 71% (41/58) клинических рекомендаций из стран с высоким уровнем доходов. Только в 10% (3/29) клинических рекомендаций из стран с низким и средним уровнем доходов и в 19% (11/58) клинических рекомендаций из стран с высоким уровнем доходов описаны планы по оценке показателей качества или приверженности соблюдению рекомендаций.В глобальном масштабе при внедрении клинических рекомендаций вопросы планирования, отчетности и измерения показателей внедрения решаются неадекватно. Приоритетной задачей является приближение стандартов разработки и внедрения клинических рекомендаций в странах с низким и средним уровнем доходов к таковым в странах с высоким уровнем доходов. В будущих клинических рекомендациях должны быть представлены стратегии по внедрению рекомендаций и оценке их осуществимости, экономической эффективности и воздействию на результаты в отношении здоровья.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease characterized by hamartomas in multiple organ systems. This study was performed in one familial and two sporadic cases with TSC. Two novel mutations (c.1884_1887delAAAG and c.5266A>G) and two previously reported mutations (c.4258_4261delTCAG and c.1960G>C) were identified by direct DNA sequencing. Of the four mutations, c.1884_1887delAAAG and c.1960G>C were found in a family and identified in the same allele by TA cloning sequencing. However, c.1960G>C was reported to be non-pathogenic. Furthermore, correlations between genotypes and phenotypes of Chinese Han patients since 2014 were performed by paired χ2 -tests in our published work review, which has not been reported. The results showed that patients with TSC2 mutations had a higher frequency of mental retardation and there were no significant differences of seizures and skin lesions with TSC1 mutations. Genetically, they had a higher frequency of familial inheritance.

The cloud IaaS provider supports diverse services for users to access big data of the real-time entertainment or the non-real-time working traffic. The IaaS provider builds data centers that include different types cloud resources/equipment, e.g., physical machines, virtual machines, networking, storages, power equipment, etc., and significantly increases cloud cost. An efficient cloud resource management is required for the cloud provider to maximize system reward while satisfying the QoS of various SLAs. This paper proposes a Reward-based adaptive global Cloud Resource Management (RCRM) that consists of three main contributions: the Large-scale and Small-scale traffic Predictions (LSP), Adaptive Cloud resource Allocation, and Maximum Net Profit. The M/M/m/m Markov chain model analyzes the service blocking and the required number of VMs for each request. For maximizing the system net profit, the cloud providers always oversell cloud resources. However, the cost of deploying data centers at different areas in the world is different. This paper adopts the VM migration-in/migration-out and task redirection to adaptively allocate cloud resources among global data centers. Numerical results demonstrate RCRM outperforms the others in dropping probability, SLA violation, violation penalty and net profit. Furthermore, the dropping probability of analysis is very close to that of simulation and justifies the correctness of the proposed Markov chain model.

We established an entitative photovoltaic (PV) module for measuring the electric power in this study. The generating electric efficiency was calculated according to the electric power. Using the heat transfer mechanism generated during the operation of PV module, thermal energy conservation law and lumped capacitance method were combined with Matlab/Simulink to establish the dynamic model of PV module. The ambient temperature, wind speed, and solar radiation of the environmental factors were the inputs used for predicting the time-varying temperature of different layers inside the module. Based on the solar cell temperature, electric power and electric efficiency could be obtained. The electric power of solar cell declined as the solar cell operating temperature increased. In this study, we used entity module to validate the accuracy of the model. The environmental factors of mounting site were applied to design the backsheet material and to improve the output performance of entity solar module. The PV dynamic model and entity validation showed that electric power and electric efficiency errors are smaller than 1.3%. The PV dynamic model can accurately predict the output performance according to the environmental factors of the site. The PV backsheet was made of glass with higher thermal conductivity to replace traditional tedlar-polyester-tedlar (TPT). Electric power and electric efficiency are increased by 2.353%. The output performance of solar module was improved effectively.

Electric cell-substrate impedance sensing (ECIS) is an emerging technique for sensitively monitoring morphological changes of adherent cells in tissue culture. In this study, human mesenchymal stem cells (hMSCs) were exposed to different concentrations of carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) for 20 h and their subsequent concentration-dependent responses in micromotion and wound healing migration were measured by ECIS. FCCP disrupts ATP synthesis and results in a decrease in cell migration rates. To detect the change of cell micromotion in response to FCCP challenge, time-series resistances of cell-covered electrodes were monitored and the values of variance were calculated to verify the difference. While Seahorse XF-24 extracellular flux analyzer can detect the effect of FCCP at 3 &mu, M concentration, the variance calculation of the time-series resistances measured at 4 kHz can detect the effect of FCCP at concentrations as low as 1 &mu, M. For wound healing migration, the recovery resistance curves were fitted by sigmoid curve and the hill slope showed a concentration-dependent decline from 0.3 &mu, M to 3 &mu, M, indicating a decrease in cell migration rate. Moreover, dose dependent incline of the inflection points from 0.3 &mu, M FCCP implied the increase of the half time for wound recovery migration. Together, our results demonstrate that partial uncoupling of mitochondrial oxidative phosphorylation reduces micromotion and wound healing migration of hMSCs. The ECIS method used in this study offers a simple and sensitive approach to investigate stem cell migration and its regulation by mitochondrial dynamics.

Electric cell–substrate impedance sensing (ECIS) has been used as a real-time impedance-based method to quantify cell behavior in tissue culture. The method is capable of measuring both the resistance and capacitance of a cell-covered microelectrode at various AC frequencies. In this study, we demonstrate the application of high-frequency capacitance measurement (f = 40 or 64 kHz) for the sensitive detection of both the micromotion and wound-healing migration of human mesenchymal stem cells (hMSCs). Impedance measurements of cell-covered electrodes upon the challenge of various concentrations of carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP), from 0.1 to 30 μM, were conducted using ECIS. FCCP is an uncoupler of mitochondrial oxidative phosphorylation (OXPHOS), thereby reducing mitochondrial ATP production. By numerically analyzing the time-series capacitance data, a dose-dependent decrease in hMSC micromotion and wound-healing migration was observed, and the effect was significantly detected at levels as low as 0.1 μM. While most reported works with ECIS use the resistance/impedance time series, our results suggest the potential use of high-frequency capacitance time series for assessing migratory cell behavior such as micromotion and wound-healing migration.

It is well-known that self-annealing of as-electroplated Cu would cause remarkable microstructure transition in few hours, inducing grain growth accompanied by elimination of grain boundaries and redistribution of impurities and crystallographic defects that determine the physical/chemical characteristics (e.g., resistivity and internal stress) of the entire Cu film. We carried out an in-situ study on this strongly time-dependent phenomenon to probe into crystallographic/microstructure and strain transitions in the self-annealing procedure. The crystallographic evolution of electroplated Cu, including grain size distribution, crystallographic orientation, grain boundaries, and residual strain, were investigated by means of in-situ X-ray diffraction (XRD) and electron backscatter diffraction (EBSD). Moreover, grain orientation spread (GOS) value was obtained via the EBSD analysis, which offers valuable information regarding the residual strain distribution in the Cu platings. The internal stress of electroplated Cu was examined via a cantilever method. Additionally, effects of self-annealing on the impurity redistribution were investigated by a time of flight secondary ion mass spectrometer (TOF-SIMS). The knowledge advances our understanding of the evolution of the electroplated Cu physical/chemical properties during self-annealing.

Mesenchymal stem cells (MSCs) are paraxial mesodermal progenitors with potent immunomodulatory properties. Reports also indicate that MSCs can undergo neural-like differentiation, offering hope for use in neurodegenerative diseases. However, ex vivo expansion of these rare somatic stem cells for clinical use leads to cellular senescence. A newer source of MSCs derived from human pluripotent stem cells (PSC) can offer the ‘best-of-both-worlds’ scenario, abrogating the concern of teratoma formation while preserving PSC proliferative capacity. PSC-derived MSCs (PSC-MSCs) also represent MSCs at the earliest developmental stage, and we found that these MSCs harbor stronger neuro-differentiation capacity than post-natal MSCs. PSC-MSCs express higher levels of neural stem cell (NSC)-related genes and transcription factors than adult bone marrow MSCs at baseline, and rapidly differentiate into neural-like cells when cultured in either standard neurogenic differentiation medium (NDM) or when the cytoskeletal modulator RhoA kinase (ROCK) is inhibited. Interestingly, when NDM is combined with ROCK inhibition, PSC-MSCs undergo further commitment, acquiring characteristics of post-mitotic neurons including nuclear condensation, extensive dendritic growth, and neuron-restricted marker expression including NeuN, β-III-tubulin and Doublecortin. Our data demonstrates that PSC-MSCs have potent capacity to undergo neural differentiation and also implicate the important role of the cytoskeleton in neural lineage commitment.

Wharton’s jelly-derived mesenchymal stromal cells (WJ-MSCs) have distinct immunomodulatory and protective effects against kidney, liver, or heart injury. Limited studies have shown that WJ-MSCs attenuates oxygen–glucose deprivation-mediated inflammation in hippocampal slices. The neuroprotective effect of intracerebral WJ-MSC transplantation against stroke has not been well characterized. The purpose of this study was to examine the neuroprotective effect of human WJ-MSC (hWJ-MSC) transplants in an animal model of stroke. Adult male Sprague–Dawley rats were anesthetized and placed in a stereotaxic frame. hWJ-MSCs, pre-labeled with chloromethyl benzamide 1,1’-dioctadecyl-3,3,3’3’- tetramethylindocarbocyanine perchlorate (CM-Dil), were transplanted to the right cerebral cortex at 10 min before a transient (60 min) right middle cerebral artery occlusion (MCAo). Transplantation of hWJ-MSCs significantly reduced neurological deficits at 3 and 5 days after MCAo. hWJ-MSC transplants also significantly reduced brain infarction and microglia activation in the penumbra. Grafted cells carrying CM-Dil fluorescence were identified at the grafted site in the ischemic core; these cells were mostly incorporated into ionized calcium-binding adaptor molecule (+) cells, suggesting these xenograft cells were immuno-rejected by the host. In another set of animals, hWJ-MSCs were transplanted in cyclosporine (CsA)-treated rats. hWJ-MSC transplants significantly reduced brain infarction, improved neurological function, and reduced neuroinflammation. Less phagocytosis of CM-dil-labeled grafted cells was found in the host brain after CsA treatment. Transplantation of hWJ-MSC significantly increased glia cell line-derived neurotrophic factor expression in the host brain. Taken together, our data support that intracerebral transplantation of hWJ-MSCs reduced neurodegeneration and inflammation in the stroke brain. The protective effect did not depend on the survival of grafted cells but may be indirectly mediated through the production of protective trophic factors from the transplants.