Deubiquitinase-targeting chimera (DUBTAC) is a promising technology for inducing targeted protein stabilization (TPS). Despite its therapeutic potential, very few proteins have been stabilized by DUBTACs to date. The limited applicability of this technology is likely due to the modest DUBTAC-induced protein stabilization effect, and the scarcity of effective deubiquitinase ligands that can be harnessed for DUBTAC development. Here, we report the discovery of MS7829 and MS8588, the first-in-class DUBTACs of cGAS, a key component of the cGAS-STING pathway. While these DUBTACs are based on a cGAS inhibitor, they effectively stabilized cGAS and activated the cGAS/STING/IRF3 signaling. To develop these cGAS DUBTACs, we optimized EN523, an OTUB1 covalent ligand, into an improved ligand, MS5105. We validated MS5105 by generating a MS5105-based CFTR DUBTAC, which was approximately 10-fold more effective in stabilizing the ΔF508-CFTR mutant protein than the previously reported EN523-based CFTR DUBTAC. Overall, this work advances the DUBTAC technology for TPS.

BACKGROUND: This observation study aimed to differentiate between lobular endocervical glandular hyperplasia (LEGH) and gastric-type mucinous carcinoma (GAS) while evaluating the feasibility and efficacy of laparoscopic surgery in the preoperative diagnosis of cervical cystic lesions.
METHODS: A retrospective study was conducted to evaluate the diagnostic process and laparoscopic surgical management of cervical cystic lesions suspected to be LEGH or GAS. Preoperatively and postoperatively, MRI, cytology, histology, tumor marker analysis, and surgical outcomes (blood loss during surgery, operative time) were assessed. Six individuals were selected based on magnetic resonance imaging (MRI) results indicating a preoperative suspicion of LEGH or GAS. These patients underwent laparoscopic surgical treatment without indications of malignancy based on preoperative histology or cytology.
RESULTS: Initially, all individuals were suspected to have LEGH based on MRI findings. Postoperatively, two patients were diagnosed with LEGH, two with adenocarcinoma in situ (AIS) and minimal deviation adenocarcinoma (MDA), and two showed no notable findings on pathology (one diagnosed endometrioid carcinoma in endometrial tissue). Patients with malignancies exhibited longer surgical times and higher intraoperative blood loss. Preoperatively, no significant variation was observed in maximal lesion diameter between adenocarcinoma and LEGH. However, lesion diameter increased significantly over time in patients with GAS.
CONCLUSIONS: Laparoscopic surgery demonstrated feasibility and provided crucial diagnostic and therapeutic outcomes, with no postoperative recurrence observed in cases of malignancy, despite the challenges associated with preoperative differentiation. These findings underscore the potential of laparoscopic surgery in enhancing both diagnostic accuracy and therapeutic efficacy for cervical cystic lesions, offering promise for improved patient outcomes and management strategies in clinical practice.

Surface-enhanced Raman spectroscopy (SERS) is a promising and highly sensitive molecular fingerprint detection technology. However, the development of SERS nanocomposites that are label-free, highly sensitive, selective, stable, and reusable for gaseous volatile organic compounds (VOCs) detection remains a challenge. Here, we report a novel TiO2NTs/AuNPs@ZIF-8 nanocomposite for the ultrasensitive SERS detection of VOCs. The three-dimensional TiO2 nanotube structure with a large specific surface area provides abundant sites for the loading of Au NPs, which possess excellent local surface plasmon resonance (LSPR) effects, further leading to the formation of a large number of SERS active hotspots. The externally wrapped porous MOF structure adsorbs more gaseous VOC molecules onto the noble metal surface. Under the synergistic mechanism of physical and chemical enhancement, a better SERS enhancement effect can be achieved. By optimizing experimental conditions, the SERS detection limit for acetophenone, a common exhaled VOC, is as low as 10-11 M. And the relative standard deviation of SERS signal intensity from different points on the same nanocomposite surface is 4.7%. The acetophenone gas achieves a 1 min response and the signal reaches stability in 4 min. Under UV irradiation, the surface-adsorbed acetophenone can be completely degraded within 40 min. The experimental results demonstrate that this nanocomposite has good detection sensitivity, repeatability, selectivity, response speed, and reusability, making it a promising sensor for gaseous VOCs.

OBJECTIVE: Since December 2022, an increase in invasive disease caused by Streptococcus pyogenes has been observed in the Czech Republic, with a shift in the clinical presentation and age of patients. Unlike in previous years, invasive disease is more common in children and adolescents under 18 years of age and in previously healthy middle-aged adults. An increase has been noticed in the number of S. pyogenes isolates from primarily sterile sites such as haemoculture, cerebrospinal fluid, pleural effusion fluid, joint fluid, and postmortem specimens. Routine emm gene typing revealed emm1 to be the predominant emm type of S. pyogenes. Between January 2023 and July 2023, 46% of all S. pyogenes isolates from invasive cases were assigned to the emm1 type. The globally spread M1UK sublineage is characterized by differences in the expression of seven genes, including the streptococcal pyrogenic toxin A (speA) gene, compared to historical emm1 iGAS strains. The aim of this study is to determine whether the more toxigenic M1UK sublineage is associated with the increase in invasive disease in the Czech Republic.
METHODS: Whole genome sequencing of 41 S. pyogenes isolates from patients with invasive disease recovered in the Czech Republic in 2018 and 2019 and from December 2022 to May 2023 was performed using the MiSeq instrument (Illumina). Bioinformatics analysis was performed using freely available online tools the Bacterial and Viral Bioinformatics Resource Center.
RESULTS: Based on whole genome sequencing data of 41 emm1 isolates of S. pyogenes from patients with invasive infectious disease recovered in 2018 and 2019 and from December 2022 to May 2023, the M1UK sublineage was found to be predominant from December 2022 to May 2023.
CONCLUSIONS: The reason for the spread of the M1UK sublineage in the Czech Republic late in 2022 and in the first half of 2023 is not entirely clear, but it may be related to reduced immunity due to limited GAS transmission during lockdowns, especially in children. Another factor that may have contributed to the high incidence of invasive infectious diseases is the seasonal circulation of respiratory viruses.

In Europe, respiratory protective devices must be certified before they can be marketed. Among the parameters of interest, inward leakage (IL) characterizes the tightness between the face seal and the face, to verify that the device is well-designed. European standard EN 13274-1 (2001) and International Organization for Standardization (ISO) standard ISO 16900-1 (2019) specify that IL should be measured using sodium chloride (NaCl) aerosol or sulfur hexafluoride (SF6) gas. For reusable masks made of nonporous materials, both test agents are considered equally acceptable. However, the few studies that have compared IL values measured with various aerosols and gases have come to divergent conclusions. This work then aimed to measure IL with the test agents recommended by the standards to determine whether they are really equivalent. Since krypton (Kr) is an interesting candidate for replacing SF6 in standard tests, IL was assessed with SF6 and Kr simultaneously, and with NaCl aerosol using various calculation methods. Tests were carried out on 5 models of full-face masks donned on a headform connected to a breathing machine simulating 3 sinusoidal breathing rates of various intensities. The respirator fit on the headform was evaluated using a controlled negative pressure method to determine a manikin fit factor. Four scenarios were then tested to represent very poor, bad, good, and excellent fit. Gas concentration was measured using a mass spectrometer, and IL was calculated for SF6 and Kr. A combination of 3 devices allowed the determination of the number-based concentration of particles with diameters between 20 nm and 2 µm, and IL was calculated for each of the 33 channels, as well as using a cumulative number concentration. In addition, to comply with standards, a conversion was carried out to calculate IL using a cumulative mass concentration. The results of this work evidenced that the IL values measured with NaCl were systematically lower than those determined with gases. IL was also shown to vary with particle size, with a maximum value exceeding that calculated with cumulative concentrations (in number or mass). As part of the revision of the standards, protocols for measuring inward leakage should be redefined. On the one hand, acceptability thresholds should be re-evaluated according to the nature of the test agent (gas or aerosol), as it is clear that the 2 options do not give the same results for a given configuration. On the other hand, the aerosol leakage measurement protocol needs to be reworked to enable the measurement of a well-defined, robust, and reproducible inward leakage value.

OBJECTIVE: To clarify the infection route in maternal death due to invasive group A streptococcal (GAS) infection and toxic shock syndrome (TSS).
METHODS: A retrospective study was conducted on maternal deaths due to GAS-TSS in Japan between January 2010 and March 2024. The final causal diagnosis of maternal death and the infection routes of GAS were analysed using medical records, laboratory data and autopsy findings.
RESULTS: Among the 616 maternal deaths during the study period, 48 (8%) involved infectious diseases. The most common infection was invasive GAS (56%, n = 27), 21 (78%) and six cases occurred during the antepartum and puerperium periods, respectively. In the GAS-TSS group, 71% (15/21) infections were originated the upper respiratory tract. However, in the puerperium cases, 67% (4/6) were infected from the genital tract. In addition, no maternal deaths due to GAS-TSS were reported during the COVID-19 pandemic period in Japan from 2020 to 2023.
CONCLUSIONS: Most antepartum GAS infections were from the upper respiratory tract. They may be reduced by preventive measures, including frequent disinfection, wearing masks and isolation from persons at high risk of carrying GAS, such as symptomatic children. On the other hand, GAS-TSS during puerperium infection via the genital tract.

In this study, a flash pyrolysis process is developed using an entrained flow reactor for recycling of waste tires. The flash pyrolysis system is tested for process stability and reproducibility of the products under similar operating conditions when operated continuously. The study is performed with two different feedstock materials, i.e., passenger car (PCT) and truck tire (TT) granulates, to understand the influence of feedstock on the yield and properties of the pyrolysis products. The different pyrolytic products i.e., pyrolytic carbon black (pCB), oil, and pyro-gas, are analyzed, and their key properties are discussed. The potential applications for the obtained pyrolytic products are discussed. Finally, a mass and energy balance analysis has been performed for the developed pyrolysis process. The study provides insight into the governing mechanisms of the flash pyrolysis process for waste tires, which is useful to optimize the process depending on the desired applications for the pyrolysis products, and also to scale up the pyrolysis process.

BACKGROUND: The aim of this study was to evaluate the refractive error in patients undergoing combined phacovitrectomy with and without gas tamponade.
METHODS: This was a retrospective chart review including patients undergoing phacoemulsification alone (Group 1), combined phacovitrectomy for epiretinal membrane (Group 2), and combined phacovitrectomy with gas tamponade for rhegmatogenous retinal detachment (RRD) (Group 3). Axial length and keratometry were measured using an optical biometric system (Argos, Alcon Laboratories. Inc.), and a three-piece intraocular lens (IOL; NX-70S) was implanted in all groups. In each group, the prediction error at 3 months was calculated using IOL power calculation formulas (SRK/T, Hill-RBF, Kane, and Barrett Universal II) for each eye. Outcome measures included the mean prediction error (MPE), its standard deviation (SD), and the mean absolute error (MAE). The change in IOL position at 3 months was also assessed using anterior segment optical coherence tomography.
RESULTS: A total of 104 eyes were included (Group 1: 30; Group 2: 34; Group 3: 40 eyes). The MPE was -0.08 ± 0.37 diopters (D), -0.26 ± 0.32 D, and -0.59 ± 0.34 D in Group 1, Group 2, and Group 3, respectively, using the Barrett Universal II formula (P < 0.01, ANOVA). The movement forward in the IOL position was 0.95 ± 0.16 mm, 0.94 ± 0.12 mm, and 1.07 ± 0.20 mm in Group 1, Group 2, and Group 3, respectively (P < 0.01). No significant difference was shown in MPE among the four formulas after combined phacovitrectomy with gas (P = 0.531).
CONCLUSIONS: Phacovitrectomy in RRD induced a significant myopic shift using any of the clinically available formulas. This suggests that myopic shift should be taken into consideration for better refractive outcomes in phacovitrectomy with gas tamponade in RRD.

UNASSIGNED: A future Streptococcus pyogenes (Strep A) vaccine will ideally prevent a significant burden of lower limb cellulitis; however, natural immune responses to proposed vaccine antigens following an episode of cellulitis remain uncharacterized.
UNASSIGNED: We enrolled 63 patients with cellulitis and 26 with invasive beta hemolytic streptococci infection, using a multiplexed assay to measure immunoglobulin G against Strep A vaccine candidate antigens, including: streptolysin O (SLO), deoxyribonuclease B (DNB), group A carbohydrate (GAC), C5a peptidase (ScpA), cell envelope proteinase (SpyCEP), and adhesion and division protein (SpyAD). Responses in the invasive cohort were used to predict the infecting etiology in the cellulitis cohort.
UNASSIGNED: Of 41 patients with cellulitis and paired serological samples, 68.3% had evidence of beta hemolytic streptococci infection by conventional anti-SLO and/or anti-DNB criteria. A positive serological response to at least 1 of the tested antigens was seen in 78.0% of the cellulitis cohort. Individually, anti-SLO (58.5%), anti-SpyAD (46.3%), and anti-ScpA (39.0%) were the most common. Based on principal component analysis, increases in these 3 antibodies, without responses to DNB, GAC, and SpyCEP characterized Streptococcus dysgalactiae subspecies equisimilis (SDSE) infection.
UNASSIGNED: SDSE appears to be the predominant cause of lower limb cellulitis. Effective Strep A vaccines incorporating antigens that provide additional cross protection against SDSE may prevent a significant burden of lower limb cellulitis.

UNASSIGNED: Garlic skin (GAS) has been proven to improve the growth performance of fattening sheep. However, the mechanism by which GAS affects fattening sheep is not yet clear. The aim of this study is to investigate the effects of adding GAS to feed on the growth performance, rumen and fecal microbiota, serum and urine metabolism, and transcriptomics of rumen epithelial cells in fattening sheep.
UNASSIGNED: GAS with 80 g/kg dry matter (DM) was added to the diet of fattening sheep to study the effects of GAS on gut microbiota, serum and urine metabolism, and transcriptome of rumen epithelial tissue in fattening sheep. Twelve Hu sheep (body weights; BW, 23.0 ± 2.3 kg and ages 120 ± 3.5 d) were randomly divided into two groups. The CON group was the basal diet, while the GAS group was supplemented with GAS in the basal diet. The trial period was 10 weeks, with the first 2 weeks being the pre-trial period.
UNASSIGNED: The daily average weight gain of fattening sheep in the GAS group was significantly higher than that in the CON group (p < 0.05), and the serum GSH-Px of the GAS group fattening sheep was significantly increased, while MDA was significantly reduced (p < 0.05). Based on the genus classification level, the addition of garlic peel in the diet changed the intestinal microbial composition, and the relative abundance was significantly upregulated by Metanobrevibater (p < 0.05), while significantly downregulated by Akkermansia, Parasutterella, and Guggenheimella (p < 0.05). Metabolomics analysis found that there were 166 significantly different metabolites in serum and 68 significantly different metabolites in urine between the GAS and CON groups (p < 0.05). GAS had an impact on amino acid metabolism, pyrimidine metabolism, methane metabolism, riboflavin metabolism, and unsaturated fatty acid synthesis pathways (p < 0.05). Transcriptome sequencing showed that differentially expressed genes were mainly enriched in immune regulatory function, improving the health of fattening sheep.
UNASSIGNED: Adding GAS can improve the energy metabolism and immune function of fattening sheep by altering gut microbiota, metabolome, and transcriptome, thereby improving the growth performance of fattening sheep.