Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of IFN‐γ immunity. Since 1996, disease‐causing mutations have been found in 11 genes, which, through allelic ...heterogeneity, underlie 21 different genetic disorders. We briefly review here progress in the study of molecular, cellular and clinical aspects of MSMD since the last comprehensive review published in 2014. Highlights include the discoveries of (1) a new genetic etiology, autosomal recessive signal peptide peptidase‐like 2 A deficiency, (2) TYK2‐deficient patients with a clinical phenotype of MSMD, (3) an allelic form of partial recessive IFN‐γR2 deficiency, and (4) two forms of syndromic MSMD: RORγ/RORγT and JAK1 deficiencies. These recent findings illustrate how genetic and immunological studies of MSMD can shed a unique light onto the mechanisms of protective immunity to mycobacteria in humans.
Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of IFN‐γ immunity. Since 1996, disease‐causing mutations have been found in 11 genes, which, through allelic heterogeneity, underlie 21 different genetic disorders. We briefly review here progress in the study of molecular, cellular and clinical aspects of MSMD since the last comprehensive review published in 2014.
Organelles play crucial roles in cellular activities and the functions of organelles are related greatly to the pH values, therefore, the bio-imaging of targeted organelles and their related pH ...sensing is of great importance in biological assays. Herein we report the fluorescence imaging of specific organelles, i.e., lysosomes and endoplasmic reticulum, and their pH sensing with surface regulated carbon dots (CDs). Carbon dots functionalized with amine groups (ACDs) are first prepared by hydrothermal treatment of citric acid and urea, and then laurylamine functionalized CDs (LCDs) are obtained via the conjugation of laurylamine with ACDs. The as-prepared ACDs and LCDs provide clear and bright imaging results for the lysosome and endoplasmic reticulum, respectively. The subcellular targeting features of the two CDs are attributed to their surface chemistries and cellular uptake pathways. Moreover, both the CDs are pH responsive within a certain pH range, i.e., 4.0-5.4 for ACDs and 6.2-7.2 for LCDs. The ACDs and LCDs are thus successfully applied to visualize the pH fluctuations of the lysosome and endoplasmic reticulum in MCF-7 cells.
Rare genetic conditions like Down syndrome (DS) are historically understudied. Infection is a leading cause of mortality in DS, along with cardiac anomalies. Currently, it is unknown how the COVID-19 ...pandemic affects individuals with DS. Herein, we report an analysis of individuals with DS who were hospitalized with COVID-19 in New York, New York, USA.
In this retrospective, dual-center study of 7246 patients hospitalized with COVID-19, we analyzed all patients with DS admitted in the Mount Sinai Health System and Columbia University Irving Medical Center. We assessed hospitalization rates, clinical characteristics, and outcomes.
We identified 12 patients with DS. Hospitalized individuals with DS are on average ten years younger than patients without DS. Patients with DS have more severe disease than controls, particularly an increased incidence of sepsis and mechanical ventilation.
We demonstrate that individuals with DS who are hospitalized with COVID-19 are younger than their non-DS counterparts, and that they have more severe disease than age-matched controls. We conclude that particular care should be considered for both the prevention and treatment of COVID-19 in these patients.
Predicting species' potential geographical range by species distribution models (SDMs) is central to understand their ecological requirements. However, the effects of using different modeling ...techniques need further investigation. In order to improve the prediction effect, we need to assess the predictive performance and stability of different SDMs.
We collected the distribution data of five common tree species (Pinus massoniana, Betula platyphylla, Quercus wutaishanica, Quercus mongolica and Quercus variabilis) and simulated their potential distribution area using 13 environmental variables and six widely used SDMs: BIOCLIM, DOMAIN, MAHAL, RF, MAXENT, and SVM. Each model run was repeated 100 times (trials). We compared the predictive performance by testing the consistency between observations and simulated distributions and assessed the stability by the standard deviation, coefficient of variation, and the 99% confidence interval of Kappa and AUC values.
The mean values of AUC and Kappa from MAHAL, RF, MAXENT, and SVM trials were similar and significantly higher than those from BIOCLIM and DOMAIN trials (p<0.05), while the associated standard deviations and coefficients of variation were larger for BIOCLIM and DOMAIN trials (p<0.05), and the 99% confidence intervals for AUC and Kappa values were narrower for MAHAL, RF, MAXENT, and SVM. Compared to BIOCLIM and DOMAIN, other SDMs (MAHAL, RF, MAXENT, and SVM) had higher prediction accuracy, smaller confidence intervals, and were more stable and less affected by the random variable (randomly selected pseudo-absence points).
According to the prediction performance and stability of SDMs, we can divide these six SDMs into two categories: a high performance and stability group including MAHAL, RF, MAXENT, and SVM, and a low performance and stability group consisting of BIOCLIM, and DOMAIN. We highlight that choosing appropriate SDMs to address a specific problem is an important part of the modeling process.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The cytoplasmic labile iron pool supplies iron to the mitochondrion for heme and iron sulfur cluster synthesis and to many cytoplasmic enzymes, thereby controlling numerous metabolic reactions. ...Surprisingly the chemical nature of this pool has never been convincingly characterised. Here we provide evidence for iron(II)glutathione being the dominant component of this pool. We report for the first time the affinity constant for the glutathione–iron(II) interaction and use this value to study the cytoplasmic speciation of iron(II). The formation of this complex is a major determinant of the electrode potential of the cytoplasmic ferrous iron pool, a means of selecting between iron(II) and manganese(II) and it provides a substrate for glutaredoxin/iron clusters at the dimer interface of glutaredoxins involved in the synthesis of Fe–S cluster proteins.
Monocytes and dendritic cells regulate adaptive and innate immunity. This study uncovers an association between mutations in the gene encoding interferon regulatory factor 8 and deficiency of ...dendritic cells and monocytes in the context of disseminated bacille Calmette–Guérin disease.
The discovery of human primary immunodeficiencies that affect the development of granulocytes, B cells, and T cells has been instrumental in defining the contribution of these cell types to protective immunity.
1
,
2
Monocytes, macrophages, and dendritic cells — all mononuclear phagocytes — have essential functions in both innate and acquired immunity. These cells initially recognize and engulf invading microbes, produce proinflammatory cytokines (e.g., interleukin-12), and process antigens for presentation to naive T cells, which consequently secrete various lymphokines (e.g., interferon-γ).
3
,
4
On activation by cytokines secreted by T cells, mononuclear phagocytes destroy ingested microorganisms. There are no known genetic causes . . .
The role of autophagy in the recovery of spinal cord injury remains controversial; in particular, the mechanism of autophagy regulated degradation of ubiquitinated proteins has not been discussed to ...date. In this study, we investigated the protective role of basic fibroblast growth factor (bFGF) both in vivo and in vitro and demonstrated that excessive autophagy and ubiquitinated protein accumulation is involved in the rat model of trauma. bFGF administration improved recovery and increased the survival of neurons in spinal cord lesions in the rat model. The protective effect of bFGF is related to the inhibition of autophagic protein LC3II levels; bFGF treatment also enhances clearance of ubiquitinated proteins by p62, which also increases the survival of neuronal PC-12 cells. The activation of the downstream signals of the PI3K/Akt/mTOR pathway by bFGF treatment was detected both in vivo and in vitro. Combination therapy including the autophagy activator rapamycin partially abolished the protective effect of bFGF. The present study illustrates that the role of bFGF in SCI recovery is related to the inhibition of excessive autophagy and enhancement of ubiquitinated protein clearance via the activation of PI3K/Akt/mTOR signaling. Overall, our study suggests a new trend for bFGF drug development for central nervous system injuries and sheds light on protein signaling involved in bFGF action.
Chelation therapy has become an important therapeutic approach for some diseases. In attempt to identify clinically useful chelators, four hexadentate ligands were synthesized by conjugating the ...corresponding bidentate ligands (3-hydroxypyridin-4-one (3,4-HOPO), 3-hydroxypyridin-2-one (3,2-HOPO), 1-hydroxypyridin-2-one (1,2-HOPO), and 3-hydroxypyran-4-one) each with a free amino group to a tripodal acid. Their p
K
a
values and affinities for iron(
iii
) were investigated. The pFe
3+
values of the hexadentate pyridinones
1
(3,4-HOPO),
3
(3,2-HOPO) and
4
(1,2-HOPO), and the pyranone
2
was found to follow the sequence
1
>
4
>
3
>
2
, which is different to the pFe
3+
value sequence of the corresponding bidentate forms (3,4-HOPO > 3,2-HOPO > 1,2-HOPO > 3-hydroxypyranone). Hexadentate 3,4-HOPOs and 1,2-HOPOs have the greatest potential as iron scavenging agents.
Chelation therapy has become an important therapeutic approach for some diseases.
Pear has an S‐RNase‐based gametophytic self‐incompatibility (SI) system. Nuclear DNA degradation is a typical feature of incompatible pollen tube death, and is among the many physiological functions ...of vacuoles. However, the specific changes that occur in vacuoles, as well as the associated regulatory mechanism in pear SI, are currently unclear. Although research in tobacco has shown that decreased activity of diacylglycerol kinase (DGK) results in the morphological change of pollen tube vacuole, whether DGK regulates the pollen tube vacuole of tree plants and whether it occurs in SI response, is currently unclear. We found that DGK activity is essential for pear pollen tube growth, and DGK4 regulates pollen tube vacuole morphology following its high expression and deposition at the tip and shank edge of the pollen tube of pear. Specifically, incompatible S‐RNase may induce cytoplasmic acidification of the pollen tube by inhibiting V‐ATPase V0 domain a1 subunit gene expression as early as 30 min after treatment, when the pollen tube is still alive. Cytoplasmic acidification induced by incompatible S‐RNase results in reduced DGK4 abundance and deposition, leading to morphological change of the vacuole and fragmentation of nuclear DNA, which indicates that DGK4 is a key factor in pear SI response.
In pear self‐incompatibility, cytoplasmic acidification of incompatible pollen tubes due to S‐RNase‐mediated inhibition of V‐ATPase V0 dominant a1 subunit gene expression reduces diacylglycerol kinase 4 (DGK4) abundance and deposition, leading to morphological changes of the vacuole and nuclear DNA fragmentation, indicating that DGK4 is a key factor in pear self‐incompatibility.
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