Miracle-dz/UniFAR-FTUs huggingface dataset:
The outer membrane and peptidoglycan layer form a single mechanical device balancing turgor

Bacteria are subject to a substantial concentration differential of osmolytes between the interior and exterior of the cell, which results in cytoplasmic turgor pressure. Failure to mechanically balance turgor pressure causes cells to burst. Here, we show that in Gram-negative bacteria, the outer membrane and peptidoglycan layer function together to resist turgor: when attached to each other, these two layers form a robust mechanical unit that allows pressure build-up in the periplasmic compartment, which in turn balances cytoplasmic turgor across the inner membrane, preventing cell death. Thus, the peptidoglycan layer is necessary but not sufficient to maintain turgor, which challenges the general view that protecting cells from bursting is the specific task of the peptidoglycan cell wall. ONE-SENTENCE SUMMARY The peptidoglycan and outer membrane are interconnected layers that cooperate to balance cytoplasmic turgor.
Synchronous high-amplitude co-fluctuations of functional brain networks during movie-watching

Recent studies have shown that functional connectivity can be decomposed into its exact framewise contributions, revealing short-lived, infrequent, and high-amplitude time points referred to as “events. ” Events contribute disproportionately to the time-averaged connectivity pattern, improve identifiability and brain-behavior associations, and differences in their expression have been linked to endogenous hormonal fluctuations and autism. Here, we explore the characteristics of events while subjects watch movies. Using two independently-acquired imaging datasets in which participants passively watched movies, we find that events synchronize across individuals and based on the level of synchronization, can be categorized into three distinct classes: those that synchronize at the boundaries between movies, those that synchronize during movies, and those that do not synchronize at all. We find that boundary events, compared to the other categories, exhibit greater amplitude, distinct co-fluctuation patterns, and temporal propagation. We show that underlying boundary events is a specific mode of co-fluctuation involving the activation of control and salience systems alongside the deactivation of visual systems. Events that synchronize during the movie, on the other hand, display a pattern of co-fluctuation that is time-locked to the movie stimulus. Finally, we found that subjects’ time-varying brain networks are most similar to one another during these synchronous events.
SIV clearance from neonatal macaques following transient CCR5 depletion

Treatment of people with HIV (PWH) with antiretroviral therapy (ART) results in sustained suppression of viremia, but HIV persists indefinitely as integrated provirus in CD4-expressing cells. Intact persistent provirus, the “rebound competent viral reservoir” (RCVR), is the primary obstacle to achieving a cure. Most variants of HIV enter CD4+ T cells by binding to the chemokine receptor, CCR5. The RCVR has been successfully depleted only in a handful of PWH following cytotoxic chemotherapy and bone marrow transplantation from donors with a mutation in CCR5. Here we show that long-term SIV remission and apparent cure can be achieved for infant macaques via targeted depletion of potential reservoir cells that express CCR5. Neonatal rhesus macaques were infected with virulent SIVmac251, then treated with ART beginning one week after infection, followed by treatment with either a CCR5/CD3-bispecific or a CD4-specific antibody, both of which depleted target cells and increased the rate of plasma viremia decrease. Upon subsequent cessation of ART, three of seven animals treated with CCR5/CD3-bispecific antibody rebounded quickly and two rebounded 3 or 6 months later. Remarkably, the other two animals remained aviremic and efforts to detect replication-competent virus were unsuccessful. Our results show that bispecific antibody treatment can achieve meaningful SIV reservoir depletion and suggest that functional HIV cure might be achievable for recently infected individuals having a restricted reservoir.
Differentiation of Large Extracellular Vesicles in Oral Fluid: Combined Protocol of Small Force Centrifugation and Pattern Analysis

Extracellular vesicles (EVs) in biofluids are highly heterogeneous entities in terms of their origins and physicochemical properties. Considering the application of EVs in diagnostic and therapeutic fields, it is of extreme importance to establish differentiating methods by which focused EV subclasses are operationally defined. Several differentiation protocols have been proposed; however, they have mainly focused on smaller types of EVs, and the heterogeneous nature of large EVs has not yet been fully explored. In this report, to classify large EVs into subgroups based on their physicochemical properties, we have developed a protocol, named EV differentiation by sedimentation patterns (ESP), in which entities in the crude large EV fraction are first moved through a density gradient of iodixanol with small centrifugation forces, and then the migration patterns of molecules through the gradients are analyzed using a non-hierarchical data clustering algorithm. Based on this method, proteins in the large EV fractions of oral fluids clustered into three groups: proteins shared with small EV cargos and enriched in immuno-related proteins (Group 1), proteins involved in energy metabolism and protein synthesis (Group 2), and proteins required for vesicle trafficking (Group 3). These observations indicate that the physiochemical properties of EVs, which are defined through low-speed gradient centrifugation, are well associated with their functions within cells. This protocol enables the detailed subclassification of EV populations that are difficult to differentiate using conventional separation methods.
Actin- and microtubule-based motors contribute to clathrin-independent endocytosis in yeast

Most eukaryotic cells utilize clathrin-mediated endocytosis as well as multiple clathrin-independent pathways to internalize proteins and membranes. Although clathrin-mediated endocytosis has been studied extensively and many machinery proteins have been identified, clathrin-independent pathways remain poorly characterized by comparison. We previously identified the first known yeast clathrin-independent endocytic pathway, which relies on the actin-modulating GTPase Rho1, the formin Bni1 and unbranched actin filaments, but does not require the clathrin coat or core clathrin machinery proteins. In this study, we sought to better understand clathrin-independent endocytosis in yeast by exploring the role of myosins as actin-based motors, since actin is required for endocytosis in yeast. We find that Myo2, which transports secretory vesicles, organelles and microtubules along actin cables to sites of polarized growth, participates in clathrin-independent endocytosis. Unexpectedly, the ability of Myo2 to transport microtubule plus ends to the cell cortex appears to be required for its role in clathrin-independent endocytosis. In addition, dynein, dynactin and proteins involved in cortical microtubule capture are also required. Thus, our results suggest that interplay between actin and microtubules contributes to clathrin-independent internalization in yeast. Summary Statement Clathrin-independent endocytosis is a poorly-understood but conserved process. Here, we provide evidence of a role for myosin and dynein as motor proteins involved the yeast clathrin-independent pathway.
Alveolar repair following LPS-induced injury requires cell-ECM interactions

During alveolar repair, alveolar type 2 (AT2) epithelial cell progenitors rapidly proliferate and differentiate into flat type 1 alveolar epithelial cells. Failure of normal alveolar repair mechanisms can lead to loss of alveolar structure (emphysema) or development of fibrosis, depending on the type and severity of injury. To test if β1-containing integrins are required during repair following acute injury, we administered E. coli lipopolysaccharide (LPS) by intratracheal injection to mice with a post-developmental deletion of β1 integrin in AT2 cells. While control mice recovered from LPS injury without structural abnormalities, β1-deficient mice had more severe inflammation and developed emphysema. In addition, recovering alveoli were repopulated with an abundance of rounded epithelial cells co-expressing type 2, type 1, and mixed intermediate cell state markers, with few mature type 1 cells. β1-deficient AT2 cells showed persistently increased proliferation after injury, which was blocked by inhibiting NF-κB activation in these cells. Lineage tracing experiments revealed that β1-deficient AT2 cells failed to differentiate into mature type 1 alveolar epithelial cells. Together, these findings demonstrate that functional alveolar repair after injury with terminal alveolar epithelial differentiation requires β1-containing integrins.
Minimum forebody drag in hypersonic continuum and rarefied flows

Abstract Minimum drag shapes of given length and base area are investigated for hypersonic flow using both Newtonian impact theory and free molecular flow theory. The drag of Newton’s minimum drag body, which has previously been evaluated by numerical means, is derived as an analytic expression. The analytical results are applicable to a range of local pressure laws allowing minimum drag shapes obtained using impact theory to be directly compared with low density flow equivalents using free molecular flow. The low density shapes are found to have larger blunt regions at the nose and significantly larger drag coefficients. For free molecular flow the drag varies with the surface reflection characteristics. As the fraction of diffuse reflection at the surface increases, the drag increases and the sensitivity of the drag to changes in the minimum drag shape is reduced.
The transcriptional control of the VEGFA-VEGFR1 (FLT1) axis in alternatively polarized murine and human macrophages

Introduction Macrophages significantly contribute to the regulation of vessel formation under physiological and pathological conditions. Although the angiogenesis-regulating role of alternatively polarized macrophages is quite controversial, a growing number of evidence shows that they can participate in the later phases of angiogenesis, including vessel sprouting and remodeling or regression. However, the epigenetic and transcriptional regulatory mechanisms controlling this angiogenesis-modulating program are not fully understood. Results Here we show that IL-4 can coordinately regulate the VEGFA-VEGFR1 (FLT1) axis via simultaneously inhibiting the proangiogenic Vegfa and inducing the antiangiogenic Flt1 expression in murine bone marrow-derived macrophages, which leads to the attenuated proangiogenic activity of alternatively polarized macrophages. The IL-4-activated STAT6 and IL-4-STAT6 signaling pathway-induced EGR2 transcription factors play a direct role in the transcriptional regulation of the Vegfa-Flt1 axis. We demonstrated that this phenomenon is not restricted to the murine bone marrow-derived macrophages, but can also be observed in different murine tissue-resident macrophages ex vivo and parasites-elicited macrophages in vivo with minor cell type-specific differences. Furthermore, IL-4 exposure can modulate the hypoxic response of genes in both murine and human macrophages leading to a blunted Vegfa/VEGFA and synergistically induced Flt1/FLT1 expression. Discussion Our findings establish that the IL-4-activated epigenetic and transcriptional program can determine angiogenesis-regulating properties in alternatively polarized macrophages under normoxic and hypoxic conditions.
The protective role of Lactobacillus rhamnosus GG postbiotic on the alteration of autophagy and inflammation pathways induced by gliadin in intestinal models

Celiac disease (CD) is an autoimmune enteropathy caused by an abnormal immune response to gliadin peptides in genetically predisposed individuals. For people with CD, the only available therapy thus far is the lifelong necessity for a gluten-free diet (GFD). Innovative therapies include probiotics and postbiotics as dietary supplements, both of which may benefit the host. Therefore, the present study aimed to investigate the possible beneficial effects of the postbiotic Lactobacillus rhamnosus GG (LGG) in preventing the effects induced by indigested gliadin peptides on the intestinal epithelium. In this study, these effects on the mTOR pathway, autophagic function, and inflammation have been evaluated. Furthermore, in this study, we stimulated the Caco-2 cells with the undigested gliadin peptide (P31-43) and with the crude gliadin peptic-tryptic peptides (PTG) and pretreated the samples with LGG postbiotics (ATCC 53103) (1 × 108). In this study, the effects induced by gliadin before and after pretreatment have also been investigated. The phosphorylation levels of mTOR, p70S6K, and p4EBP-1 were increased after treatment with PTG and P31-43, indicating that the intestinal epithelial cells responded to the gliadin peptides by activating the mTOR pathway. Moreover, in this study, an increase in the phosphorylation of NF-κβ was observed. Pretreatment with LGG postbiotic prevented both the activation of the mTOR pathway and the NF-κβ phosphorylation. In addition, P31-43 reduced LC3II staining, and the postbiotic treatment was able to prevent this reduction. Subsequently, to evaluate the inflammation in a more complex intestinal model, the intestinal organoids derived from celiac disease patient biopsies (GCD-CD) and controls (CTR) were cultured. Stimulation with peptide 31-43 in the CD intestinal organoids induced NF-κβ activation, and pretreatment with LGG postbiotic could prevent it. These data showed that the LGG postbiotic can prevent the P31-43-mediated increase in inflammation in both Caco-2 cells and in intestinal organoids derived from CD patients.
Alzheimer's disease pathology: pathways between chronic vascular risk factors and blood-brain barrier dysfunction in a cohort of patients with different types of dementia

Background Blood brain barrier (BBB) breakdown is considered a potential mechanism of dementia. The Alzheimer's disease (AD) biomarkers and vascular factors are also associated with BBB permeability. Objective In the present study, the combination effects of neuropathological biomarkers of AD and chronic vascular risk factors for BBB were investigated. Methods The cerebrospinal fluid (CSF)/serum albumin ratio (Qalb), an indicator of BBB permeability, was measured in a total of 95 hospitalized dementia patients. The demographics, clinical information, and laboratory tests were collected from the inpatient records. The CSF neuropathological biomarkers of AD and apolipoprotein E (APOE) genotype were also collected. The mediation analysis model was used to calculate the associations among neuropathological biomarkers of AD (mediator), the Qalb, and chronic vascular risk factors. Results Three types of dementia, AD (n = 52), Lewy body dementia (LBD, n = 19), and frontotemporal lobar degeneration (n = 24), were included with a mean Qalb of 7.18 (± 4.36). The Qalb was significantly higher in dementia patients with type 2 diabetes mellitus (T2DM, p = 0.004) but did not differ based on the presence of APOE ε4 allele, CMBs, or amyloid/tau/neurodegeneration (ATN) framework. The Qalb was negatively associated with the levels of Aβ1-42 (B = −20.775, p = 0.009) and Aβ1-40 (B = −305.417, p = 0.005) and positively associated with the presence of T2DM (B = 3.382, p < 0.001) and the levels of glycosylated hemoglobin (GHb, B = 1.163, p < 0.001) and fasting blood glucose (FBG, B = 1.443, p < 0.001). GHb is a direct chronic vascular risk factor for higher Qalb (total effect B = 1.135, 95% CI: 0.611–1.659, p < 0.001). Ratios of Aβ1-42/Aβ1-40 or t-tau/Aβ1-42 were mediators of the association between the Qalb and GHb; the direct effect of GHb on the Qalb was 1.178 (95% CI: 0.662–1.694, p < 0.001). Conclusion Glucose exposure can directly or indirectly affect BBB integrity through Aβ and tau, indicating glucose affects BBB breakdown and glucose stability plays an important role in dementia protection and management.
Loud noise-exposure changes the firing frequency of subtypes of layer 5 pyramidal neurons and Martinotti cells in the mouse auditory cortex

Introduction Loud noise-exposure can generate noise-induced tinnitus in both humans and animals. Imaging and in vivo studies show that noise exposure affects the auditory cortex; however, cellular mechanisms of tinnitus generation are unclear. Methods Here we compare membrane properties of layer 5 (L5) pyramidal cells (PCs) and Martinotti cells expressing the cholinergic receptor nicotinic alpha 2 subunit gene (Chrna2) of the primary auditory cortex (A1) from control and noise-exposed (4–18 kHz, 90 dB, 1.5 h, followed by 1.5 h silence) 5–8 week old mice. PCs were furthermore classified in type A or type B based on electrophysiological membrane properties, and a logistic regression model predicting that afterhyperpolarization (AHP) and afterdepolarization (ADP) are sufficient to predict cell type, and these features are preserved after noise trauma. Results One week after a loud noise-exposure no passive membrane properties of type A or B PCs were altered but principal component analysis showed greater separation between type A PCs from control and noise-exposed mice. When comparing individual firing properties, noise exposure differentially affected type A and B PC firing frequency in response to depolarizing current steps. Specifically, type A PCs decreased initial firing frequency in response to +200 pA steps (p = 0.020) as well as decreased steady state firing frequency (p = 0.050) while type B PCs, on the contrary, significantly increased steady state firing frequency (p = 0.048) in response to a + 150 pA step 1 week after noise exposure. In addition, L5 Martinotti cells showed a more hyperpolarized resting membrane potential (p = 0.04), higher rheobase (p = 0.008) and an increased initial (p = 8.5 × 10–5) and steady state firing frequency (p = 6.3 × 10–5) in slices from noise-exposed mice compared to control. Discussion These results show that loud noise can cause distinct effects on type A and B L5 PCs and inhibitory Martinotti cells of the primary auditory cortex 1 week following noise exposure. As the L5 comprises PCs that send feedback to other areas, loud noise exposure appears to alter levels of activity of the descending and contralateral auditory system.
How do epiphytic and surrounding seawater bacterial communities shift with the development of the Saccharina japonica farmed in the Northern China?

Epibacteria of seaweeds play an important role for the development of hosts and are influenced by the planktonic surrounding seawater bacteria. However, to date, the knowledges related to both epiphytic and surrounding seawater bacterial communities associated with northern farmed Saccharina japonica are very limited. In this study, using 16S rRNA gene amplicon sequencing, the shifts of epiphytic and surrounding seawater bacterial communities of the northern farmed S. japonica from mature sporophytes, sporelings (3 time points) to juvenile sporophytes (2 time points) were investigated. The dominant genera of epibacterial communities were Alcanivorax (mature sporophytes and 4-week-old sporelings), Bacillus (7-week-old sporelings and 9-week-old sporelings), Halomonas (4-week-old juvenile sporophytes) and Cobetia (9-week-old juvenile sporophytes). Meanwhile, the Chao1 indexes and beta diversity of epibacterial communities were significantly different with the development of S. japonica (p < 0.05). Furthermore, Alcanivorax, Bacillus and Halomonas were both dominant and core genera, indicating that these taxa may be beneficial to the development of S. japonica. The alpha diversity indexes of both epiphytic and surrounding seawater bacterial communities were significantly different for 9-week-old juvenile sporophytes. Therefore, the epibacterial communities were influenced by both development of S. japonica and the surrounding seawater bacterial communities. This study not only extends the understanding of the bacterial communities associated with the northern farmed S. japonica, but also help to make production management by monitoring the variations in both epiphytic and surrounding seawater bacterial communities.
Numerical Methods for Large Sparse Linear Least Squares Problems

Large sparse least squares problems arise in many applications, including geodetic network adjustments and finite element structural analysis. Although geodesists and engineers have been solving such problems for years, it is only relatively recently that numerical analysts have turned attention to them. In this paper we present a survey of numerical methods for large sparse linear least squares problems, focusing mainly on developments since the last comprehensive surveys of the subject published in 1976. We consider direct methods based on elimination and on orthogonalization, as well as various iterative methods. The ramifications of rank deficiency, constraints, and updating are also discussed.
Echocardiographic analysis of dogs before and after surgical treatment of brachycephalic obstructive airway syndrome

Brachycephalic dogs with brachycephalic obstructive airway syndrome (BOAS) are a valuable animal model for obstructive sleep apnea (OSA) in humans. Clinical signs of upper airway obstruction improve after surgical treatment of BOAS, but the impact of surgery on morphology and function of the heart has not been studied. Therefore, we aimed to compare the echocardiographic variables of dogs before and after surgical treatment of BOAS. We included 18 client-owned dogs with BOAS (7 French Bulldogs, 6 Boston Terriers, and 5 Pugs) scheduled for surgical correction. We performed a complete echocardiographic examination before and 6 to 12 (median 9) months after surgery. Seven non-brachycephalic dogs were included in the control group. After surgery, BOAS patients had a significantly (p < 0.05) larger left atrium to aortic ratio (LA/Ao), left atrium in the long axis index, and thickness of the left ventricular posterior wall in diastole index. They also had a higher late diastolic annular velocity of the interventricular septum (Am) and increased global right ventricular strain and left ventricular global strain in the apical 4-chamber view, as well as a higher caudal vena cava collapsibility index (CVCCI). Before surgery, BOAS patients had a significantly lower CVCCI, Am, peak systolic annular velocity of the interventricular septum (Si), and early diastolic annular velocity of the interventricular septum (Ei) compared to non-brachycephalic dogs. After surgery, BOAS patients had a smaller right ventricular internal diameter at base index, right ventricular area in systole index, mitral annular plane systolic excursion index, and tricuspid annular plane systolic excursion index, as well as lower values of Am, Si, Ei, and late diastolic annular velocity of the interventricular septum, and a larger LA/Ao compared to non-brachycephalic dogs. Significant differences between BOAS patients and non-brachycephalic dogs indicate higher right heart pressures and decreased systolic and diastolic ventricular function in BOAS dogs, which is in accordance with the results of studies in OSA patients. In parallel with the marked clinical improvement, right heart pressures decreased, and right ventricular systolic and diastolic function improved after surgery.