The calcium calmodulin (Ca
/CaM) dependent protein kinase II (CaMKII) decodes Ca
frequency oscillations. The CaMKIIα isoform is predominantly expressed in the brain and has a central role in ...learning. I matched residue and organismal evolution with collective motions deduced from the atomic structure of the human CaMKIIα holoenzyme to learn how its ring architecture abets function. Protein dynamic simulations showed its peripheral kinase domains (KDs) are conformationally coupled via lateral spread along the central hub. The underlying β-sheet motions in the hub or association domain (AD) were deconvolved into dynamic couplings based on mutual information. They mapped onto a coevolved residue network to partition the AD into two distinct sectors. A second, energetically stressed sector was added to ancient bacterial enzyme dimers for assembly of the ringed hub. The continued evolution of the holoenzyme after AD-KD fusion targeted the sector's ring contacts coupled to the KD. Among isoforms, the α isoform emerged last and, it alone, mutated rapidly after the poikilotherm-homeotherm jump to match the evolution of memory. The correlation between dynamics and evolution of the CaMKII AD argues single residue substitutions fine-tune hub conformational spread. The fine-tuning could increase CaMKIIα Ca
frequency response range for complex learning functions.
Cholangiocarcinoma (CCA) is a heterogeneous disease arising from a complex interaction between host‐specific genetic background and multiple risk factors. Globally, CCA incidence rates exhibit ...geographical variation, with much higher incidence in parts of the Eastern world compared to the West. These differences are likely to reflect differences in geographical risk factors as well as genetic determinants. Of note, over the past few decades, the incidence rates of CCA appear to change and subtypes of CCA appear to show distinct epidemiological trends. These trends need to be interpreted with caution given the issues of diagnosis, recording and coding of subtypes of CCA. Epidemiological evidences suggest that in general population some risk factors are less frequent but associated with a higher CCA risk, while others are more common but associated with a lower risk. Moreover, while some risk factors are shared by intrahepatic and both extrahepatic forms, others seem more specific for one of the two forms. Currently some pathological conditions have been clearly associated with CCA development, and other conditions are emerging; however, while their impact in increasing CCA risk as single etiological factors has been provided in many studies, less is known when two or more risk factors co‐occur in the same patient. Moreover, despite the advancements in the knowledge of CCA aetiology, in Western countries about 50% of cases are still diagnosed without any identifiable risk factor. It is therefore conceivable that other still undefined etiologic factors are responsible for the recent increase of CCA (especially iCCA) incidence worldwide.
Cholangiocarcinomas are cancers arising from bile ducts, either found within the liver (intrahepatic) or outside the liver (extrahepatic). In Western countries, deaths due to intrahepatic cancers are ...rising at a higher rate than deaths due to extrahepatic cancers. This may be due to rising cases of liver disease and misclassification of the different cancer types.
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•Choledochal cysts were found to be most strongly associated with both iCCA and eCCA.•Cirrhosis was a significant CCA risk, with a stronger association with iCCA than ...eCCA.•Choledocholithiasis had a stronger association with eCCA than iCCA.•In Eastern countries, cirrhosis and HBV conferred a greater risk of iCCA than in Western countries.•Rising global incidence of iCCA may be linked to increases in T2DM, cirrhosis, alcoholic liver disease and cholelithiasis.
Cholangiocarcinoma (CCA) carries a poor prognosis, is increasing in incidence and its causes are poorly understood. Although some risk factors are known, they vary globally and collectively account for a minority of cases. The aim of this study was to perform a comprehensive meta-analysis of risk factors for intrahepatic (iCCA) and extrahepatic cholangiocarcinoma (eCCA), from Eastern and Western world studies.
A literature search of case-control studies was performed to identify potential risk factors for iCCA and eCCA. Pooled odds ratios (ORs) with 95% CIs and heterogeneity were calculated. Funnel plots were used to assess publication bias, and meta-regression was used to select risk factors for comparison between Eastern and Western studies.
A total of 13 risk factors were selected from 25 case-control studies in 7 geographically diverse countries. The strongest risk factors for both iCCA and eCCA were biliary cysts and stones, cirrhosis, hepatitis B and hepatitis C. Choledochal cysts conferred the greatest risk of both iCCA and eCCA with pooled ORs of 26.71 (95% CI 15.80–45.16) and 34.94 (24.36–50.12), respectively. No significant associations were found between hypertension and obesity for either iCCA or eCCA. Comparing Eastern and Western populations, there was a difference for the association of hepatitis B with iCCA (coefficient = −0.15195; 95% CI −0.278 to −0.025; p = 0.022).
This is the most comprehensive meta-analysis of CCA risk factors to date. Some risk factors, such as diabetes, although less strong, are increasing globally and may be contributing to rising rates of this cancer.
Cholangiocarcinoma (CCA) is a cancer arising in the bile ducts inside (intrahepatic CCA) and connected to the liver (extrahepatic CCA). It is a very aggressive cancer: 95% of patients die within 5 years. CCA rates are increasing globally, but the causes of CCA are poorly understood. The few risk factors that are known account for only a minority of cases. In this study, we found that the strongest risk factors for both intrahepatic and extrahepatic CCA are cysts and stones in the bile ducts, cirrhosis, and hepatitis B and C viruses. Some risk factors for CCA, such as diabetes, although less strong, are increasing globally and may be contributing to rising rates of CCA.
Cholangiocarcinoma is a disease entity comprising diverse epithelial tumours with features of cholangiocyte differentiation: cholangiocarcinomas are categorized according to anatomical location as ...intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA). Each subtype has a distinct epidemiology, biology, prognosis, and strategy for clinical management. The incidence of cholangiocarcinoma, particularly iCCA, has increased globally over the past few decades. Surgical resection remains the mainstay of potentially curative treatment for all three disease subtypes, whereas liver transplantation after neoadjuvant chemoradiation is restricted to a subset of patients with early stage pCCA. For patients with advanced-stage or unresectable disease, locoregional and systemic chemotherapeutics are the primary treatment options. Improvements in external-beam radiation therapy have facilitated the treatment of cholangiocarcinoma. Moreover, advances in comprehensive whole-exome and transcriptome sequencing have defined the genetic landscape of each cholangiocarcinoma subtype. Accordingly, promising molecular targets for precision medicine have been identified, and are being evaluated in clinical trials, including those exploring immunotherapy. Biomarker-driven trials, in which patients are stratified according to anatomical cholangiocarcinoma subtype and genetic aberrations, will be essential in the development of targeted therapies. Targeting the rich tumour stroma of cholangiocarcinoma in conjunction with targeted therapies might also be useful. Herein, we review the evolving developments in the epidemiology, pathogenesis, and management of cholangiocarcinoma.
The rapid advances in the internet and communication fields have resulted in a huge increase in the network size and the corresponding data. As a result, many novel attacks are being generated and ...have posed challenges for network security to accurately detect intrusions. Furthermore, the presence of the intruders with the aim to launch various attacks within the network cannot be ignored. An intrusion detection system (IDS) is one such tool that prevents the network from possible intrusions by inspecting the network traffic, to ensure its confidentiality, integrity, and availability. Despite enormous efforts by the researchers, IDS still faces challenges in improving detection accuracy while reducing false alarm rates and in detecting novel intrusions. Recently, machine learning (ML) and deep learning (DL)‐based IDS systems are being deployed as potential solutions to detect intrusions across the network in an efficient manner. This article first clarifies the concept of IDS and then provides the taxonomy based on the notable ML and DL techniques adopted in designing network‐based IDS (NIDS) systems. A comprehensive review of the recent NIDS‐based articles is provided by discussing the strengths and limitations of the proposed solutions. Then, recent trends and advancements of ML and DL‐based NIDS are provided in terms of the proposed methodology, evaluation metrics, and dataset selection. Using the shortcomings of the proposed methods, we highlighted various research challenges and provided the future scope for the research in improving ML and DL‐based NIDS.
(1) A systematic study is conducted to select recent articles on various ML and DL‐based NIDS published during the past 3 years (2017 ‐ April 2020).(2) Extensively discussed various features of papers including proposed methodology, strength, weakness, evaluation metrics, and the used datasets.(3) Based on these observations, recent trends of using AI methods are provided for NIDS, followed by highlighting different challenges in ML/DL‐based NIDS and future directions in this important domain.
Chiral sulfones are of great importance in medicinal chemistry and chemical synthesis. Efficient methods for preparing enantiomerically enriched sulfone‐containing molecules can therefore be of ...significant value; such methods, however, are uncommon. Herein, we report the first general palladium‐catalyzed sulfonylation of vinyl cyclic carbonates with sodium sulfinates. A series of enantiomerically enriched tertiary allylic sulfones were synthesized in good yields with excellent enantiomeric ratios. Both aliphatic‐ and aryl‐substituted vinyl cyclic carbonates are suitable reactants with excellent results. This reaction features broad substrates scope, readily available starting materials, excellent regio‐ and enantioselectivity, and synthesis of sulfone‐bearing quaternary carbon stereocenters. Through the sulfonylation of geranyl derived cyclic carbonate 1 h, we achieve the formal total synthesis of (+)‐agelasidine A.
The first general example of regio‐ and enantioselective palladium catalyzed allylic sulfonylation of vinyl cyclic carbonates provides an efficient and direct way to construct sulfone‐bearing quaternary carbon stereocenters. A three steps formal total synthesis of (+)‐agelasidine A is achieved which exemplifies the practical use of this protocol in a synthetic setting.
In quest of effective materials and technologies for detecting toxic gas molecules, an attempt is made to detect phosgene gas molecule using MoS
2
by employing dispersion corrected density functional ...theory calculations. Doping Si into the S-vacancy of MoS
2
monolayer results in improvement of adsorption capability of phosgene gas molecule, reaching adsorption energy of − 1.228 eV. It is revealed that Si-doped MoS
2
sheet is thermodynamically stable at high temperatures, and hence, room temperature stability is expected. Origin of interaction between phosgene and adsorbent is analyzed by calculating density of states, charge transfer, and vibrational frequency. Strong binding and more charge transfer modulate band gap and work function of the Si-doped MoS
2
material post-phosgene adsorption indicate that such system is highly sensitive to phosgene. It is further shown that the sensing material is completely recovered by applying 0.6 V/Å magnitude vertical positive electric field. The reason for reduced stability of the system is revealed by variations in charge transfer process and induced dipole interaction due to the charge redistribution. The results suggest potential application of MoS
2
-based sheets for sensing phosgene gas molecule, where external electric field efficiently aids reversible adsorption process.
Hereditary xerocytosis is thought to be a rare genetic condition characterized by red blood cell (RBC) dehydration with mild hemolysis. RBC dehydration is linked to reduced Plasmodium infection ...in vitro; however, the role of RBC dehydration in protection against malaria in vivo is unknown. Most cases of hereditary xerocytosis are associated with gain-of-function mutations in PIEZO1, a mechanically activated ion channel. We engineered a mouse model of hereditary xerocytosis and show that Plasmodium infection fails to cause experimental cerebral malaria in these mice due to the action of Piezo1 in RBCs and in T cells. Remarkably, we identified a novel human gain-of-function PIEZO1 allele, E756del, present in a third of the African population. RBCs from individuals carrying this allele are dehydrated and display reduced Plasmodium infection in vitro. The existence of a gain-of-function PIEZO1 at such high frequencies is surprising and suggests an association with malaria resistance.
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•Expression of a gain-of-function Piezo1 allele models hereditary xerocytosis in mice•Mice expressing gain-of-function Piezo1 allele are protected from cerebral malaria•A third of the African population carry a PIEZO1 gain-of-function allele (E756del)•RBCs from E756del carriers are dehydrated and show reduced susceptibility to Plasmodium
A gain-of-function mutation in the mechanically activated channel PIEZO1 is associated with resistance to the malaria parasite Plasmodium falciparum.
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