Chronic obstructive pulmonary disease related to wood smoke and impact of the combined exposure to tobacco.

BACKGROUND: Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2023 highlights the need to explore aetiotypes of chronic obstructive pulmonary disease (COPD) beyond the tobacco-smoking COPD. Exposure to wood smoke (WS) is a risk factor for COPD in women, but the effect of the combined exposure to tobacco smoke (TS) in the general population and among COPD patients, and the characteristics of WS-COPD are unclear. METHOD: This was an analysis of data from PREPOCOL (Prevalence of COPD in Five Colombian Cities Situated at Low, Medium, and High Altitude), a random cross-sectional population-based study (n = 5,539) focusing on the effect of combined WS and TS exposure and WS-COPD characterisation. RESULTS: Prevalence of COPD was significantly higher in those exposed to both WS and TS (16.0%) than in those exposed to WS (6.7%) or TS (7.8%) only (P < 0.001). Exposure to WS was associated with COPD in men (OR 1.53, P = 0.017). WS-COPD individuals were more frequently female, older, shorter and had higher forced expiratory volume in 1 sec (FEV1) (all P < 0.05). Those exposed to both WS and TS had more symptoms and worse airflow limitation (P < 0.001). CONCLUSIONS: This was the first random population-based study showing that WS is an associated risk factor for COPD also in men, and that people exposed to both WS and TS have a significantly higher prevalence of COPD. Similarly, COPD subjects exposed to both types of smoke have more symptoms and greater airflow obstruction. This suggests an additive effect of WS and TS.

CONTEXTE: L'Initiative mondiale pour les maladies pulmonaires obstructives chroniques (Global Initiative for Chronic Obstructive Lung Disease, GOLD) 2023 met en évidence l'importance d'explorer les différents étiotypes de la maladie pulmonaire obstructive chronique (COPD, pour l'anglais « chronic obstructive pulmonary disease ¼) en dehors de la COPD liée au tabagisme. L'exposition à la fumée de bois (WS, pour l'anglais « wood smoke ¼) représente un facteur de risque de la COPD chez les femmes, cependant, l'impact de l'exposition simultanée à la fumée de tabac (TS, pour l'anglais « tobacco smoke ¼) chez la population générale et chez les patients atteints de COPD, ainsi que les caractéristiques spécifiques de la WS-COPD, demeurent peu clairs. MÉTHODES: Il s'agit d'une étude transversale aléatoire basée sur la population (n = 5 539) qui analyse les données de PREPOCOL (Prevalence of COPD in Five Colombian Cities Situated at Low, Medium, and High Altitude). L'étude se concentre sur l'effet de l'exposition combinée à la WS et à la TS ainsi que sur la caractérisation de la WS-COPD. RÉSULTATS: La prévalence de la COPD était significativement plus élevée chez les personnes exposées à la fois à la WS et à la TS (16,0%) que chez celles exposées uniquement à la WS (6,7%) ou à la TS (7,8%) (P < 0,001). L'exposition à la WS était associée à la COPD chez les hommes (OR 1,53 ; P = 0,017). Les personnes atteintes de WS-COPD étaient plus fréquemment des femmes, d'un âge plus avancé, de plus petite taille et présentaient un volume expiratoire maximal en 1 seconde (FEV1) plus élevé (tous P < 0,05). Les personnes exposées à la fois à la WS et à la TS ont montré plus de symptômes et une plus grande limitation du débit d'air (P < 0,001). CONCLUSION: Il s'agit de la première étude aléatoire basée sur la population qui démontre que la WS est un facteur de risque lié à la COPD, même chez les hommes, et que les individus exposés à la fois à la WS et à la TS présentent une prévalence significativement plus élevée de la COPD. De plus, les personnes souffrant de COPD qui sont exposés aux deux types de fumée manifestent davantage de symptômes et une obstruction pulmonaire plus sévère. Cela laisse supposer qu'il y a un effet cumulatif de la WS et de la TS.

Retroperitoneum revisited: a review of radiological literature and updated concept of retroperitoneal fascial anatomy with imaging features and correlating anatomy.

PURPOSE: Spread of disease in the retroperitoneum is dictated by the complex anatomy of retroperitoneal fasciae and is still incompletely understood. Conflicting reports have led to insufficient and incorrect anatomical concepts in radiological literature. METHODS: This review will discuss previous concepts prevalent in radiological literature and their shortcomings will be highlighted. New insights from recent anatomical and embryological research, together with imaging examples, will be used to clarify patterns of disease spread in the retroperitoneum that remain unexplained by these concepts. RESULTS: The fusion fascia and the renal fascia in particular give rise to planes and spaces that act as vectors for spread of disease in the retroperitoneum. Some of these planes and structures, such as the caudal extension of the renal fascia, have previously not been described in radiological literature. CONCLUSION: New insights, including the various fasciae, potential spaces and planes, are incorporated into an updated combined retroperitoneal fascial concept.

Comparison of recovery of sheep, goats, and calves from reversible electrical head-only and head-to-body stunning for halal meat production.

AIMS: To compare the recovery of lambs, goats, and calves from head-only (HO) or high-frequency head-to-body stunning and evaluate the complementary use of behaviour and electroencephalography (EEG) to assess return to consciousness after electrical stunning in these species. METHODS: Six-month-old lambs, adult goats and calves (< 7 days old) were subjected to reversible head-only stunning (50 Hz, 1 A, 2 seconds) or reversible high-frequency head-to-body stunning (RHTB: HO followed by 2,000 Hz, 2 A, 4-second stun to body). Following stunning, behavioural recovery was assessed in 21 lambs, 22 goats, and 20 calves. Latencies to first perform behaviours (end of convulsions, head lift, attempt to right, successful righting, attempt to stand, successful standing) after stunning were scored from video recordings. Recovery of electrical brain activity indicative of consciousness was assessed using EEG in a separate cohort of minimally-anaesthetised lambs, goats and calves (n = 20 per species). EEG traces collected before and after stunning were classified as normal, epileptiform, isoelectric, or transitional activity. Following stunning, the duration of epileptiform and isoelectric activity combined (states of brain activity incompatible with conscious awareness) was calculated, as was latency to return of normal (pre-stun) EEG. RESULTS: The RHTB stun was reversible in all three species, although one sheep failed to recover and was euthanised. Both methods caused tonic and clonic convulsions in all species. Behavioural recovery of sheep and calves was similar for both methods while goats took longer to recover from RHTB than HO stunning. There was no evidence of differences between methods in the duration of EEG incompatible with consciousness or the latency to recovery of normal EEG. CONCLUSIONS: Head-to-body stunning as applied here produced a reversible electrical stun in lambs, adult goats and young calves, although the benefits in terms of meat quality and operator safety are uncertain. Goats took longer to recover behaviourally from head-to-body stunning, possibly due to disrupted motor function, but there was no indication that post-stun unconsciousness lasted longer than following head-only stunning in any species. The normal behaviour for the animals' developmental age should be considered when deciding on behavioural indicators of recovery. The minimal anaesthesia model provided excellent quality EEG data that was valuable for interpretation of the behavioural responses. CLINICAL RELEVANCE: For the purposes of pre-slaughter stunning of sheep, goats and young calves, recovery appears comparable between the two methods, with all but 1/63 animals in the behaviour study recovering normal function.

Spatial colocalization and combined survival benefit of natural killer and CD8 T cells despite profound MHC class I loss in non-small cell lung cancer.

Background: MHC class I (MHC-I) loss is frequent in non-small cell lung cancer (NSCLC) rendering tumor cells resistant to T cell lysis. NK cells kill MHC-I-deficient tumor cells, and although previous work indicated their presence at NSCLC margins, they were functionally impaired. Within, we evaluated whether NK cell and CD8 T cell infiltration and activation vary with MHC-I expression. Methods: We used single-stain immunohistochemistry (IHC) and Kaplan-Meier analysis to test the effect of NK cell and CD8 T cell infiltration on overall and disease-free survival. To delineate immune covariates of MHC-I-disparate lung cancers, we used multiplexed immunofluorescence (mIF) imaging followed by multivariate statistical modeling. To identify differences in infiltration and intercellular communication between IFNγ-activated and non-activated lymphocytes, we developed a computational pipeline to enumerate single cell neighborhoods from mIF images followed by multivariate discriminant analysis. Results: Spatial quantitation of tumor cell MHC-I expression revealed intra- and inter-tumoral heterogeneity, which was associated with the local lymphocyte landscape. IHC analysis revealed that high CD56 + cell numbers in patient tumors were positively associated with disease-free survival (DFS) (HR=0.58, p =0.064) and over-all survival (OS) (HR=0.496, p =0.041). The OS association strengthened with high counts of both CD56 + and CD8 + cells (HR=0.199, p <1×10 -3 ). mIF imaging and multivariate discriminant analysis revealed enrichment of both CD3 + CD8 + T cells and CD3 - CD56 + NK cells in MHC-I-bearing tumors (p<0.05). To infer associations of functional cell states and local cell-cell communication, we analyzed spatial single cell neighborhood profiles to delineate the cellular environments of IFNγ +/- NK cells and T cells. We discovered that both IFNγ + NK and CD8 T cells were more frequently associated with other IFNγ + lymphocytes in comparison to IFNγ - NK cells and CD8 T cells (p<1×10 -30 ). Moreover, IFNγ + lymphocytes were most often found clustered near MHC-I + tumor cells. Conclusions: Tumor-infiltrating NK cells and CD8 T cells jointly affected control of NSCLC tumor progression. Co-association of NK and CD8 T cells was most evident in MHC-I-bearing tumors, especially in the presence of IFNγ. Frequent co-localization of IFNγ + NK cells with other IFNγ + lymphocytes in near-neighbor analysis suggests NSCLC lymphocyte activation is coordinately regulated. What is already known on this topic: MHC-I loss occurs frequently in NSCLC and corresponds with waning immunity in the tumor microenvironment (TME). NK cells recognize "missing-self" targets and could be leveraged to target NSCLC tumors with MHC-I loss. While NK cell presence at tumor margins has been documented in NSCLC, they were shown to lose function in this environment. What this study adds: We developed spatial analysis pipelines leveraging the local heterogeneity of the TME at single cell resolution to test whether NK cells and T cells together contribute antitumoral immunity in NSCLC. We discovered that a high density of tumor-infiltrating NK cells corresponded with DFS, and this association was increased in patients with high coincident CD8 T cells, especially those in central tumor. Intriguingly, both cell types were found clustered together in MHC-I-bearing tumors, especially when both expressed IFNγ, suggesting coordinated lymphocyte activities may enhance immune control of NSCLC. How this study might affect research practice or policy: This study provides a rationale for developing novel immunotherapies that simultaneously increase NK and T cell anti-tumoral immunity. Associations linking NK cells with patient survival and increased immune effector activity in NSCLC, even in MHC-I-deficient tumors, further highlights the need to devise and deploy NK cell activating strategies which may be highly efficacious in CD8 T cell refractory NSCLC.

Glutathione-Based Photoaffinity Probe Identifies Caffeine as a Positive Allosteric Modulator of the Calcium-Sensing Receptor.

The calcium-sensing receptor (CaSR), abundantly expressed in the parathyroid gland and kidney, plays a central role in calcium homeostasis. In addition, CaSR exerts multimodal roles, including inflammation, muscle contraction, and bone remodeling, in other organs and tissues. The diverse functions of CaSR are mediated by many endogenous and exogenous ligands, including calcium, amino acids, glutathione, cinacalcet, and etelcalcetide, that have distinct binding sites in CaSR. However, strategies to evaluate ligand interactions with CaSR remain limited. Here, we developed a glutathione-based photoaffinity probe, DAZ-G, that analyzes ligand binding to CaSR. We showed that DAZ-G binds to the amino acid binding site in CaSR and acts as a positive allosteric modulator of CaSR. Oxidized and reduced glutathione and phenylalanine effectively compete with DAZ-G conjugation to CaSR, while calcium, cinacalcet, and etelcalcetide have cooperative effects. An unexpected finding was that caffeine effectively competes with DAZ-G's conjugation to CaSR and acts as a positive allosteric modulator of CaSR. The effective concentration of caffeine for CaSR activation (<10 µM) is easily attainable in plasma by ordinary caffeine consumption. Our report demonstrates the utility of a new chemical probe for CaSR and discovers a new protein target of caffeine, suggesting that caffeine consumption can modulate the diverse functions of CaSR.

Indications and Outcomes of Emergency Keratoplasty in a Major New Zealand Eye Tertiary Referral Center, 2000 to 2021.

PURPOSE: To report the indications and outcomes of emergency keratoplasty over a 21-year period in Greenlane Clinical Centre, the major tertiary eye referral center in Auckland, New Zealand (Aotearoa). METHODS: A retrospective review of medical records of all emergency keratoplasties performed in Greenlane Clinical Centre from January 2000 to September 2021 was conducted. Demographic, preoperative, intraoperative, and 1-year postoperative data were collected. RESULTS: Emergency keratoplasty was performed in 102 eyes of 97 patients (54 men), comprising 5.6% of transplants performed (N = 1830) in this period. The mean age was 53 years (range = 4-95 years, SD = 20). Patients of Maori ethnicity were overrepresented (31%). Corneal perforation was present in 90% of eyes, and microbial keratitis was the most common indication. Bacteria were the most commonly isolated organisms (38%). The mean preoperative and 12-month postoperative best potential corrected distance visual acuity was 1.6 and 1.2 (logMAR), respectively. All cases of therapeutic keratoplasty achieved initial therapeutic success, with no eyes lost or requiring repeat emergency keratoplasty. Complications included nonhealing epithelial defects (19%), cataract (19%), glaucoma (15%), allograft rejection (13%), and corneal melting (5%). Fifteen cases (15%) had documented graft failure at 12 months. Multivariate analysis revealed that younger age was the only statistically significant factor associated with failure at 12 months. CONCLUSIONS: Emergency keratoplasty was the indication for 5.6% of keratoplasties performed. Our results compare favorably with those in the literature, possibly because of early intervention and lower incidence of fungal keratitis. The reported overrepresentation of Maori has important implications for health access and delivery in New Zealand.

Search for Periodic Time Variations of the Solar

We report a search for time variations of the solar ^{8}B neutrino flux using 5804 live days of Super-Kamiokande data collected between May 31, 1996, and May 30, 2018. Super-Kamiokande measured the precise time of each solar neutrino interaction over 22 calendar years to search for solar neutrino flux modulations with unprecedented precision. Periodic modulations are searched for in a dataset comprising five-day interval solar neutrino flux measurements with a maximum likelihood method. We also applied the Lomb-Scargle method to this dataset to compare it with previous reports. The only significant modulation found is due to the elliptic orbit of the Earth around the Sun. The observed modulation is consistent with astronomical data: we measured an eccentricity of (1.53±0.35)%, and a perihelion shift of (-1.5±13.5) days.

Bioinformatic Prediction and High Throughput In Vivo Screening to Identify Cis-Regulatory Elements for the Development of Algal Synthetic Promoters.

Algae biotechnology holds immense promise for revolutionizing the bioeconomy through the sustainable and scalable production of various bioproducts. However, their development has been hindered by the lack of advanced genetic tools. This study introduces a synthetic biology approach to develop such tools, focusing on the construction and testing of synthetic promoters. By analyzing conserved DNA motifs within the promoter regions of highly expressed genes across six different algal species, we identified cis-regulatory elements (CREs) associated with high transcriptional activity. Combining the algorithms POWRS, STREME, and PhyloGibbs, we predicted 1511 CREs and inserted them into a minimal synthetic promoter sequence in 1, 2, or 3 copies, resulting in 4533 distinct synthetic promoters. These promoters were evaluated in vivo for their capacity to drive the expression of a transgene in a high-throughput manner through next-generation sequencing post antibiotic selection and fluorescence-activated cell sorting. To validate our approach, we sequenced hundreds of transgenic lines showing high levels of GFP expression. Further, we individually tested 14 identified promoters, revealing substantial increases in GFP expression─up to nine times higher than the baseline synthetic promoter, with five matching or even surpassing the performance of the native AR1 promoter. As a result of this study, we identified a catalog of CREs that can now be used to build superior synthetic algal promoters. More importantly, here we present a validated pipeline to generate building blocks for innovative synthetic genetic tools applicable to any algal species with a sequenced genome and transcriptome data set.

Efficacy of injection of autologous adipose tissue in the treatment of patients with complex and recurrent fistula-in-ano of cryptoglandular origin.

BACKGROUND: Adipose tissue injections, a rich source of mesenchymal stem cells, have been successfully used to promote anal fistula healing. This study aimed to investigate the efficacy of adipose tissue injection in treating patients with complex and recurrent fistulas of cryptoglandular origin. METHODS: We conducted a prospective, single-center, open-label, non-randomized, interventional clinical trial from January 2020 to December 2022. We enrolled nine patients, who were evaluated after at least 12 months of follow-up. All patients had seton removal, fistula tract excision or curettage, and a mucosal flap if possible or, alternatively, an internal opening suture. We used a commercially available system to collect and process adipose tissue prior to injection. This system allowed the collection, microfragmentation, and filtration of tissue. RESULTS: Selected cases included six men and three women with a median age of 42 (range 31-55) years. All patients had an extended disease course period, ranging from 3 to 13 (mean 6.6) years, and a history of multiple previous surgeries, including two to eight interventions (a mean of 4.4 per case). All fistulas were high transsphincteric, four cases horseshoe and two cases with secondary suprasphincteric or peri-elevator tract fistulas. Six cases (66%) achieved complete fistula healing at a mean follow-up of 18 (range 12-36) months. Three cases (33.3%) experienced reduced secretion and decreased anal discomfort. CONCLUSIONS: In patients with complex and recurrent fistulas, such as the ones described, many from palliative treatments with setons, the adjuvant injection of adipose tissue might help achieve complete healing or improvement in a significant percentage of cases. CLINICALTRIALS: The study protocol was prospectively registered on ClinicalTrials.gov (NCT04750499).

Variation of Length of Parieto-Occipital Sulcus in Different Age and Sex Groups of Bangladeshi People.

Parieto-occipital sulcus is one of the major sulcus of the cerebral hemisphere which separates the occipital lobe from the parietal lobe. Morphology of this sulcus varies with age, sex, manual skill, handedness and in many diseases. For various clinical investigations and surgery, detailed morphological knowledge of this sulcus is very much essential for the surgeons and radiologists. This study is carried out to establish a normal standard in length of the parieto-occipital sulcus in different age and sex groups of Bangladeshi people. A cross-sectional, descriptive type of study was conducted in the department of Anatomy, Mymensingh Medical College, Bangladesh from July 2016 to July 2017. About 60 specimens were collected from medico-legal cases and divided into four age groups including, Group A (20-29 years), Group B (30-39 years), Group C (40-49 years) and Group D (50 years and above). The mean length of parieto-occipital sulcus was 3.92±0.559cm to 3.29±0.434 cm in male and 3.81±0.715cm to 3.03±0.551cm in female. The difference in mean length of the parieto-occipital sulcus for both left and right hemisphere between male and female was statistically non-significant in all age groups. For statistical analysis, differences between age and sex groups were analyzed by using students unpaired 't' test. In this study, the length of the parieto-occipital sulcus showed gradual decreasing values with advancing age.

Micronutrient deficiencies and anemia in the follow-up after gastroesophageal cancer surgery.

Due to insufficient dietary intake and altered digestion and absorption of nutrients, patients after gastroesophageal cancer surgery are at risk of becoming malnourished and consequently develop micronutrient deficiencies. The aim of this study was to determine the prevalence of micronutrient deficiencies and anemia during follow-up after gastroesophageal cancer surgery. This single-center cross-sectional study included patients after resection for esophageal or gastric cancer visiting the outpatient clinic in 2016 and 2017. Only patients without signs of recurrent disease were included. All patients were guided by a dietician in the pre- and postoperative phase. Dietary supplements or enteral tube feeding was prescribed in case of inadequate dietary intake. Blood samples were examined for possible deficiencies or abnormalities in hemoglobin, prothrombin time, iron, ferritin, folic acid, calcium, zinc, vitamin A, vitamin B1, vitamin B6, vitamin B12, vitamin D and vitamin E. The percentage of patients with micronutrient deficiencies were scored. Of the 335 patients visiting the outpatient clinic, measurements were performed in 263 patients (221 after esophagectomy and 42 after gastrectomy), resulting in an inclusion rate of 79%. In the esophagectomy group, deficiencies in iron (36%), vitamin D (33%) and zinc (20%) were most prevalent. After gastric resection, deficiencies were most frequently observed in vitamin D (52%), iron (33%), zinc (28%) and ferritin (17%). Low levels of hemoglobin were found in 21% of patients after esophagectomy and 24% after gastrectomy. Despite active nutritional guidance, deficiencies in vitamin D, iron, zinc and ferritin, as well as low levels of hemoglobin, are frequently observed following gastroesophageal resection for cancer. These micronutrients should be periodically checked during follow-up and supplemented if needed.

Postpartum development of metabolic dysfunction-associated steatotic liver disease in a lean mouse model of gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is associated with increased postpartum risk for metabolic dysfunction-associated steatotic liver disease (MASLD). GDM-related MASLD predisposes to advanced liver disease, necessitating a better understanding of its development in GDM. This preclinical study evaluated the MASLD development in a lean GDM mouse model with impaired insulin secretion capacity. Lean GDM was induced by short-term 60% high-fat diet and low-dose streptozotocin injections (60 mg/kg for 3 days) before mating in C57BL/6N mice. The control dams received only high-fat diet or low-fat diet. Glucose homeostasis was assessed during pregnancy and postpartum, whereas MASLD was assessed on postpartum day 30 (PP30). GDM dams exhibited a transient hyperglycemic phenotype during pregnancy, with hyperglycaemia reappearing after lactation. Lower insulin levels and impaired glucose-induced insulin response were observed in GDM mice during pregnancy and postpartum. At PP30, GDM dams displayed higher hepatic triglyceride content compared controls, along with increased MAS (MASLD) activity scores, indicating lipid accumulation, inflammation, and cell turnover indices. Additionally, at PP30, GDM dams showed elevated plasma liver injury markers. Given the absence of obesity in this double-hit GDM model, the results clearly indicate that impaired insulin secretion driven pregnancy hyperglycaemia has a distinct contribution to the development of postpartum MASLD.

Transfer of micro-organisms from dry surface biofilms and the influence of long survival under conditions of poor nutrition and moisture on the virulence of Staphylococcusaureus.

BACKGROUND: Biofilms on dry hospital surfaces can enhance the persistence of micro-organisms on dry harsh clinical surfaces and can potentially act as reservoirs of infectious agents on contaminated surfaces. AIM: This study was conducted to quantify the transfer of viable Staphylococcus aureus cells from dry biofilms through touching and to investigate the impact of nutrient and moisture deprivation on virulence levels in S. aureus. METHODS: Dry biofilms of S. aureus ATCC 25923 and a defective biofilm-forming ability mutant, S. aureus 1132, were formed in 24-well plates under optimized conditions mimicking dry biofilm formation on clinical surfaces. Microbial cell transfer was induced through the touching of the dry biofilms, which were quantified on nutrient agar. To investigate the impact of nutrient and moisture deprivation on virulence levels, dry and standard biofilms as well as planktonic cells of S. aureus ATCC 25923 were inoculated into Galleria mellonella and their kill rates compared. FINDINGS: Results of this study showed that viable cells from dry biofilms of S. aureus ATCC 25923 were significantly more virulent and readily transferrable from dry biofilms through a touch test, therefore representing a greater risk of infection. The biofilm-forming capability of S. aureus strains had no significant impact on their transferability with more cells transferring when biofilm surfaces were wet. CONCLUSIONS: These findings indicate that dry biofilms on hospital surfaces may serve as a reservoir for the dissemination of pathogenic micro-organisms in hospitals, thus highlighting the importance of regular cleaning and adequate disinfection of hospital surfaces.

An in vitro evaluation of the fatigue behavior of resin composite materials as part of a translational research cycle.

PURPOSE: This study aimed to reproduce and translate clinical presentations in an in vitro set-up and evaluate laboratory outcomes of mechanical properties (flexural strength, fatigue resistance, wear resistance) and link them to the clinical outcomes of the employed materials in the Radboud Tooth Wear Project (RTWP). MATERIALS AND METHODS: Four dental resin composites were selected. 30 discs (Ø12.0 mm, 1.2 mm thick) were fabricated for each of Clearfil TM AP-X (AP), Filtek TM Supreme XTE (FS), Estenia TM C&B (ES), and Lava Ultimate (LU). Cyclic loading (200 N, 2 Hz frequency) was applied concentrically to 15 specimens per group with a spherical steatite indenter (r = 3.18 mm) in water in a contact-load-slide-liftoff motion (105 cycles). The wear scar was analysed using profilometry and the volume loss was digitally computed. Finally, all specimens were loaded (fatigued specimens with their worn surface loaded in tension) until fracture in a biaxial flexure apparatus. The differences in volume loss and flexural strength were determined using regression analysis. RESULTS: Compared to AP and FS, ES and LU showed a significantly lower volume loss (p < 0.05). Non-fatigued ES specimens had a similar flexural strength compared to nonfatigued AP, while non-fatigued FS and LU specimens had a lower flexural strength (p < 0.001; 95 %CI: -80.0 - 51.8). The fatigue test resulted in a significant decrease of the flexural strength of ES specimens, only (p < 0.001; 95 %CI: -96.1 - -54.6). CLINICAL RELEVANCE: These outcomes concur with the outcomes of clinical studies on the longevity of these composites in patients with tooth wear. Therefore, the employed laboratory test seems to have the potential to test materials in a clinically relevant way.

Human SARS-CoV-2 challenge uncovers local and systemic response dynamics.

The COVID-19 pandemic is an ongoing global health threat, yet our understanding of the dynamics of early cellular responses to this disease remains limited1. Here in our SARS-CoV-2 human challenge study, we used single-cell multi-omics profiling of nasopharyngeal swabs and blood to temporally resolve abortive, transient and sustained infections in seronegative individuals challenged with pre-Alpha SARS-CoV-2. Our analyses revealed rapid changes in cell-type proportions and dozens of highly dynamic cellular response states in epithelial and immune cells associated with specific time points and infection status. We observed that the interferon response in blood preceded the nasopharyngeal response. Moreover, nasopharyngeal immune infiltration occurred early in samples from individuals with only transient infection and later in samples from individuals with sustained infection. High expression of HLA-DQA2 before inoculation was associated with preventing sustained infection. Ciliated cells showed multiple immune responses and were most permissive for viral replication, whereas nasopharyngeal T cells and macrophages were infected non-productively. We resolved 54 T cell states, including acutely activated T cells that clonally expanded while carrying convergent SARS-CoV-2 motifs. Our new computational pipeline Cell2TCR identifies activated antigen-responding T cells based on a gene expression signature and clusters these into clonotype groups and motifs. Overall, our detailed time series data can serve as a Rosetta stone for epithelial and immune cell responses and reveals early dynamic responses associated with protection against infection.

Xenon Antiaggregant Effects.

In in vitro model of short-term therapeutic inhalation of Xe/O2 mixture, xenon in millimolar concentrations led to a pronounced decrease in induced platelet aggregation in the platelet-enriched blood plasma. The maximum and statistically significant decrease occurred in response to induction by collagen (by ≈30%, p≤0.01) and ADP (by ≈25%, p≤0.01). A slightly weaker but statistically significant reduction in aggregation appeared in response to ristocetin (by ≈12%, p≤0.01) and epinephrine (by ≈9%, p≤0.01). It should be noted that the spontaneous aggregation exceeded the reference values in the control group. Nevertheless, even at minimal absolute values, spontaneous platelet aggregation decreased by 2 times in response to xenon (p≤0.01). The reasons for the decrease of spontaneous and induced aggregation are xenon accumulation in the lipid bilayer of the membrane with subsequent nonspecific (mechanical) disassociation of membrane platelet structures and specific block of its distinct from neuronal NMDA receptor.

Mef2d potentiates type-2 immune responses and allergic lung inflammation.

Innate lymphoid cells (ILCs) and adaptive T lymphocytes promote tissue homeostasis and protective immune responses. Their production depends on the transcription factor GATA3, which is further elevated specifically in ILC2s and T helper 2 cells to drive type-2 immunity during tissue repair, allergic disorders, and anti-helminth immunity. The control of this crucial up-regulation is poorly understood. Using CRISPR screens in ILCs we identified previously unappreciated myocyte-specific enhancer factor 2d (Mef2d)-mediated regulation of GATA3-dependent type-2 lymphocyte differentiation. Mef2d-deletion from ILC2s and/or T cells specifically protected against an allergen lung challenge. Mef2d repressed Regnase-1 endonuclease expression to enhance IL-33 receptor production and IL-33 signaling and acted downstream of calcium-mediated signaling to translocate NFAT1 to the nucleus to promote type-2 cytokine-mediated immunity.

Conditions for the spread of CRISPR-Cas immune systems into bacterial populations.

Bacteria contain a wide variety of innate and adaptive immune systems which provide protection to the host against invading genetic material, including bacteriophages (phages). It is becoming increasingly clear that bacterial immune systems are frequently lost and gained through horizontal gene transfer (HGT). However, how and when new immune systems can become established in a bacterial population has remained largely unstudied. We developed a joint epidemiological and evolutionary model that predicts the conditions necessary for the spread of a CRISPR-Cas immune system into a bacterial population lacking this system. We find that whether bacteria carrying CRISPR-Cas will spread (increase in frequency) into a bacterial population depends on the abundance of phages and the difference in the frequency of phage resistance mechanisms between bacteria carrying a CRISPR-Cas immune system, and those not (denoted as ${f}_{\Delta }$). Specifically, the abundance of cells carrying CRISPR-Cas will increase if there is a higher proportion of phage resistance (either via CRISPR-Cas immunity or surface modification) in the CRISPR-Cas possessing population than in the cells lacking CRISPR-Cas. We experimentally validated these predictions using Pseudomonas aeruginosa PA14 and phage DMS3vir as a model. Specifically, by varying the initial ratios of different strains of bacteria that carry alternative forms of phage resistance we confirmed that the spread of cells carrying CRISPR-Cas through a population can be predicted based on phage density and the relative frequency of resistance phenotypes. Understanding which conditions promote the spread of CRISPR-Cas systems helps to predict when and where these defences can establish in bacterial populations after a horizontal gene transfer event, both in ecological and clinical contexts.