Chronic Granulomatous Disease (CGD) is a rare inherited disorder in which phagocytes lack NADPH oxidase activity. The most common form is the X-linked CGD (X-CGD), caused by mutations in the CYBB gene. Clinical, functional and genetic characterizations of 16 CGD cases of male patients and their relatives were done. We classified them as suffering from different variants of CGD (X910, X91− or X91+) according to NOX2 expression and NADPH oxidase activity in neutrophils. Twelve mutations were novel (10 X910-CGD and 2 X91− -CGD). One X910-CGD was due to a new and extremely rare double missense mutation Thr208Arg-Thr503Ile. We investigated the pathological impact of each single using stable transfection of each mutated cDNA in the NOX2 knock-out PLB-985 cell line. Both mutations leading to X91−-CGD were also novel; one deletion -67delT was localized in the promoter region of CYBB, the second one c.253-1879A>G mutation activates a splicing donor site, which unveils a cryptic acceptor site, leading to the inclusion of a 124-nucleotide pseudo-exon between exons 3 and 4 and responsible for the partial loss of NOX2 expression. Both X91−-CGD mutations were characterized by a low cytochrome b558 expression and a faint NADPH oxidase activity. The functional impact of new missense mutations is discussed in the context of a new 3D-model of the dehydrogenase domain of NOX2. Our study demonstrates that low NADPH oxidase activity found in both X91−-CGD patients correlates with mild clinical forms of CGD whereas X910-CGD and X91+-CGD cases remain the most clinically severe forms.

Cancer cell plasticity is the ability of tumor cells to switch phenotypes and is one of the predominant requisites of cancer cells capable of undergoing metastasis. Cancer cell plasticity is also recognised as one of the major contributors to intra-tumoral heterogeneity, a critical factor underlying the progression of malignant tumors which is known to modify tumor response and induce resistance against various modes of therapy thus posing a barrier to efficient cancer management. Cancer cell plasticity is acquired by the subversion of cell signaling pathways like MAPK, PI3K, STAT3, Wnt, Hedgehog and Notch as well as cellular programs such as epithelial to mesenchymal transition (EMT) and phenotypic plasticity. This complex phenomenon has been studied in many cancer types like pancreatic cancer, colon cancer and breast cancer. Some cancers like breast cancer are known to exhibit a hierarchical organization with cancer stem cells (CSCs) at the pinnacle of the pyramid due to their ability to promote tumorigenesis, metastasis and therapy resistance. CSCs which can undergo phenotypic changes resulting in heterogenous cell populations with differing potential to develop programs necessary for the metastatic process lies at the core of the cancer cell plasticity hypothesis. Our expanding knowledge of this field can lead to the development of more therapeutic strategies that can be used in cancer and other solid tumors that exhibit similar mechanisms of plasticity. This review will explore the current understanding we have of breast cancer on the intrinsic molecular mechanisms of cancer cell plasticity and the resistance to various types of cancer therapy that arise as a result of plasticity. We conclude by exploring the potential novel therapies that specifically target the pathways leading to plasticity and can be leveraged to treat patients living with the disease. Keywords: Cancer cell plasticity, Epithelial to Mesenchymal Transition (EMT), therapy resistance, targeted therapy.

Our knowledge of biodiversity hinges on sufficient data, reliable methods, and realistic models. Without an accurate assessment of species distributions, we cannot effectively target and stem biodiversity loss. Species range maps are the foundation of such efforts, but countless studies have failed to account for the most basic assumptions of reliable species mapping practices, undermining the credibility of their results and potentially misleading and hindering conservation and management efforts. Here, we use examples from the recent literature and broader conservation community to highlight the substantial shortfalls in current practices and their consequences for both analyses and conservation management. We detail how different decisions on data filtering impact the outcomes of analysis and provide practical recommendations and steps for more reliable analysis, whilst understanding the limits of what available data will reliably allow and what methods are most appropriate. Whilst “perfect” analyses are not possible for many taxa given limited data, and biases, ensuring we use data within reasonable limits and understanding inherent assumptions is crucial to ensure appropriate use. By embracing and enacting such best practices, we can ensure both the accuracy and improved comparability of biodiversity analyses going forward, ultimately enhancing our ability to use data to facilitate our protection of the natural world.

The binary fluidization of Geldart-D type non-spherical wood particles and spherical LDPE particles was investigated in a laboratory-scale bed. The experiment was performed for varying static bed height, wood particles count, as well as superficial gas velocity. The LDPE velocity field were quantified using Particle Image Velocimetry (PIV). The wood particles orientation and velocity are measured using Particle Tracking Velocimetry (PTV). A machine learning pixel-wise classification model was trained and applied to acquire wood and LDPE particle masks for PIV and PTV processing, respectively. The results show significant differences in the fluidization behavior between LDPE only case and binary fluidization case. The effects of wood particles on the slugging frequency, mean, and variation of bed height, and characteristics of the particle velocities/orientations were quantified and compared. This comprehensive experimental dataset serves as a benchmark for validating numerical models.

We have reported the electronic, magnetic, and optical properties of the top layer carbon-doped hexagonal Boron Nitride(h-BN) bilayer at B/N-sites using the density functional theory implemented in Quantumwise VNL-ATK package. The calculated structural and electronic properties of the h-BN bilayer are in agreement with the previously reported results. A single carbon doping on B and N sites modifies the large band gap semiconducting behaviour of h-BN bilayer similar to dilute magnetic semi-conducting material with a net magnetic moment of 1.001 μ B and 0.998 μ B , respectively. For double doping at B/N sites net magnetic moment increases to 1.998 μ B and 1.824 μ B , respectively. Whereas for triply carbon doped bilayer system at B/N sites, the system changes to metallic behaviour. Upon carbon doping at N-site, we obtained transition from Non-Magnetic semiconductor(Pristine) → Magnetic semiconductor(1C) → Half-Metal ferromagnetic(2C) → Metal(3C). Whereas, in case of doping at the B-site, we observed transition from Non-Magnetic Semiconductor(Pristine) → Magnetic Semiconductor(1C) → Metal (2C, 3C). Analysis from the PDOS plot of the car- bon doped systems reveals that the net magnetic moments are contributed by the 2p orbitals of carbon and partial contribution from the neighboring nitrogen and boron atoms, respectively. As 1,2C doping at the B-site reduces the energy band gap to 0.81-1.8 eV which falls in the visible spectrum and thus such system further opens up an opportunity to be utilised as a photocatalys material. Our carbon doped systems show a magnetic semiconducting behavior with a nite magnetic moment which is one of the criteria for a spintronic material. So, our system looks promising in this regard. Also, Carbon doping can be considered as a simple approach to tune the band gap of the Boron Nitride bilayer system.

Objectives: This rapid review aims to evaluate the impact of the COVID-19 pandemic on incidence of head and neck cancer (HNC) and stage distribution at diagnosis. Design: Rapid Review and Meta-analysis Participants: comparative data for new HNC patients between a pre-pandemic cohort (before March 2020) and a pandemic cohort (after March 2020 during the lockdown period). Main Outcomes Measured: data on tumour stage, incidence, referral pathway (number of new patient referrals) or workload levels (number of HNC treatments). Data on stage were summarised as odds ratios (OR) with 95% confidence intervals (CI), data related to changes in numbers of diagnoses, referrals and workload levels were summarised as a narrative synthesis. Results: 31 reports were included in this review. Individually 16 out of 23 studies did not show a significant impact on stage relative to the pre-pandemic period. However, the meta-analysis revealed that patients diagnosed with HNC during the pandemic were 16% more likely to have nodal involvement (OR=1.16; 95% CI 1.00–1.35), 17% more likely to have a late overall stage (OR=1.17; 95% CI 1.01–1.36), and 32% more likely to present with advanced tumour extent (T3 and T4 stage) (OR=1.32; 95% CI 1.08–1.62). Data on incidence was extremely limited and not currently sufficient to assess trends in burden of disease. Conclusions: This review indicates that during the COVID-19 pandemic there was upstaging of HNC at diagnosis, suggesting the provision of care to HNC patients was significantly affected.

1. A survey on the recent COVID-19 epidemic in China was conducted. 2. The epidemic likely made over 85% of people in China sick in December 2022. 3. The epidemic likely ended in early January 2023. 4. The epidemic had the features of spreading more rapidly and widely and having a higher symptomatic rate than previously thought. 5. The above features could lead to many severe cases and deaths due to the shortages of medical resources. 6. The above features greatly enhanced the population immunity in China, which will accelerate the end of the COVID-19 pandemic and reduce the emergence of risky variants of SARS-CoV-2 in China.

Lignocellulose is the most abundant natural biopolymer on earth and a potential raw material for the production of fuels and chemicals. However, only some organisms such as bacteria and fungi produce the necessary enzymes to metabolize it. In this work we detected the presence of extracellular cellulases in the genome of five species of Scenedesmus. These microalgae grow in both, freshwater and saltwater regions as well as in soils, displaying highly flexible metabolic properties. The comparison of sequences of the different cellulases with hydrolytic enzymes from other organisms by means of multi-sequence alignments and phylogenetic trees showed that these enzymes belong to the families of glycosyl hydrolases 1, 5, 9 and 10. In addition, most of these presented a greater similarity of sequence with enzymes from invertebrates, fungi, bacteria and other microalgae than with cellulases from plants; and the 3D modeling data obtained showed that both the main structures of the modeled proteins and the main amino acid residues implicated in catalysis and substrate binding are well conserved in Scenedesmus enzymes. We propose that these cellulase-producing phototrophic microorganisms could act as catalysts for the hydrolysis of cellulosic biomass fueled by sunlight.

The article is concerned with the analytical solution to the integro-differential system of balance and kinetic equations that describe the crystal growth phenomenon in a binary system for various nucleation kinetics. The effect of impurity concentration on the evolutionary behavior of crystals is shown. The nonlinear dynamics of a supercooled binary melt is studied with allowance for the withdrawal mechanism of product crystals from a metastable liquid of the crystallizer.

SARS-CoV-2 and its ever-emerging variants, are spread from host-to-host via expelled respiratory aerosols and saliva droplets. Knowing the number of virions which are exhaled by a person requires precise measurements of the size, count, velocity and trajectory of the virus-laden particles that are ejected directly from the mouth. These measurements are achieved in 3D, at 15000 images/second, and are applied when speaking, yelling, and coughing. In this study 33 events have been analysed by post-processing ~500000 images. Using these data, the flow rate of SARS-CoV-2 virions have been evaluated. At high concentrations, 10^7 virions/mL, it is found that 136 to 231 virions are ejected during a single cough, where the virion flow rate peak is capable of reaching 32 virions within a millisecond. This peak can reach tens of virions/ms when yelling, but reduced to only a few virions/ms when speaking. At medium concentrations, ~10^5 virions/mL, those results are hundreds of times lower. The total number of virions that are ejected when yelling at 110db, instead of speaking at 85db, increases by two to three fold. From the measured data analysed in this article, the flow rate of other diseases such as influenza, tuberculosis or measles, can also be estimated. As these data are openly accessible, they can be used by modellers for the simulation of saliva droplet transport and evaporation, allowing to further advance our understanding of airborne pathogen transmission.

Interferon-beta, the most widely prescribed medication for multiple sclerosis, is generally considered safe. Nevertheless, rarely serious and/or life-threatening side effects have been reported such as thrombotic microangiopathy. A few mechanisms have been proposed to explain how interferon causes thrombotic microangiopathy, but insufficient immunological studies have been unable to pin this phenomenon down to a single pathophysiologic pathway. We report thrombotic microangiopathy due to acquired complement factor I deficiency in a male receiving interferon-beta treatment for multiple sclerosis. After three years of starting the therapy, the 28-year-old patient presented with malignant hypertension causing seizures, rapidly progressive renal failure requiring hemodialysis, and hemolytic anemia. Corticosteroid and plasma exchange sessions permitted hemolysis control. Nonetheless, the patient remained hemodialysis-dependent. Exploration of the complement system found a complement factor I deficiency whose activity normalized at the control carried out after two years. We concluded that IFNβ treatment may cause complement factor I deficit, which can lead to thrombotic microangiopathy and severe renal failure.

The Role of multidetector CT scan in the Management of Prosthetic Aortic Valve thrombosis: A Case Report.Sheriff N Dodoo, MD1; Christelle Yakana Moyine, MD2; Alicia Agyemang-Sarpong3; Abdullah Ismail, MD2; Nina Le, DO2; Falgun Patel, MD4; Nima Ghasemzadeh, MD4; Ronnie Ramadan, MD4; Khaja Salahuddin Mohammed, MD4; Glen Henry, MD4; Ioannis Parastatidis, MD PHD5Georgia Heart Institute, Northeast Georgia Medical Center, 743 Spring Street NE, Gainesville, GA 30501, U.S.A. Email: [email protected] of Internal Medicine, Northeast Georgia Medical Center, 743 Spring Street NE, Gainesville, GA 30501, U.S.A.Postgraduate Medical Education, Harvard Medical School, Boston Massachusetts, USAGeorgia Heart Institute, Interventional Cardiology, Northeast Georgia Medical Center 200 S Enota Dr NE, Gainesville, GA 30501, U.S.A.Georgia Heart Institute, Northeast Georgia Medical Center 100 S Enota Dr NE, Gainesville, GA 30501, U.S.A.

Aim: To investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the highly selective oral p38α/β MAP-kinase inhibitor Org 48775-0, a first-in-human study was conducted. Methods: In the SAD study part, an oral dose of Org 48775-0 ranging from 0.3 mg to 600 mg was evaluated in healthy males. In the MAD study part, dose levels of 30, 70 and 150 mg were evaluated with dosing for six consecutive days, twice daily. Both studies were performed in a double-blind, randomized, placebo-controlled, cross-over fashion and evaluated pharmacokinetics (PK), pharmacodynamics (PD; inhibition of LPS-induced TNFα release) and routine clinical and laboratory data. Moreover, the effect of a standardized fat meal on PK and PD parameters of Org 48775-0 was evaluated, and PK and PD parameters of Org 48775-0 were compared between healthy males and postmenopausal females. Results: All adverse events observed in the SAD and MAD cohorts were mild, transient and completely reversible without medical intervention. Pharmacokinetics were linear up to single dose s of 400 mg. Org 48775-0 doses equal to and greater than 30 mg significantly inhibited LPS-induced TNFα release (42.3% increase in inhibition, 95% CI=-65.2; -4.3) compared to placebo. In the MAD study, Org 48775-0 treatment inhibited the LPS-induced TNFα release during the entire steady state period. Levels of inhibition amounted 30-75% for 30 mg, 53-80% for 70 mg, and 77-92% for 150 mg Org 48775-0. Conclusion: This study demonstrates that Org 48775-0 has the capacity to significantly inhibit MAP-kinase activity in humans, without raising safety concerns.

Fluorescent pseudomonads represent one of the largest groups of bacteria inhabiting the surfaces of plants, but their genetic composition in planta is poorly understood. Here, we examined the population structure and diversity of fluorescent pseudomonads isolated from sugar beet grown at two geographic locations (Oxford, UK and Auckland, New Zealand). To seek evidence for niche adaptation, bacteria were sampled from three types of leaves (immature, mature and senescent) and then characterized using a combination of genotypic and phenotypic analysis. We first performed multilocus sequence analysis (MLSA) of three housekeeping genes (gapA, gltA, acnB) in a total of 152 isolates (96 from Oxford, 56 from Auckland). The concatenated sequences were grouped into 81 sequence types and 22 distinct operational taxonomic units (OTUs). Significant levels of recombination were detected, particularly for the Oxford isolates (rate of recombination to mutation (r/m) = 5.23 for the whole population). Subsequent ancestral analysis performed in STRUCTURE found evidence of six ancestral populations, and their distributions significantly differed between Oxford and Auckland strains. Next, the ability to grow on 95 carbon sources was assessed using the BiologTM GN2 microtiter plates. A distance matrix was generated from the raw growth data (A660) and subjected to multidimensional scaling (MDS) analysis. There was a significant correlation between the substrate utilization profiles and MLSA genotypes. Both phenotypic and genotypic analyses indicated presence of a geographic structure for strains from Oxford and Auckland. Significant differences were genotypically detected between strains isolated from immature versus mature/senescent leaves. The fluorescent pseudomonads thus showed an ecotypic population structure, suggestive of adaptation to both geographical and local plant environments.

The diet of an individual animal is subject to change over time, both in response to short-term food fluctuations and over longer time scales as an individual ages and meets different challenges over its life cycle. A metabarcoding approach was used to elucidate the diet of different life stages of a songbird, the Eurasian reed warbler (Acrocephalus scirpaceus) over the summer breeding season of 2017. The faeces of adult, juvenile and nestling warblers were screened for invertebrate DNA, enabling identification of prey species. Dietary analysis was coupled with monitoring of Diptera in the field using yellow sticky traps. Seasonal changes in warbler diet were subtle whereas age class had a greater influence on overall diet composition. Age classes showed high dietary overlap, but significant dietary differences were mediated through the selection of prey, i) from different taxonomic groups, ii) with different habitat origins (aquatic versus terrestrial) and iii) of different average approximate sizes. Our results highlight the value of metabarcoding data for enhancing ecological studies of insectivores in dynamic environments.

Three COVID-19 cases were simultaneously confirmed as deep venous thrombosis (DVT). Ultrasound-guided IVCF implantation is an effective method that can be considered as a precautionary strategy for preventing lethal pulmonary embolism occurrence, especially for critical DVT-COVID-19 patients who are not suitable to be transferred to a routine X-ray operation room.

Aircraft cabins have high-performance ventilation systems, yet typically hold large numbers of people in close proximity for long periods. The current study estimated airborne virus exposure and infection reductions for vacant middle seats and masking in aircraft. Tracer particle data reported by U.S. Transportation Command (TRANSCOM) and CFD simulations reported by Boeing were used, along with NIOSH data, to build nonlinear regression models with particle exposure and distance from particle source as variables. These models that estimate exposure at given distances from the viral source were applied to evaluate exposure reductions when middle seats are vacant compared to full occupancy. Reductions averaged 54% for the seat row where an infectious passenger is located and 36% for a 24-row cabin containing one infectious passenger, with middle seats vacant. Analysis of the TRANSCOM data showed that universal masking (surgical masks) reduced exposures by 62% and showed masking and physical distancing provide further reductions when practiced together. For a notional scenario involving 10 infectious passengers, compared with no intervention, masking, distancing, and both would prevent 6.2, 3.8 and 7.6 secondary infections, respectively, using the Wells-Riley equation. These results suggest distancing and masking reduce SARS CoV-2 exposure risk when an infectious passenger is present.

Competitive interactions between distantly related clades could cause complementary diversity patterns of these clades over large spatial scales. One such example might be ants and birds in the eastern Himalaya; ants are very common at low elevations but almost absent at mid-elevations where the abundance of other arthropods and insectivorous bird diversity peaks. Here, we ask if ants at low elevations could compete with birds for arthropod prey. Specifically, we studied the impact of the Asian weaver ant (Oecophylla smaragdina), a common aggressive ant at low elevations. Diet analysis using molecular methods demonstrate extensive diet overlap between weaver ants and songbirds at both low and mid-elevations. Trees without weaver ants have greater non-ant arthropod abundance and leaf damage. Experimental removal of weaver ants results in an increase in the abundance of non-ant arthropods. Notably, numbers of Coleoptera and Lepidoptera were most affected by removal experiments and were prominent components of both bird and weaver ant diets. Our results suggest that songbirds and weaver ants might potentially compete with each other for arthropod prey at low elevations, thereby contributing to lower insectivorous bird diversity at low elevations in eastern Himalaya. Competition with ants may shape vertebrate diversity patterns across broad biodiversity gradients.