Search

Many speciality organic chemical products, such as pharmaceuticals are crystals that exhibit multiple morphological forms and habits that are of critical importance not only to the end use properties of the products, but also to their downstream processing, such as in filtration and handling and in transport and storage. It is known that minor changes in operating conditions, such as cooling rates and supesaturation can have significant impact on the product leading to batch-to-batch variation. As a result, precision manufacture of crystalline products demands on-line techniques for real-time measurement of crystal morphology. The use of a non-invasive on-line imaging technique in a batch reactor for monitoring cooling crystallization of (L)-glutamic acid which exhibits two polymorphs, alpha and beta is described. The technique was found to allow real-time observation of some temporal moments that are critical in the crystallization process, in particular the crystallization onset and transformation between the two polymorphs. For validation and benchmarking purpose, an off-line system f or particle characterization, the PharmaVision 830, and photo-microscope were also used in the study in parallel with the on-line imaging system. [ABSTRACT FROM AUTHOR]

• WQI developed with high sensitivity to parameter values outside the legal limits. • The rating curves were adjusted to describe the specific conditions of the river. • WQI that considers the protection of the aquatic biota in its assessment. • WQI that clearly reflects temporal and spatial variability. • The WQI offers a baseline to define the strategies to be implemented. A novel method is proposed for the development of ecosystem specific water quality indices in accordance with specific guidelines for the protection of aquatic life and with the capacity to demonstrate annual cycles, spatial and temporal variations, and trends in water quality. An ecosystem-specific water quality index for the Santiago-Guadalajara River (SGR-WQI) was developed using a method based entirely on multivariate statistical methods and historical data distributions. The SGR-WQI was developed using data from 13 water quality monitoring stations in the Santiago-Guadalajara River basin, collected monthly from 2009 to 2019 by the State Water Commission of Jalisco, México. The behaviour of 44 water quality parameters was statistically analyzed. It was found that 17 of the parameters best represented the water quality of the River. Parameter selection also considered the legal limits, established by the Government of Mexico, for the protection of aquatic life. To consider the protection of aquatic biota in the assessment of the index, a method was proposed to incorporate these limits in the development of rating curves providing the WQI with high sensitivity to parameter values that are outside the legal limits. Furthermore, a well-structured method based on multivariate statistical techniques was used to determine the parameter weights that best distinguish between sampling points and seasons, clearly reflecting temporal and spatial variability, as well as to demonstrate the annual cycle and trends in water quality. The methodology proposed can be used elsewhere to develop ecosystem specific water quality indices that evaluate surface water for protection of aquatic life in accordance with local limits/standards/guidelines and that adequately reflect spatial and temporal variability in agreement with the specific context. [ABSTRACT FROM AUTHOR]

Multiple lymphomatous polyposis (MLP) is an uncommon type of primary non-Hodgkin gastrointestinal (GI) B-cell lymphoma characterized by the presence of multiple polyps along the GI tract. Malignant cells of MLP have mantle cell characteristics and thus are considered to be the counterpart of the mantle cell lymphoma (MCL) in the GI tract. Since 1961, no more than 70 well-documented cases have been published. We report the case of 53-year-old man diagnosed as having MLP. The patient presented with diffuse abdominal pain, chronic lower GI bleeding, peripheral lymphadenopathy, and weight loss. The lymphomatous polyps extended from the esophagus to the rectum, with bone marrow infiltration. Immunohistologic findings were characteristic of MCL. The patient was treated with a combined cyclophosphamide, vincristine, and prednisone chemotherapy regimen, resulting in a partial response. [ABSTRACT FROM AUTHOR]

Classically, chemokines coordinate leukocyte trafficking during immune responses; however, many chemokines have also been reported to possess direct antibacterial activity in vitro. Yet, the bacterial killing mechanism of chemokines and the biochemical properties that define which members of the chemokine superfamily are antimicrobial remain poorly understood. Here we report that the antimicrobial activity of chemokines is defined by their ability to bind phosphatidylglycerol and cardiolipin, two anionic phospholipids commonly found in the bacterial plasma membrane. We show that only chemokines able to bind these two phospholipids kill Escherichia coli and Staphylococcus aureus and that they exert rapid bacteriostatic and bactericidal effects against E. coli with a higher potency than the antimicrobial peptide beta-defensin 3. Furthermore, our data support that bacterial membrane cardiolipin facilitates the antimicrobial action of chemokines. Both biochemical and genetic interference with the chemokine-cardiolipin interaction impaired microbial growth arrest, bacterial killing, and membrane disruption by chemokines. Moreover, unlike conventional antibiotics, E. coli failed to develop resistance when placed under increasing antimicrobial chemokine pressure in vitro. Thus, we have identified cardiolipin and phosphatidylglycerol as novel binding partners for chemokines responsible for chemokine antimicrobial action. Our results provide proof of principle for developing chemokines as novel antibiotics resistant to bacterial antimicrobial resistance mechanisms., Competing Interests: CONFLICT OF INTEREST B.F.V has ownership interests in Protein Foundry, LLC and XLock Biosciences, Inc. All other authors declare no competing interests.

Deterministic formation of membrane scission necks by protein machinery with multiplexed functions is critical in biology. A microbial example is M2 viroporin, a proton pump from the influenza A virus that is multiplexed with membrane remodeling activity to induce budding and scission in the host membrane during viral maturation. In comparison, the dynamin family constitutes a class of eukaryotic proteins implicated in mitochondrial fission, as well as various budding and endocytosis pathways. In the case of Dnm1, the mitochondrial fission protein in yeast, the membrane remodeling activity is multiplexed with mechanoenzyme activity to create fission necks. It is not clear why these functions are combined in these scission processes, which occur in drastically different compositions and solution conditions. In general, direct experimental access to changing neck sizes induced by individual proteins or peptide fragments is challenging due to the nanoscale dimensions and influence of thermal fluctuations. Here, we use a mechanical model to estimate the size of scission necks by leveraging small-angle X-ray scattering structural data of protein-lipid systems under different conditions. The influence of interfacial tension, lipid composition, and membrane budding morphology on the size of the induced scission necks is systematically investigated using our data and molecular dynamic simulations. We find that the M2 budding protein from the influenza A virus has robust pH-dependent membrane activity that induces nanoscopic necks within the range of spontaneous hemifission for a broad range of lipid compositions. In contrast, the sizes of scission necks generated by mitochondrial fission proteins strongly depend on lipid composition, which suggests a role for mechanical constriction.

Swarming is a macroscopic phenomenon in which surface bacteria organize into a motile population. The flagellar motor that drives swarming in Pseudomonas aeruginosa is powered by stators MotAB and MotCD. Deletion of the MotCD stator eliminates swarming, whereas deletion of the MotAB stator enhances swarming. Interestingly, we measured a strongly asymmetric stator availability in the wild-type (WT) strain, with MotAB stators produced at an approximately 40-fold higher level than MotCD stators. However, utilization of MotCD stators in free swimming cells requires higher liquid viscosities, while MotAB stators are readily utilized at low viscosities. Importantly, we find that cells with MotCD stators are ~10× more likely to have an active motor compared to cells uses the MotAB stators. The spectrum of motility intermittency can either cooperatively shut down or promote flagellum motility in WT populations. In P. aeruginosa , transition from a static solid-like biofilm to a dynamic liquid-like swarm is not achieved at a single critical value of flagellum torque or stator fraction but is collectively controlled by diverse combinations of flagellum activities and motor intermittencies via dynamic stator utilization. Experimental and computational results indicate that the initiation or arrest of flagellum-driven swarming motility does not occur from individual fitness or motility performance but rather related to concepts from the "jamming transition" in active granular matter.IMPORTANCEIt is now known that there exist multifactorial influences on swarming motility for P. aeruginosa , but it is not clear precisely why stator selection in the flagellum motor is so important. We show differential production and utilization of the stators. Moreover, we find the unanticipated result that the two motor configurations have significantly different motor intermittencies: the fraction of flagellum-active cells in a population on average with MotCD is active ~10× more often than with MotAB. What emerges from this complex landscape of stator utilization and resultant motor output is an intrinsically heterogeneous population of motile cells. We show how consequences of stator recruitment led to swarming motility and how the stators potentially relate to surface sensing circuitry., Competing Interests: The authors declare no conflict of interest.

It is unclear how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to the strong but ineffective inflammatory response that characterizes severe Coronavirus disease 2019 (COVID-19), with amplified immune activation in diverse cell types, including cells without angiotensin-converting enzyme 2 receptors necessary for infection. Proteolytic degradation of SARS-CoV-2 virions is a milestone in host viral clearance, but the impact of remnant viral peptide fragments from high viral loads is not known. Here, we examine the inflammatory capacity of fragmented viral components from the perspective of supramolecular self-organization in the infected host environment. Interestingly, a machine learning analysis to SARS-CoV-2 proteome reveals sequence motifs that mimic host antimicrobial peptides (xenoAMPs), especially highly cationic human cathelicidin LL-37 capable of augmenting inflammation. Such xenoAMPs are strongly enriched in SARS-CoV-2 relative to low-pathogenicity coronaviruses. Moreover, xenoAMPs from SARS-CoV-2 but not low-pathogenicity homologs assemble double-stranded RNA (dsRNA) into nanocrystalline complexes with lattice constants commensurate with the steric size of Toll-like receptor (TLR)-3 and therefore capable of multivalent binding. Such complexes amplify cytokine secretion in diverse uninfected cell types in culture (epithelial cells, endothelial cells, keratinocytes, monocytes, and macrophages), similar to cathelicidin's role in rheumatoid arthritis and lupus. The induced transcriptome matches well with the global gene expression pattern in COVID-19, despite using <0.3% of the viral proteome. Delivery of these complexes to uninfected mice boosts plasma interleukin-6 and CXCL1 levels as observed in COVID-19 patients., Competing Interests: Competing interests statement:The authors declare no competing interest.

Peptide-induced transmembrane pore formation is commonplace in biology. Examples of transmembrane pores include pores formed by antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs) in bacterial membranes and eukaryotic membranes, respectively. In general, however, transmembrane pore formation depends on peptide sequences, lipid compositions, and intensive thermodynamic variables and is difficult to observe directly under realistic solution conditions, with structures that are challenging to measure directly. In contrast, the structure and phase behavior of peptide-lipid systems are relatively straightforward to map out experimentally for a broad range of conditions. Cubic phases are often observed in systems involving pore-forming peptides; however, it is not clear how the structural tendency to induce negative Gaussian curvature (NGC) in such phases is quantitatively related to the geometry of biological pores. Here, we leverage the theory of anisotropic inclusions and devise a facile method to estimate transmembrane pore sizes from geometric parameters of cubic phases measured from small-angle X-ray scattering (SAXS) and show that such estimates compare well with known pore sizes. Moreover, our model suggests that although AMPs can induce stable transmembrane pores for membranes with a broad range of conditions, pores formed by CPPs are highly labile, consistent with atomistic simulations.

Background: Fine particulate matter (PM2.5) and nitrogen dioxide (NO2) measures of ambient air pollution are associated with accelerated age-related cognitive impairment, and Alzheimer's disease and related dementias (ADRD)., Objective: We examined associations between air pollution, four cognitive factors, and the moderating role of apolipoprotein E (APOE) genotype in the understudied period of midlife., Methods: Participants were ∼1,100 men in the Vietnam Era Twin Study of Aging. Baseline cognitive assessments were from 2003 to 2007. Measures included past (1993-1999) and recent (3 years prior to baseline assessment) PM2.5 and NO2 exposure, in-person assessment of episodic memory, executive function, verbal fluency, and processing speed, and APOE genotype. Average baseline age was 56 years with a 12-year follow-up. Analyses adjusted for health and lifestyle covariates., Results: Performance in all cognitive domains declined from age 56 to 68. Higher PM2.5 exposures were associated with worse general verbal fluency. We found significant exposure-by-APOE genotype interactions for specific cognitive domains: PM2.5 with executive function and NO2 with episodic memory. Higher PM2.5 exposure was related to worse executive function in APOE ɛ4 carriers, but not in non-carriers. There were no associations with processing speed., Conclusion: These results indicate negative effects of ambient air pollution exposure on fluency alongside intriguing differential modifications of cognitive performance by APOE genotype. APOE ɛ4 carriers appeared more sensitive to environmental differences. The process by which air pollution and its interaction with genetic risk for ADRD affects risk for later life cognitive decline or progression to dementia may begin in midlife.

Lake Cajititlán is a subtropical and endorheic lake, which is heavily impacted by nutrient pollution. Agricultural runoff and poorly treated wastewater have entered this reservoir at alarming rates during past rainy seasons, causing the cultural eutrophication of this body of water and resulting in several massive fish kill events. In this study, shotgun metagenomic sequencing was used to examine the taxonomic and functional structure of microbial communities in Lake Cajititlán during the rainy season. Several water quality features and their interactions with microbial communities were also assessed to identify the major factors affecting the water quality and biota, specifically fish species. According to current water quality regulations, most of the physicochemical variables analyzed (dissolved oxygen, pH, Secchi disk, NH 4 + , NO 3 - , blue-green algae, total phosphorus, and chlorophyll- a ) were outside of the permissible limits. Planktothrix agardhii and Microcystis aeruginosa were the most abundant phytoplankton species, and the dominant bacterial genera were Pseudomonas , Streptomyces , and Flavobacterium , with Pseudomonas fluorescens , Stenotrophomonas maltophilia , and Aeromonas veronii representing the most abundant bacterial species. All of these microorganisms have been reported to be potentially harmful to fish, and the latter three ( P. fluorescens , S. maltophilia , A. veronii ) also contain genes associated with pathogenicity in fish mortality ( fur , lux S, aer , act , aha , exu , lip , ser ). Genetic evidence from the microbial communities analyzed herein reveals that anthropogenic sources of nutrients in the lake altered genes involved in nitrogen, phosphorus, sulfur, and carbon metabolism, mainly at the beginning of the rainy season. These findings suggest that abiotic factors influence the structure of the microbial communities, along with the major biogeochemical cycles of Lake Cajititlán, resulting in temporal variations and an excess of microorganisms that can thrive in high-nutrient and low-oxygen environments. After reviewing the literature, this appears to be the first study that focuses on characterizing the water quality of a subtropical hypereutrophic lake through associations between physicochemical variables and shotgun metagenomic data. In addition, there are few studies that have coupled the metabolism of aquatic ecosystems with nutrient cycles., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Díaz-Torres, Lugo-Melchor, de Anda, Orozco-Nunnelly, Gradilla-Hernández and Senés-Guerrero.)

Fission protein 1 (FIS1) and dynamin-related protein 1 (DRP1) were initially described as being evolutionarily conserved for mitochondrial fission, yet in humans the role of FIS1 in this process is unclear and disputed by many. In budding yeast where Fis1p helps to recruit the DRP1 ortholog from the cytoplasm to mitochondria for fission, an N-terminal "arm" of Fis1p is required for function. The yeast Fis1p arm interacts intramolecularly with a conserved tetratricopeptide repeat core and governs in vitro interactions with yeast DRP1. In human FIS1, NMR and X-ray structures show different arm conformations, but its importance for human DRP1 recruitment is unknown. Here, we use molecular dynamics simulations and comparisons to experimental NMR chemical shifts to show the human FIS1 arm can adopt an intramolecular conformation akin to that observed with yeast Fis1p. This finding is further supported through intrinsic tryptophan fluorescence and NMR experiments on human FIS1 with and without the arm. Using NMR, we observed the human FIS1 arm is also sensitive to environmental changes. We reveal the importance of these findings in cellular studies where removal of the FIS1 arm reduces DRP1 recruitment and mitochondrial fission similar to the yeast system. Moreover, we determined that expression of mitophagy adapter TBC1D15 can partially rescue arm-less FIS1 in a manner reminiscent of expression of the adapter Mdv1p in yeast. These findings point to conserved features of FIS1 important for its activity in mitochondrial morphology. More generally, other tetratricopeptide repeat-containing proteins are flanked by disordered arms/tails, suggesting possible common regulatory mechanisms., Competing Interests: Conflict of interest R. B. H. and K. A. N. have financial interest in Cytegen, a company developing therapies to improve mitochondrial function. However, neither the research described herein was supported by Cytegen nor was in collaboration with the company. The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Deposition of human amyloids is associated with complex human diseases such as Alzheimer's and Parkinson's. Amyloid proteins are also produced by bacteria. The bacterial amyloid curli, found in the extracellular matrix of both commensal and pathogenic enteric bacterial biofilms, forms complexes with extracellular DNA, and recognition of these complexes by the host immune system may initiate an autoimmune response. Here, we isolated early intermediate, intermediate, and mature curli fibrils that form throughout the biofilm development and investigated the structural and pathogenic properties of each. Early intermediate aggregates were smaller than intermediate and mature curli fibrils, and circular dichroism, tryptophan, and thioflavin T analyses confirmed the establishment of a beta-sheet secondary structure as the curli conformations matured. Intermediate and mature curli fibrils were more immune stimulatory than early intermediate fibrils in vitro. The intermediate curli was cytotoxic to macrophages independent of Toll-like receptor 2. Mature curli fibrils had the highest DNA content and induced the highest levels of Isg15 expression and TNFα production in macrophages. In mice, mature curli fibrils induced the highest levels of anti-double-stranded DNA autoantibodies. The levels of autoantibodies were higher in autoimmune-prone NZBWxF/1 mice than wild-type C57BL/6 mice. Chronic exposure to all curli forms led to significant histopathological changes and synovial proliferation in the joints of autoimmune-prone mice; mature curli was the most detrimental. In conclusion, curli fibrils, generated during biofilm formation, cause pathogenic autoimmune responses that are stronger when curli complexes contain higher levels of DNA and in mice predisposed to autoimmunity., Competing Interests: The authors have declared that no competing interests exist.