Mixed Tin Valence in the Tin(II/IV)-Nitridophosphate Sn3P8N16.

Sn3P8N16 combines the structural versatility of nitridophosphates and Sn within one compound. It was synthesized as dark gray powder in a high-pressure high-temperature reaction at 800 °C and 6 GPa from Sn3N4 and P3N5. The crystal structure was elucidated from single-crystal diffraction data (space group C2/m (no. 12), a = 12.9664(4), b = 10.7886(4), c = 4.8238(2) Å, ß = 109.624(1)°) and shows a 3D-network of PN4 tetrahedra, incorporating Sn in oxidation states +II and +IV. The Sn cations are located within eight-membered rings of vertex-sharing PN4 tetrahedra, stacked along the [001] direction. A combination of solid-state nuclear magnetic resonance spectroscopy, 119Sn Mössbauer spectroscopy and density functional theory calculations was used to confirm the mixed oxidation of Sn. Temperature-dependent powder X-ray diffraction measurements reveal a low thermal expansion of 3.6 ppm/K up to 750 °C, beyond which Sn3P8N16 starts to decompose.

Clinical Outcomes Associated With Various Microvascular Injury Patterns Identified by CMR After STEMI.

BACKGROUND: The prognostic significance of various microvascular injury (MVI) patterns after ST-segment elevation myocardial infarction (STEMI) is not well known. OBJECTIVES: This study sought to investigate the prognostic implications of different MVI patterns in STEMI patients. METHODS: The authors analyzed 1,109 STEMI patients included in 3 prospective studies. Cardiac magnetic resonance (CMR) was performed 3 days (Q1-Q3: 2-5 days) after percutaneous coronary intervention (PCI) and included late gadolinium enhancement imaging for microvascular obstruction (MVO) and T2∗ mapping for intramyocardial hemorrhage (IMH). Patients were categorized into those without MVI (MVO-/IMH-), those with MVO but no IMH (MVO+/IMH-), and those with IMH (IMH+). RESULTS: MVI occurred in 633 (57%) patients, of whom 274 (25%) had an MVO+/IMH- pattern and 359 (32%) had an IMH+ pattern. Infarct size was larger and ejection fraction lower in IMH+ than in MVO+/IMH- and MVO-/IMH- (infarct size: 27% vs 19% vs 18% [P < 0.001]; ejection fraction: 45% vs 50% vs 54% [P < 0.001]). During a median follow-up of 12 months (Q1-Q3: 12-35 months), a clinical outcome event occurred more frequently in IMH+ than in MVO+/IMH- and MVO-/IMH- subgroups (19.5% vs 3.6% vs 4.4%; P < 0.001). IMH+ was the sole independent MVI parameter predicting major adverse cardiovascular events (HR: 3.88; 95% CI: 1.93-7.80; P < 0.001). CONCLUSIONS: MVI is associated with future adverse outcomes only in patients with a hemorrhagic phenotype (IMH+). Patients with only MVO (MVO+/IMH-) had a prognosis similar to patients without MVI (MVO-/IMH-). This highlights the independent prognostic importance of IMH in assessing and managing risk after STEMI.

Changes in the term neonatal electroencephalogram with general anesthesia - a systematic review with narrative synthesis.

While effects of general anesthesia on neuronal activity in the human neonatal brain are incompletely understood, electroencephalography (EEG) provides some insight and may identify age-dependent differences. A systematic search (MEDLINE, Embase, PUBMED, Cochrane Library to November 2023) retrieved English language publications reporting EEG during general anesthesia for cardiac or non-cardiac surgery in term neonates (37 to 44 weeks post-menstrual age). Data were extracted and risk of bias (ROBINS-I Cochrane tool) and quality of evidence (GRADE checklist) assessed. From 1155 abstracts, nine publications (157 neonates; 55.7% male) fulfilled eligibility criteria. Data were limited and study quality was very low. The occurrence of discontinuity, a characteristic pattern of alternating higher and lower amplitude EEG segments, was reported with general anesthesia (94 of 119 neonates, six publications) and with hypothermia (23 of 23 neonates, two publications). Decreased power in the delta (0.5-4Hz) frequency range was also reported with increasing anesthetic dose (39 neonates; three publications). While evidence gaps were identified, both increasing sevoflurane concentration and decreasing temperature are associated with increasing discontinuity.

CBP/P300 BRD Inhibition Reduces Neutrophil Accumulation and Activates Antitumor Immunity in TNBC.

Tumor-associated neutrophils (TANs) have been shown to promote immunosuppression and tumor progression, and a high TAN frequency predicts poor prognosis in triple-negative breast cancer (TNBC). Dysregulation of CREB binding protein (CBP)/P300 function has been observed with multiple cancer types. The bromodomain (BRD) of CBP/P300 has been shown to regulate its activity. In this study, we found that IACS-70654, a novel and selective CBP/P300 BRD inhibitor, reduced TANs and inhibited the growth of neutrophil-enriched TNBC models. In the bone marrow, CBP/P300 BRD inhibition reduced the tumor-driven abnormal differentiation and proliferation of neutrophil progenitors. Inhibition of CBP/P300 BRD also stimulated the immune response by inducing an IFN response and MHCI expression in tumor cells and increasing tumor-infiltrated CTLs. Moreover, IACS-70654 improved the response of a neutrophil-enriched TNBC model to docetaxel and immune checkpoint blockade. This provides a rationale for combining a CBP/P300 BRD inhibitor with standard-of-care therapies in future clinical trials for neutrophil-enriched TNBC.

Catenovulum adriaticum sp. nov., isolated from algae in the harbour of Susak, Croatia.

The use of algae as feedstock for industrial purposes, such as in bioethanol production, is desirable. During a search for new agarolytic marine bacteria, a novel Gram-stain-negative, strictly aerobic, and agarolytic bacterium, designated as TS8T, was isolated from algae in the harbour of the island of Susak, Croatia. The cells were rod-shaped and motile. The G+C content of the sequenced genome was 38.6 mol%. Growth was observed at 11-37 °C, with 0.5-13 % (w/v) NaCl, and at pH 6.0-9.0. The main fatty acids were summed feature 3 (C16 : 1 ω6c and/or C16 : 1 ω7c), summed feature 8 (C18 : 1 ω7c and/or C18 : 1 ω6c), and C16 : 0. The main respiratory quinone was ubiquinone-8. The major polar lipids were phosphatidylethanolamine and phosphatidylglycerol. Analysis of 16S rRNA gene sequences indicated that the newly isolated strain belongs to the genus Catenovulum. Based on 16S rRNA gene sequence data, strain TS8T is closely related to Catenovulum sediminis D2T (95.7 %), Catenovulum agarivorans YM01T (95.0 %), and Catenovulum maritimum Q1T (93.2 %). Digital DNA-DNA hybridization values between TS8T and the other Catenovulum strains were below 25 %. Based on genotypic, phenotypic, and phylogenetic data, strain TS8T represents a new species of the genus Catenovulum, for which the name Catenovulum adriaticum sp. nov. is proposed. The type strain is TS8T (=DSM 114830T=NCIMB 15451T).

Open-Angle and Steroid-Induced Glaucoma in Patients With Retinitis Pigmentosa: A Dangerous Liaison.

Previous studies have reported that patients with retinitis pigmentosa (RP) may develop open-angle and angle-closure glaucoma. We conducted a chart review of patients with RP. Two siblings with RP associated with a mutation in the PDE6B gene (c. 1540del, p.Leu514Trpfs*61) developed cystoid macular edema (CME) as part of the disease. For this reason, they both underwent intravitreal steroid injections. Both brothers developed steroid-induced glaucoma (SIG). Despite undergoing maximal medical therapy, they underwent seton implants to control their intraocular pressure. A third female patient with RP due to a mutation in the RPGR gene underwent cataract surgery. Topical steroids were prescribed and developed SIG. Increased intraocular pressure remains a complication of topical, injected, and systemic steroids. However, steroids may be needed to treat post-operatively and patients with CME. This case series unveils a complex association between RP and key comorbidities in these patients, with a focus on cataracts, glaucoma, and macular edema. Cataract surgery in patients with RP shows a link to the emergence of glaucoma, particularly in those with RPGR and PDE6B gene mutations, revealing a novel association with PDE6B mutations not previously documented. Furthermore, the paper explores a unique parallel with Schwartz-Matsuo syndrome, suggesting that patients with RP undergoing cataract surgery may develop increased intraocular pressure due to an outflow disturbance akin to Schwartz syndrome. This novel perspective deepens our understanding of the pathophysiological mechanisms governing intraocular pressure dynamics in patients with RP. To our knowledge, this is the first report of steroid-induced glaucoma in patients with RP due to mutations in the PDE6B gene. Intraocular pressure evaluation remains of utmost importance in the follow-up of patients with the disease.

Predictability of intelligence and age from structural connectomes.

In this study, structural images of 1048 healthy subjects from the Human Connectome Project Young Adult study and 94 from ADNI-3 study were processed by an in-house tractography pipeline and analyzed together with pre-processed data of the same subjects from braingraph.org. Whole brain structural connectome features were used to build a simple correlation-based regression machine learning model to predict intelligence and age of healthy subjects. Our results showed that different forms of intelligence as well as age are predictable to a certain degree from diffusion tensor imaging detecting anatomical fiber tracts in the living human brain. Though we did not identify significant differences in the prediction capability for the investigated features depending on the imaging feature extraction method, we did find that crystallized intelligence was consistently better predictable than fluid intelligence from structural connectivity data through all datasets. Our findings suggest a practical and scalable processing and analysis framework to explore broader research topics employing brain MR imaging.

Zygospore development of Spirogyra (Charophyta) investigated by serial block-face scanning electron microscopy and 3D reconstructions.

Sexual reproduction of Zygnematophyceae by conjugation is a less investigated topic due to the difficulties of the induction of this process and zygospore ripening under laboratory conditions. For this study, we collected field sampled zygospores of Spirogyra mirabilis and three additional Spirogyra strains in Austria and Greece. Serial block-face scanning electron microscopy was performed on high pressure frozen and freeze substituted zygospores and 3D reconstructions were generated, allowing a comprehensive insight into the process of zygospore maturation, involving storage compound and organelle rearrangements. Chloroplasts are drastically changed, while young stages contain both parental chloroplasts, the male chloroplasts are aborted and reorganised as 'secondary vacuoles' which initially contain plastoglobules and remnants of thylakoid membranes. The originally large pyrenoids and the volume of starch granules is significantly reduced during maturation (young: 8 ± 5 µm³, mature: 0.2 ± 0.2 µm³). In contrast, lipid droplets (LDs) increase significantly in number upon zygospore maturation, while simultaneously getting smaller (young: 21 ± 18 µm³, mature: 0.1 ± 0.2 and 0.5 ± 0.9 µm³). Only in S. mirabilis the LD volume increases (34 ± 29 µm³), occupying ~50% of the zygospore volume. Mature zygospores contain barite crystals as confirmed by Raman spectroscopy with a size of 0.02 - 0.05 µm³. The initially thin zygospore cell wall (~0.5 µm endospore, ~0.8 µm exospore) increases in thickness and develops a distinct, electron dense mesospore, which has a reticulate appearance (~1.4 µm) in Spirogyra sp. from Greece. The exo- and endospore show cellulose microfibrils in a helicoidal pattern. In the denser endospore, pitch angles of the microfibril layers were calculated: ~18 ± 3° in S. mirabilis, ~20 ± 3° in Spirogyra sp. from Austria and ~38 ± 8° in Spirogyra sp. from Greece. Overall this study gives new insights into Spirogyra sp. zygospore development, crucial for survival during dry periods and dispersal of this genus.

"I Want to Do Something" - Exploring What Makes Activities Meaningful for Community-Dwelling People Living With Dementia: A Focused Ethnographic Study.

Supporting ageing in place, quality of life, and activity engagement are public health priorities for people with dementia. The importance of maintaining opportunities for meaningful activities has been widely acknowledged for those with dementia in long-term care, but little is known about what makes activities meaningful for, and how they are experienced by, people with different types of dementia in their own homes. This study used focussed ethnographic methods to explore the motivations and meanings of everyday activity engagement within the homes of 10 people with memory-led Alzheimer's disease and 10 people with posterior cortical atrophy. While participants' interactions with their everyday environments were challenged by their diagnoses, they were all finding ways to continue meaning-making via various activities. The main findings are encapsulated in three themes: (1) The fun and the function of activities; (2) Reciprocities of care, and (3) The constitution and continuity of (a changing) self. Ongoing engagement with both fun and functional activities offered participants living with different dementias opportunities to connect with others, to offer care and support (as well as receive it), and to maintain a sense of self and identity. Implications are discussed regarding the development and delivery of tailored interventions and support to enable continued engagement in meaningful activities for people with different types of dementia living in the community.

Advances in preclinical TCR characterization: leveraging cell avidity to identify functional TCRs.

T-cell therapy has emerged as an effective approach for treating viral infections and cancers. However, a significant challenge is the selection of T-cell receptors (TCRs) that exhibit the desired functionality. Conventionally in vitro techniques, such as peptide sensitivity measurements and cytotoxicity assays, provide valuable insights into TCR potency but are labor-intensive. In contrast, measuring ligand binding properties (z-Movi technology) could provide an accelerated processing while showing robust correlations with T-cell functions. In this study, we assessed whether cell avidity can predict functionality also in the context of TCR-engineered T cells. To this end, we developed a flexible system for TCR re-expression by generating a Jurkat-derived T cell clone lacking TCR and CD3 expression through CRISPR-Cas9-mediated TRBC knockout. The knockin of a transgenic TCR into the TRAC locus restored TCR/CD3 expression, allowing for CD3-based purification of TCR-engineered T cells. Subsequently, we characterized these engineered cell lines by functional readouts, and assessment of binding properties through the z-Movi technology. Our findings revealed a strong correlation between the cell avidities and functional sensitivities of Jurkat TCR-T cells. Altogether, by integrating cell avidity measurements with our versatile T cell engineering platform, we established an accelerated system for enhancing the in vitro selection of clinically relevant TCRs.

Symptom-based staging for logopenic variant primary progressive aphasia.

BACKGROUND AND PURPOSE: Logopenic variant primary progressive aphasia (lvPPA) is a major variant presentation of Alzheimer's disease (AD) that signals the importance of communication dysfunction across AD phenotypes. A clinical staging system is lacking for the evolution of AD-associated communication difficulties that could guide diagnosis and care planning. Our aim was to create a symptom-based staging scheme for lvPPA, identifying functional milestones relevant to the broader AD spectrum. METHODS: An international lvPPA caregiver cohort was surveyed on symptom development under an 'exploratory' survey (34 UK caregivers). Feedback from this survey informed the development of a 'consolidation' survey (27 UK, 10 Australian caregivers) in which caregivers were presented with six provisional clinical stages and feedback was analysed using a mixed-methods approach. RESULTS: Six clinical stages were endorsed. Early symptoms included word-finding difficulty, with loss of message comprehension and speech intelligibility signalling later-stage progression. Additionally, problems with hearing in noise, memory and route-finding were prominent early non-verbal symptoms. 'Milestone' symptoms were identified that anticipate daily-life functional transitions and care needs. CONCLUSIONS: This work introduces a new symptom-based staging scheme for lvPPA, and highlights milestone symptoms that could inform future clinical scales for anticipating and managing communication dysfunction across the AD spectrum.

A Novel Variant in the FBN1 Gene Causing Marfan Syndrome: A Case Report.

Our purpose is to report a patient with a novel variant in the fibrillin-1 (FBN1) gene causing the Marfan syndrome (MFS). The 29-year-old female patient with musculoskeletal, cardiovascular, and ocular findings compatible with the MFS had a novel pathogenic mutation on the FBN1 gene. We report on a patient whose clinical findings are compatible with the MFS. This patient's variant on the FBN1 gene leading to the syndrome has not been previously described. Additional investigations are needed to determine whether this variant contributes to the development of camptodactyly in patients with the syndrome.

Building Nitridic Networks with Phosphorus and Germanium-from GeIIP2N4 to GeIVPN3.

Nitridophosphates and nitridogermanates attract high interest in current research due to their structural versatility. Herein, the elastic properties of GeP2N4 were investigated by single-crystal X-ray diffraction (XRD) upon compression to 44.4(1) GPa in a diamond anvil cell. Its isothermal bulk modulus was determined to be 82(6) GPa. At 44.4(1) GPa, laser heating resulted in the formation of multiple crystalline phases, one of which was identified as unprecedented germanium nitridophosphate GePN3. Its structure was elucidated from single-crystal XRD data (C2/c (no. 15), a = 8.666(5), b = 8.076(4), c = 4.691(2) Å, ß = 101.00(7)°) and is built up from layers of GeN6 octahedra and PN4 tetrahedra. The GeN6 octahedra form double zigzag chains, while the PN4 tetrahedra are found in single zigzag chains. GePN3 can be recovered to ambient conditions with a unit cell volume increase of about 12%. It combines PV and GeIV in a condensed nitridic network for the first time.

Staphylococcus aureus FtsZ and PBP4 bind to the conformationally dynamic N-terminal domain of GpsB.

In the Firmicutes phylum, GpsB is a membrane associated protein that coordinates peptidoglycan synthesis with cell growth and division. Although GpsB has been studied in several bacteria, the structure, function, and interactome of Staphylococcus aureus GpsB is largely uncharacterized. To address this knowledge gap, we solved the crystal structure of the N-terminal domain of S. aureus GpsB, which adopts an atypical, asymmetric dimer, and demonstrates major conformational flexibility that can be mapped to a hinge region formed by a three-residue insertion exclusive to Staphylococci. When this three-residue insertion is excised, its thermal stability increases, and the mutant no longer produces a previously reported lethal phenotype when overexpressed in Bacillus subtilis. In S. aureus, we show that these hinge mutants are less functional and speculate that the conformational flexibility imparted by the hinge region may serve as a dynamic switch to fine-tune the function of the GpsB complex and/or to promote interaction with its various partners. Furthermore, we provide the first biochemical, biophysical, and crystallographic evidence that the N-terminal domain of GpsB binds not only PBP4, but also FtsZ, through a conserved recognition motif located on their C-termini, thus coupling peptidoglycan synthesis to cell division. Taken together, the unique structure of S. aureus GpsB and its direct interaction with FtsZ/PBP4 provide deeper insight into the central role of GpsB in S. aureus cell division.

Identification of FasL as a crucial host factor driving COVID-19 pathology and lethality.

The dysregulated immune response and inflammation resulting in severe COVID-19 are still incompletely understood. Having recently determined that aberrant death-ligand-induced cell death can cause lethal inflammation, we hypothesized that this process might also cause or contribute to inflammatory disease and lung failure following SARS-CoV-2 infection. To test this hypothesis, we developed a novel mouse-adapted SARS-CoV-2 model (MA20) that recapitulates key pathological features of COVID-19. Concomitantly with occurrence of cell death and inflammation, FasL expression was significantly increased on inflammatory monocytic macrophages and NK cells in the lungs of MA20-infected mice. Importantly, therapeutic FasL inhibition markedly increased survival of both, young and old MA20-infected mice coincident with substantially reduced cell death and inflammation in their lungs. Intriguingly, FasL was also increased in the bronchoalveolar lavage fluid of critically-ill COVID-19 patients. Together, these results identify FasL as a crucial host factor driving the immuno-pathology that underlies COVID-19 severity and lethality, and imply that patients with severe COVID-19 may significantly benefit from therapeutic inhibition of FasL.

Synthetic Peptides: Promising Modalities for the Targeting of Disease-Related Nucleic Acids.

DNA and RNA play pivotal roles in life processes by storing and transferring genetic information, modulating gene expression, and contributing to essential cellular machinery such as ribosomes. Dysregulation and mutations in nucleic acid-related processes are implicated in numerous diseases. Despite the critical impact on health of nucleic acid mutations or dysregulation, therapeutic compounds addressing these biomolecules remain limited. Peptides have emerged as a promising class of molecules for biomedical research, offering potential solutions for challenging drug targets. This review focuses on the use of synthetic peptides to target disease-related nucleic acids. We discuss examples of peptides targeting double-stranded DNA, including the clinical candidate Omomyc, and compounds designed for regulatory G-quadruplexes. Further, we provide insights into both library-based screenings and the rational design of peptides to target regulatory human RNA scaffolds and viral RNAs, emphasizing the potential of peptides in addressing nucleic acid-related diseases.

Presence and utility of electrocardiographic abnormalities in long-term childhood cancer survivors.

BACKGROUND: We assessed the prevalence and diagnostic value of ECG abnormalities for cardiomyopathy surveillance in childhood cancer survivors. METHODS: In this cross-sectional study, 1381 survivors (≥5 years) from the Dutch Childhood Cancer Survivor Study part 2 and 272 siblings underwent a long-term follow-up ECG and echocardiography. We compared ECG abnormality prevalences using the Minnesota Code between survivors and siblings, and within biplane left ventricular ejection fraction (LVEF) categories. Among 880 survivors who received anthracycline, mitoxantrone or heart radiotherapy, logistic regression models using least absolute shrinkage and selection operator identified ECG abnormalities associated with three abnormal LVEF categories (<52% in male/<54% in female, <50% and <45%). We assessed the overall contribution of these ECG abnormalities to clinical regression models predicting abnormal LVEF, assuming an absence of systolic dysfunction with a <1% threshold probability. RESULTS: 16% of survivors (52% female, mean age 34.7 years) and 14% of siblings had major ECG abnormalities. ECG abnormalities increased with decreasing LVEF. Integrating selected ECG data into the baseline model significantly improved prediction of sex-specific abnormal LVEF (c-statistic 0.66 vs 0.71), LVEF <50% (0.66 vs 0.76) and LVEF <45% (0.80 vs 0.86). While no survivor met the preset probability threshold in the first two models, the third model used five ECG variables to predict LVEF <45% and was applicable for ruling out (sensitivity 93%, specificity 56%, negative predictive value 99.6%). Calibration and internal validation tests performed well. CONCLUSION: A clinical prediction model with ECG data (left bundle branch block, left atrial enlargement, left heart axis, Cornell's criteria for left ventricular hypertrophy and heart rate) may aid in ruling out LVEF <45%.

Dexmedetomidine target controlled infusion for awake craniotomy†.

A 73-year-old woman underwent an awake craniotomy for the resection of a supratentorial brain tumour. We provided sedation for the surgery using a dexmedetomidine target controlled infusion using the Dyck pharmacokinetic model. Using a target controlled infusion allowed more rapid titration to the desired plasma level compared with a manual infusion, without any unexpected cardiovascular, respiratory or other complications. Rapid titration of sedation during awake craniotomy is desirable, allowing deeper sedation during stimulating parts of the surgery, followed by lighter sedation - or absence of sedation - during cortical mapping. While this can be performed manually, we found utilising the Dyck model in this case simple and quick to use, avoiding the need to manually calculate infusion rates. We believe this is the first report of using a target controlled infusion model to administer dexmedetomidine for awake craniotomy, and suggest it could be considered as an alternative to administering a manual infusion.

Simultaneous analysis of cannabinoids and terpenes in Cannabis sativa inflorescence using full comprehensive two-dimensional liquid chromatography coupled to smart active modulation.

Nowadays, the higher peak capacity achievable by comprehensive two-dimensional liquid chromatography (LC×LC) for the analysis of vegetal samples is well-recognized. In addition, numerous compounds may be present in very different amounts. Cannabinoids and terpenes represent the main components of Cannabis sativa inflorescence samples, whose quantities are relevant for many application purposes. The analyses of both families are performed by different methods, at least two different separation methodologies, mainly according to their chemical characteristics and concentration levels. In this work, concentration differences and sample complexity issues were addressed using an LC×LC method that incorporates an optimized modulation strategy, namely smart active modulation, for the simultaneous analysis of cannabinoids and terpenes. The system was built by interposing an active flow splitter pump between both dimensions. This set up aimed to exploit the known advantages of LC×LC. In addition, here we proposed to use the splitter pump for online control over the splitting ratio to facilitate the selective dilution of different eluted fractions containing compounds with highly different concentrations. This work represents the first application and demonstration of smart active modulation (SAM) in LC×LC to simultaneously determine analytes with significant differences in concentration levels present in complex samples. The proposed method was tested with eight different strains, from which fingerprints were taken, and numerous cannabinoids and terpenes were identified in these samples. With this strategy, between 49 and 54 peaks were obtained in the LC×LC chromatograms corresponding to different strains. THCA-A was the main component in six strains, while CBDA was the main component in the other two strains. The main terpenes found were myrcene (in five strains), limonene (in two strains), and humulene (in one strain). Additionally, numerous other cannabinoids and terpenes were identified in these samples, providing valuable compositional information for growers, as well as medical and recreational users. The SAM strategy here proposed is simple and it can be extended to other complex matrices.