Leukaemia of various subtypes are driven by distinct chromosomal rearrangement or genetic abnormalities. The leukaemogenic fusion transcripts or genetic mutations serve as molecular markers for ...minimal residual disease (MRD) monitoring. The current study evaluated the applicability of several droplet digital PCR assays for the detection of these targets at RNA and DNA levels (atypical BCR::ABL1 e19a2, e23a2ins52, e13a2ins74, rare types of CBFB::MYH11 (G and I), PCM1::JAK2, KMT2A::ELL2, PICALM::MLLT10 fusion transcripts and CEBPA frame-shift and insertion/duplication mutations) with high sensitivity. The analytical performances were assessed by the limit of blanks, limit of detection, limit of quantification and linear regression. Our data demonstrated serial MRD monitoring for patients at molecular level could become "digitalized", which was deemed important to guide clinicians in treatment decision for better patient care.
During cerebral cortex development, pyramidal neurons migrate through the intermediate zone and integrate into the cortical plate. These neurons undergo the multipolar-bipolar transition to initiate ...radial migration. While perturbation of this polarity acquisition leads to cortical malformations, how this process is initiated and regulated is largely unknown. Here we report that the specific upregulation of the Rap1 guanine nucleotide exchange factor, RapGEF2, in migrating neurons corresponds to the timing of this polarity transition. In utero electroporation and live-imaging studies reveal that RapGEF2 acts on the multipolar-bipolar transition during neuronal migration via a Rap1/N-cadherin pathway. Importantly, activation of RapGEF2 is controlled via phosphorylation by a serine/threonine kinase Cdk5, whose activity is largely restricted to the radial migration zone. Thus, the specific expression and Cdk5-dependent phosphorylation of RapGEF2 during multipolar-bipolar transition within the intermediate zone are essential for proper neuronal migration and wiring of the cerebral cortex.
Studies on healthcare-seeking behaviour usually adopted a patient care perspective, or restricted to specific disease conditions. However, pre-diagnosis symptoms may be more relevant to ...healthcare-seeking behaviour from a patient perspective. We described healthcare-seeking behaviours by specific symptoms related to respiratory and gastrointestinal-related infections.
We conducted a longitudinal population-based telephone survey in Hong Kong. We collected data on healthcare-seeking behaviour specific to symptoms of respiratory and gastrointestinal-related infections and also associated demographic factors. We performed descriptive analyses and estimated the proportion of participants who sought medical consultation, types of services utilized and duration from symptom onset to healthcare seeking, by different age groups. Post-stratification was used to compensate non-response and multiple imputation to handle missing and right-censored data.
We recruited 2564 participants who reported a total of 4370 illness episodes and 7914 symptoms. Fatigue was the most frequently reported symptom, followed by headache and runny nose, with 30-day incidence rate of 9.1, 7.7, and 7.7% respectively. 78% of the participants who had fever sought medical consultation, followed by those with rash (60%) and shortness of breath (58%). Older adults (aged ≥55y) who had symptoms including fever, sore throat, and headache had a significantly higher consultation rate comparing to the other age groups. The 30-day incidence rates of influenza-like illness (ILI) and acute respiratory illness (ARI) were 0.8 and 7.2% respectively, and the consultation rates among these participants were 91 and 64%. Private general practitioner clinics was the main service utilized by participants for most of the symptoms considered, especially those related to acute illness such as fever, diarrhoea and vomiting. Chinese medicine clinics were mostly likely to be visited by participants with low back pain, myalgia and fatigue. Among participants who have sought medical services, most were within 3 days of symptom onset.
Healthcare-seeking behaviour were different by symptoms and age. Characterization of these patterns provides crucial parameters for estimating the full burden of common infectious diseases from facility-based surveillance system, for planning and allocation of healthcare resources.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
SUMMARY
Severe acute respiratory syndrome (SARS) is a recently emerged infectious disease caused by a novel coronavirus, but its immunopathological mechanisms have not yet been fully elucidated. We ...investigated changes in plasma T helper (Th) cell cytokines, inflammatory cytokines and chemokines in 20 patients diagnosed with SARS. Cytokine profile of SARS patients showed marked elevation of Th1 cytokine interferon (IFN)‐γ, inflammatory cytokines interleukin (IL)‐1, IL‐6 and IL‐12 for at least 2 weeks after disease onset, but there was no significant elevation of inflammatory cytokine tumour necrosis factor (TNF)‐α, anti‐inflammatory cytokine IL‐10, Th1 cytokine IL‐2 and Th2 cytokine IL‐4. The chemokine profile demonstrated significant elevation of neutrophil chemokine IL‐8, monocyte chemoattractant protein‐1 (MCP‐1), and Th1 chemokine IFN‐γ‐inducible protein‐10 (IP‐10). Corticosteroid reduced significantly IL‐8, MCP‐1 and IP‐10 concentrations from 5 to 8 days after treatment (all P < 0·001). Together, the elevation of Th1 cytokine IFN‐γ, inflammatory cytokines IL‐1, IL‐6 and IL‐12 and chemokines IL‐8, MCP‐1 and IP‐10 confirmed the activation of Th1 cell‐mediated immunity and hyperinnate inflammatory response in SARS through the accumulation of monocytes/macrophages and neutrophils.
One of greatest challenges to the successful treatment of cancer is drug resistance. An exciting approach is the eradication of cancer stem cells (CSCs). However, little is known about key signals ...regulating the formation and expansion of CSCs. Moreover, lack of a reliable predictive preclinical model has been a major obstacle to discover new cancer drugs and predict their clinical activity. Here, in ovarian cancer, a highly chemoresistant tumor that is rapidly fatal, we provide the first evidence demonstrating the causal involvement of mechanical stimulus in the CSC phenotype using a customizable microfluidic platform and three-dimensional spheroids, which most closely mimic tumor behavior. We found that ovarian cancer cells significantly acquired the expression of epithelial-to-mesenchymal transition and CSC markers and a remarkable chemoresistance to clinically relevant doses of frontline chemotherapeutic drugs cisplatin and paclitaxel when grown under fluid shear stress, which corroborates with the physiological attainable levels in the malignant ascites, but not under static condition. Furthermore, we uncovered a new link of microRNA-199a-3p, phosphatidylinositol 3-kinase/Akt, and multidrug transporter activation in shear stress-induced CSC enrichment. Our findings shed new light on the significance of hydrodynamics in cancer progression, emphasizing the need of a flow-informed framework in the development of therapeutics.
Identifying individual correlates of infectivity of influenza virus is important for disease control and prevention. Viral shedding is used as a proxy measure of infectivity in many studies. However, ...the evidence for this is limited.
In a detailed study of influenza virus transmission within households in 2008-12, we recruited index cases with confirmed influenza infection from outpatient clinics, and followed up their household contacts for 7-10 days to identify secondary infections. We used individual-based hazard models to characterize the relationship between individual viral shedding and individual infectivity.
We analyzed 386 households with 1147 household contacts. Index cases were separated into 3 groups according to their estimated level of viral shedding at symptom onset. We did not find a statistically significant association of virus shedding with transmission. Index cases in medium and higher viral shedding groups were estimated to have 21% (95% CI: -29%, 113%) and 44% (CI: -16%, 167%) higher infectivity, compared with those in the lower viral shedding group.
Individual viral load measured by RT-PCR in the nose and throat was at most weakly correlated with individual infectivity in households. Other correlates of infectivity should be examined in future studies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
For >70 years, a 4-fold or greater rise in antibody titer has been used to confirm influenza virus infections in paired sera, despite recognition that this heuristic can lack sensitivity. Here we ...analyze with a novel Bayesian model a large cohort of 2353 individuals followed for up to 5 years in Hong Kong to characterize influenza antibody dynamics and develop an algorithm to improve the identification of influenza virus infections. After infection, we estimate that hemagglutination-inhibiting (HAI) titers were boosted by 16-fold on average and subsequently decrease by 14% per year. In six epidemics, the infection risks for adults were 3%-19% while the infection risks for children were 1.6-4.4 times higher than that of younger adults. Every two-fold increase in pre-epidemic HAI titer was associated with 19%-58% protection against infection. Our inferential framework clarifies the contributions of age and pre-epidemic HAI titers to characterize individual infection risk.
Whole virion inactivated vaccine CoronaVac (C) and Spike (S) mRNA BNT162b2 (B) vaccines differ greatly in their ability to elicit neutralizing antibodies but have somewhat comparable effectiveness in ...protecting from severe COVID-19. We conducted further analyses for a randomized trial (Cobovax study, NCT05057169) of third dose homologous and heterologous booster vaccination, i.e. four interventions CC-C, CC-B, BB-C and BB-B. Here, we assess vaccine immunogenicity beyond neutralizing function, including S and non-S antibodies with Fc receptor (FcR) binding, antibody avidity and T cell specificity to 6 months post-vaccination. Ancestral and Omicron S-specific IgG and FcR binding are significantly higher by BNT162b2 booster than CoronaVac, regardless of first doses. Nucleocapsid (N) antibodies are only increased in homologous boosted CoronaVac participants (CC-C). CoronaVac primed participants have lower baseline S-specific CD4+ IFNγ+ cells, but are significantly increased by either CoronaVac or BNT162b2 boosters. Priming vaccine content defined T cell peptide specificity preference, with S-specific T cells dominating B primed groups and non-S structural peptides contributing more in C primed groups, regardless of booster type. S-specific CD4+ T cell responses, N-specific antibodies, and antibody effector functions via Fc receptor binding may contribute to protection and compensate for less potent neutralizing responses in CoronaVac recipients.Here the authors provide exploratory analyses of a clinical trial evaluating immunogenicity of inactivated and mRNA SARS-CoV-2 vaccines, and show that CoronaVac primed groups have disparate T cell responses and nucleocapsid specific antibodies compared to BNT162b2 that may protect in the absence of robust neutralizing antibody responses.
Background. Previous studies have established that antibody titer measured by the hemagglutination-inhibiting (HAI) assay is correlated with protection against influenza virus infection, with an HAI ...titer of 1:40 generally associated with 50% protection. Methods. We recruited index cases with confirmed influenza virus infection from outpatient clinics, and followed up their household contacts for 7-10 days to identify secondary infections. Serum samples collected from a subset of household contacts were tested by HAI and microneutralization (MN) assays against prevalent influenza viruses. We analyzed the data using an individual hazard-based transmission model that adjusted for age and vaccination history. Results. Compared to a reference group with antibody titers <1:10, we found that HAI titers of 1:40 against influenza A(H1N1) and A(H3N2) were associated with 31% (95% confidence interval CI, 13%-46%) and 31% (CI, 1%-53%) protection against polymerase chain reaction (PCR)-confirmed A(H1N1) and A(H3N2) virus infection, respectively, while an MN titer of 1:40 against A(H3N2) was associated with 49% (95% CI, 7%-81%) protection against PCR-confirmed A(H3N2) virus infection. Conclusions. An HAI titer of 1:40 was associated with substantially less than 50% protection against PCR-confirmed influenza virus infection within households, perhaps because of exposures of greater duration or intensity in that confined setting.
Giant clams live in symbiosis with phototrophic dinoflagellates, which reside extracellularly inside zooxanthellal tubules located mainly in the colourful and extensible outer mantle. As symbiotic ...dinoflagellates have no access to the ambient seawater, they need to obtain inorganic carbon (Ci) from the host for photosynthesis during illumination. The outer mantle has a host-mediated and light-dependent carbon-concentrating mechanism to augment the supply of Ci to the symbionts during illumination. Iridocytes can increase the secretion of H+ through vacuolar H+-ATPase to dehydrate HCO3- present in the hemolymph to CO2. CO2 can permeate the basolateral membrane of the epithelial cells of the zooxanthellal tubules, and rehydrated back to HCO3- in the cytoplasm catalysed by carbonic anhydrase 2. This study aimed to elucidate the molecular mechanism involved in the transport of HCO3- across the apical membrane of these epithelial cells into the luminal fluid surrounding the symbionts. We had obtained the complete cDNA coding sequence of a homolog of electrogenic Na+-HCO3- cotransporter 2 (NBCe2-like gene) from the outer mantle of the fluted giant clam, Tridacna squamosa. NBCe2-like gene comprised 3,399 bp, encoding a protein of 1,132 amino acids of 127.3 kDa. NBCe2-like protein had an apical localization in the epithelial cells of zooxanthellal tubules, denoting that it could transport HCO3- between the epithelial cells and the luminal fluid. Furthermore, illumination augmented the transcript level and protein abundance of NBCe2-like gene/NBCe2-like protein in the outer mantle, indicating that it could mediate the increased transport of HCO3- into the luminal fluid to support photosynthesis in the symbionts.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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