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يدرس هذا الكتاب التغيرات السريعه فى الأسواق، وتوسع الاتحادات والمؤسسات التجارية، وكيفيه تأقلم التسويق مع هذه المتغيرات، لآنه أكثر بكثير من نوع بسيط من النشاط الاقتصادى، فهو فلسفه اقتصاديه تهدف إلى تلبيه الاحتياجات والإجابه على الاستفسارات أنه كتاب يساعدنا فى الحصول على تصور واسع جدا على التسويق وتطبيقاته فى الأسواق الوطنية أو العالمية، ويقدم أنماط من التسويق الحديث والسياسات التسويقية القوية لبعض الشركات، أن الأسلوب الواضح والاستخدام الكبير للأمثلة والنماذج التى يتصف بها هذا الكتاب تجمعل منه كتابا مهما وحيويا يساعدنا فى أمتلاك المعارف والخبرات الضرورية.
Book
Nasopharyngeal carcinoma: an evolving paradigm
The past three decades have borne witness to many advances in the understanding of the molecular biology and treatment of nasopharyngeal carcinoma (NPC), an Epstein–Barr virus (EBV)-associated cancer endemic to southern China, southeast Asia and north Africa. In this Review, we provide a comprehensive, interdisciplinary overview of key research findings regarding NPC pathogenesis, treatment, screening and biomarker development. We describe how technological advances have led to the advent of proton therapy and other contemporary radiotherapy approaches, and emphasize the relentless efforts to identify the optimal sequencing of chemotherapy with radiotherapy through decades of clinical trials. Basic research into the pathogenic role of EBV and the genomic, epigenomic and immune landscape of NPC has laid the foundations of translational research. The latter, in turn, has led to the development of new biomarkers and therapeutic targets and of improved approaches for individualizing immunotherapy and targeted therapies for patients with NPC. We provide historical context to illustrate the effect of these advances on treatment outcomes at present. We describe current preclinical and clinical challenges and controversies in the hope of providing insights for future investigation.Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV)-associated malignancy endemic to southern China, southeast Asia and north Africa. The authors of this Review present a comprehensive overview of advances from the past three decades on the pathogenic role of EBV, and the genomic, epigenomic and immune landscape of NPC, which have led to the development of new biomarkers, therapeutic targets and improved treatment approaches for patients with NPC.
Journal Article
Dispersive Fourier transform based dual-comb ranging
Laser-based light detection and ranging (LIDAR) offers a powerful tool to real-timely map spatial information with exceptional accuracy and owns various applications ranging from industrial manufacturing, and remote sensing, to airborne and in-vehicle missions. Over the past two decades, the rapid advancements of optical frequency combs have ushered in a new era for LIDAR, promoting measurement precision to quantum noise limited level. For comb LIDAR systems, to further improve the comprehensive performances and reconcile inherent conflicts between speed, accuracy, and ambiguity range, innovative demodulation strategies become crucial. Here we report a dispersive Fourier transform (DFT) based LIDAR method utilizing phase-locked Vernier dual soliton laser combs. We demonstrate that after in-line pulse stretching, the delay of the flying pulses can be identified via the DFT-based spectral interferometry instead of temporal interferometry or pulse reconstruction. This enables absolute distance measurements with precision starting from 262 nm in single shot, to 2.8 nm after averaging 1.5 ms, in a non-ambiguity range over 1.7 km. Furthermore, our DFT-based LIDAR method distinctly demonstrates an ability to completely eliminate dead zones. Such an integration of frequency-resolved ultrafast analysis and dual-comb ranging technology may pave a way for the design of future LIDAR systems.
Here the authors develop a dispersive Fourier transform (DFT) based LIDAR method utilizing phase-locked Vernier dual soliton laser combs and demonstrate improved precision in the measurements.
Journal Article
Delayed application of silver nanoparticles reveals the role of early inflammation in burn wound healing
Burn injury is common, and antimicrobial agents are often applied immediately to prevent wound infection and excessive inflammatory response. Although inflammation is essential for clearing bacteria and creating an environment conducive to the healing process, it is unclear what time-frame inflammation should be present for optimal wound healing. This study critically investigated the role of early inflammation in burn wound healing, and also revealed the molecular mechanisms underlying the pro-healing effects of silver nanoparticles (AgNPs). We created a burn injury mouse model using wild-type and
Smad3
−/− mice, which were topically treated with AgNPs at different post-burn days, and examined the healing processes of the various groups. We also delineated the molecular pathways underlying the anti-inflammation and pro-healing effects of AgNPs by morphological and histological analysis, immuno-histochemistry, and western blotting. Our results showed that (1) AgNPs regulated pro-inflammatory cytokine IL-6 production of keratinocytes and neutrophils infiltration through KGF-2/p38 signaling pathway, (2) Topical AgNPs treatment immediately after burn injury significantly supressed early inflammation but resulted in delayed healing, (3) A short delay in AgNPs application (post-burn day 3 in our model) allowed early inflammation in a controlled manner, and led to optimal burn wound healing. Thus, our current study showed that some degree of early inflammation was beneficial, but prolonged inflammation was detrimental for burn wound healing. Further evaluation and clinical translation of this finding is warranted.
Journal Article
Generalized and scalable trajectory inference in single-cell omics data with VIA
Inferring cellular trajectories using a variety of omic data is a critical task in single-cell data science. However, accurate prediction of cell fates, and thereby biologically meaningful discovery, is challenged by the sheer size of single-cell data, the diversity of omic data types, and the complexity of their topologies. We present VIA, a scalable trajectory inference algorithm that overcomes these limitations by using lazy-teleporting random walks to accurately reconstruct complex cellular trajectories beyond tree-like pathways (e.g., cyclic or disconnected structures). We show that VIA robustly and efficiently unravels the fine-grained sub-trajectories in a 1.3-million-cell transcriptomic mouse atlas without losing the global connectivity at such a high cell count. We further apply VIA to discovering elusive lineages and less populous cell fates missed by other methods across a variety of data types, including single-cell proteomic, epigenomic, multi-omics datasets, and a new in-house single-cell morphological dataset.
Scalable trajectory inference for multi-omic single cell datasets is challenging in terms of capturing non-tree complex topologies. Here the authors present a method, VIA, that scales to millions of cells across multiple omic modalities using lazy-teleporting random walks.
Journal Article
Panoramic-reconstruction temporal imaging for seamless measurements of slowly-evolved femtosecond pulse dynamics
Single-shot real-time characterization of optical waveforms with sub-picosecond resolution is essential for investigating various ultrafast optical dynamics. However, the finite temporal recording length of current techniques hinders comprehensive understanding of many intriguing ultrafast optical phenomena that evolve over a timescale much longer than their fine temporal details. Inspired by the space-time duality and by stitching of multiple microscopic images to achieve a larger field of view in the spatial domain, here a panoramic-reconstruction temporal imaging (PARTI) system is devised to scale up the temporal recording length without sacrificing the resolution. As a proof-of-concept demonstration, the PARTI system is applied to study the dynamic waveforms of slowly evolved dissipative Kerr solitons in an ultrahigh-
Q
microresonator. Two 1.5-ns-long comprehensive evolution portraits are reconstructed with 740 fs resolution and dissipative Kerr soliton transition dynamics, in which a multiplet soliton state evolves into a stable singlet soliton state, are depicted.
Real-time characterization of ultrafast dynamics comes with a tradeoff between temporal resolution and recording length. Here, Li et al. use a temporal reconstruction technique inspired by panoramic microscopy to image the dynamics of slowly evolved dissipative Kerr solitons in a microresonator.
Journal Article
Short-term and long-term outcomes after Roux-en-Y hepaticojejunostomy versus hepaticoduodenostomy following laparoscopic excision of choledochal cyst in children
BackgroundCholedochal cysts are congenital dilations of the biliary tree. Complete cyst excision and biliary-enteric reconstruction have been the standard operations. In our center, more than 95% of choledochal cyst excision is now performed laparoscopically. Majority of current studies describe laparoscopic-assisted reconstruction using Roux-en-Y hepaticojejunostomy (HJ). However, only a few have studied laparoscopic hepaticoduodenostomy (HD) as an alternative method of biliary-enteric reconstruction. In this study, we focused on comparing longer-term outcomes between laparoscopic HJ and HD reconstruction following choledochal cyst excision.MethodsWe performed retrospective analysis of 54 children who had undergone laparoscopic choledochal cyst excision and biliary-enteric reconstruction between October 2004 and April 2018. Short-term outcomes including operative time, complications such as anastomotic leakage and bleeding, and hospital stays were included. Long-term outcomes including contrast reflux into biliary tree, cholangitis, anastomotic strictures, and need of reoperation were analyzed.ResultsOf the 54 patients, 21 of them underwent laparoscopic HD and 33 underwent laparoscopic Roux-en-Y HJ anastomosis reconstruction. There were no significant differences in gestation, gender, age at operation, antenatal diagnosis, and Todani type of choledochal cyst between HD and HJ group. Operative time was significantly shortened in HD group (p = 0.001). Median time to enteral feeding was 3 days in both groups. Median intensive care unit (p = 0.001) and hospital stay (p = 0.019) were significantly shorter in HD group. There was no perioperative mortality. There was no significant difference in anastomotic leakage requiring reoperation (p = 0.743). There were no significant differences in long-term outcomes including anastomotic stricture (p = 0.097), cholangitis (p = 0.061), symptoms of recurrent abdominal pain or gastritis (p = 0.071), or need of reoperation (p = 0.326). All patients had normal postoperative serum bilirubin level.ConclusionsLaparoscopic excision of choledochal cyst with HD reconstruction is safe and feasible with better short-term outcomes and comparable long-term outcomes compared to Roux-en-Y HJ reconstruction.
Journal Article
Differentiated human airway organoids to assess infectivity of emerging influenza virus
Novel reassortant avian influenza H7N9 virus and pandemic 2009 H1N1 (H1N1pdm) virus cause human infections, while avian H7N2 and swine H1N1 virus mainly infect birds and pigs, respectively. There is no robust in vitro model for assessing the infectivity of emerging viruses in humans. Based on a recently established method, we generated long-term expanding 3D human airway organoids which accommodate four types of airway epithelial cells: ciliated, goblet, club, and basal cells. We report differentiation conditions which increase ciliated cell numbers to a nearly physiological level with synchronously beating cilia readily discernible in every organoid. In addition, the differentiation conditions induce elevated levels of serine proteases, which are essential for productive infection of human influenza viruses and low-pathogenic avian influenza viruses. We also established improved 2D monolayer culture conditions for the differentiated airway organoids. To demonstrate the ability of differentiated airway organoids to identify human-infective virus, 3D and 2D differentiated airway organoids are applied to evaluate two pairs of viruses with known distinct infectivity in humans, H7N9/Ah versus H7N2 and H1N1pdm versus an H1N1 strain isolated from swine (H1N1sw). The human-infective H7N9/Ah virus replicated more robustly than the poorly human-infective H7N2 virus; the highly human-infective H1N1pdm virus replicated to a higher titer than the counterpart H1N1sw. Collectively, we developed differentiated human airway organoids which can morphologically and functionally simulate human airway epithelium. These differentiated airway organoids can be applied for rapid assessment of the infectivity of emerging respiratory viruses to human.
Journal Article
Gut microbiota composition is associated with SARS-CoV-2 vaccine immunogenicity and adverse events
ObjectiveThe gut microbiota plays a key role in modulating host immune response. We conducted a prospective, observational study to examine gut microbiota composition in association with immune responses and adverse events in adults who have received the inactivated vaccine (CoronaVac; Sinovac) or the mRNA vaccine (BNT162b2; BioNTech; Comirnaty).DesignWe performed shotgun metagenomic sequencing in stool samples of 138 COVID-19 vaccinees (37 CoronaVac and 101 BNT162b2 vaccinees) collected at baseline and 1 month after second dose of vaccination. Immune markers were measured by SARS-CoV-2 surrogate virus neutralisation test and spike receptor-binding domain IgG ELISA.ResultsWe found a significantly lower immune response in recipients of CoronaVac than BNT162b2 vaccines (p<0.05). Bifidobacterium adolescentis was persistently higher in subjects with high neutralising antibodies to CoronaVac vaccine (p=0.023) and their baseline gut microbiome was enriched in pathways related to carbohydrate metabolism (linear discriminant analysis (LDA) scores >2 and p<0.05). Neutralising antibodies in BNT162b2 vaccinees showed a positive correlation with the total abundance of bacteria with flagella and fimbriae including Roseburia faecis (p=0.028). The abundance of Prevotella copri and two Megamonas species were enriched in individuals with fewer adverse events following either of the vaccines indicating that these bacteria may play an anti-inflammatory role in host immune response (LDA scores>3 and p<0.05).ConclusionOur study has identified specific gut microbiota markers in association with improved immune response and reduced adverse events following COVID-19 vaccines. Microbiota-targeted interventions have the potential to complement effectiveness of COVID-19 vaccines.
Journal Article
Congenital lung malformations
Congenital lung malformations (CLMs) are rare developmental anomalies of the lung, including congenital pulmonary airway malformations (CPAM), bronchopulmonary sequestration, congenital lobar overinflation, bronchogenic cyst and isolated congenital bronchial atresia. CLMs occur in 4 out of 10,000 live births. Postnatal presentation ranges from an asymptomatic infant to respiratory failure. CLMs are typically diagnosed with antenatal ultrasonography and confirmed by chest CT angiography in the first few months of life. Although surgical treatment is the gold standard for symptomatic CLMs, a consensus on asymptomatic cases has not been reached. Resection, either thoracoscopically or through thoracotomy, minimizes the risk of local morbidity, including recurrent infections and pneumothorax, and avoids the risk of malignancies that have been associated with CPAM, bronchopulmonary sequestration and bronchogenic cyst. However, some surgeons suggest expectant management as the incidence of adverse outcomes, including malignancy, remains unknown. In either case, a planned follow-up and a proper transition to adult care are needed. The biological mechanisms through which some CLMs may trigger malignant transformation are under investigation.
KRAS
has already been confirmed to be somatically mutated in CPAM and other genetic susceptibilities linked to tumour development have been explored. By summarizing current progress in CLM diagnosis, management and molecular understanding we hope to highlight open questions that require urgent attention.
Congenital lung malformations are rare developmental anomalies of the lung that can lead to recurrent infections, pneumothorax and malignancy in some patients. This Primer summarizes the epidemiology, pathophysiology and diagnosis of this disorder, and discusses current disease management and quality of life of patients.
Journal Article