Wiley最新文献

Background: The pentanucleotide (TTTCA) repeat expansion (exp) insertion, along with the accompanying (TTTTA)exp, causes familial cortical myoclonic tremor with epilepsy (FCMTE). The genotype-phenotype correlations and intergenerational instabilities related to (TTTCA)exp and (TTTTA)exp are still unclear.

Objective: The aim was to investigate the genotype-phenotype correlations and intergenerational instabilities related to (TTTCA)exp and (TTTTA)exp in FCMTE1.

Methods: We performed targeted long-read sequencing on 77 FCMTE1 patients. After quality control, metrics such as total repeat count, respective (TTTTA)exp and (TTTCA)exp count, and interruptions were assessed in 73 patients. Correlations between metrics and the patients' clinical features, as well as repeat instability during parental transmission, were analyzed.

Results: Among 73 alleles, the average total repeat counts were 848 ± 152 units, with (TTTTA)exp and (TTTCA)exp averaging 498 ± 196 units and 356 ± 110 units, respectively. (TTTCA)exp counts were inversely correlated with the age at onset for cortical tremor (Spearman's rho = -0.348, P = 0.005) and epilepsy (Spearman's rho = -0.424, P = 0.003). A negative correlation was found between (TTTCA)exp counts and relatively moderate seizure pattern with prodrome (odds ratio = 0.988, 95% confidence interval: 0.980-0.995, P = 0.002). During parental transmission, (TTTCA)exp counts increased significantly (P = 0.007), with maternal transmission showing a significantly larger increase compared to paternal transmission (P = 0.013).

Conclusion: The (TTTCA)exp insertion serves as the length-dependent pathogenic component within the two-motif repeat expansion. Its differential expanding nature during parental transmissions is highly associated with the genetic anticipation in FCMTE1. © 2024 International Parkinson and Movement Disorder Society.

In this study, we disclose for the first time that formate salt can be used as a bifunctional reagent for the synthesis of phenol derivatives and as a CO source for carbonylative cross-coupling processes using the COware gas reactor under activation free conditions. Key to this success is the in-situ synthesis of aryl formate via an unprecedented nickel/organophotocatalyst system under blue LED irradiation. This developed system demonstrated high applicability to various aryl iodide substrates for synthesizing phenol derivatives. Moreover, the generated CO could be utilized in a range of carbonylative C-heteroatom and C-C processes. Notably, commercially available H¹³COONa salt can serve as a bifunctional reagent for both synthesizing phenols and generating ¹³CO.

Background: Population-scale databases majorly contribute to variant interpretation. The recently released Genome Aggregation Database (gnomAD) v4 offers a >5-fold increased sample size compared to v2.1.1. Pathogenic variants absent from v2.1.1 are now registered in v4 at a considerable rate. The implications on variant interpretation in dystonia are unknown.

Methods: All curated variants linked to the most common dominant forms of isolated dystonia were extracted from the International Parkinson's Disease and Movement Disorder Society Gene database. We compared variant population-frequencies and gene constraint metrics between gnomAD v2.1.1 and v4.

Results: The majority of dystonia-causing variants (192/247, 77.7%) remained absent from the newer gnomAD version. Of 219 variants absent from v2.1.1, 27 (12.3%) appeared for the first time in v4.1, including well-established pathogenic alleles. Gene constraints for GNAL and KMT2B significantly decreased in v4.

Conclusions: A growing number of dystonia-linked alleles are seen in gnomAD v4. The presence in population-scale data does not preclude pathogenicity. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Introduction: Developing a more effective treatment for the global impact of diabetic kidney disease is crucial. This study examined the renoprotective effects of combining glucagon-like peptide-1 receptor agonists (GLP-1 RA) with sodium-glucose cotransporter 2 inhibitors (SGLT2i) compared to SGLT2is alone in type 2 diabetes (DM).

Materials and methods: This retrospective cohort study used data from the TriNetX Global Collaborative Network. Type 2 DM patients with estimated glomerular filtration rates ≥60 mL/min/1.73 m² who used GLP-1 RA or SGLT2i between January 1, 2013, and December 31, 2023. Propensity score matching balanced baseline characteristics, resulting in 71,186 patients in each group (combined GLP-1 RA and SGLT2i therapy vs SGLT2i alone). Cox regression model was adopted to compare outcomes over a 5-year period, including major adverse kidney events (MAKE), acute kidney injury (AKI), end-stage kidney disease (ESKD), and all-cause mortality.

Results: After matching, the average age was 57.1 ± 10.8 years for the GLP-1 RA plus SGLT2i group and 57.2 ± 11.7 years for the SGLT2i-only group. The GLP-1 RA plus SGLT2i group had significantly lower risk of MAKE (hazard ratio [HR]: 0.73, 95% confidence interval [CI]: 0.69-0.77), AKI (HR: 0.82, 95% C0I: 0.77-0.87), ESKD (HR: 0.61, 95% CI: 0.47-0.78), and all-cause mortality (HR: 0.54, 95% CI: 0.50-0.58) compared to the SGLT2i-only group. Moreover, subgroup analyses showed consistent benefits across different subgroups.

Conclusions: Dual therapy with GLP-1 RA and SGLT2i is supported to enhance renal outcomes and address the growing burden of diabetic kidney disease.

Liquid-liquid phase separation (LLPS) refers to a spontaneous separation behavior of biomacromolecules under specific physiological conditions, playing a crucial role in regulating various biological processes. Recent advances in synthetic peptides have greatly improved our understanding of peptide-based coacervate droplets and expanded their applications in biomedicine. Numerous peptide sequences have been reported that undergo phase separation, enabling the concentration and sequestration of different guest molecules for purposes such as drug delivery, catalytic performance, and bioanalytical techniques. Particularly, some of these peptides offer significant advantages in controlled drug release, efficient cell transfection, accelerated reaction kinetics, and selective biomarker detection. This review provides an overview of recent developments in peptide-based LLPS, exploring various strategies for designing peptide sequences and their biomedical applications. It also addresses the challenges and future directions for LLPS peptide vehicles as promising biomaterials.

A growing demand for plant-based proteins and renewable nitrogen supplies has necessitated an intensification of legume cultivation in Europe. However, the cultivation of grain legumes is inherently exposed to various risks, including lodging and fungal infections. Mixed cropping of pea (Pisum sativum L.) and barley (Hordeum vulgare L.) presents a promising approach to increase plant-based protein production while also improving yield stability. We performed a multi-environment-mixed cropping comparison with pure pea and pure barley to determine the effects of the cultivation method on root rot resistance, N supply in successive crops, grain yield, and economic performance. While the economic performance was similar for pure pea and mixed cropping, we observed a lower variability of the farmer's gross margin in mixed cropping compared with pure cropping across 3 years and two locations. Especially in seasons with high precipitation, the mixed cropping approach prevented lodging and harvest losses. The N supply in the successive crop was equal or higher in mixed cropping compared with pure pea cropping. No variation in the pea root rot infestation levels was observed between mixed and pure cropping, indicating a general demand for resistance breeding. Our experiment indicated genotype-specific effects on the gross margin in regard to culture (pure pea and mixed cropping). Leafy genotypes in particular demonstrate substantial performance gains when cultivated in mixed cropping systems. The conclusion is that mixed cropping leads to similarly positive crop rotation nitrogen effects as pure pea cropping, with the advantage of reduced gross margin and yield variability.

The spread of point-of-care (PoC) diagnostic tests using electrochemical sensors poses a significant environmental challenge, especially in limited-resource settings due to the lack of waste management infrastructure. This issue is expected to intensify with the emergence of the Internet of Medical Things (IoMT), necessitating eco-friendly solutions for disposable devices. This review discusses efforts to develop green and sustainable PoC diagnostic devices, clarifying terms like biodegradability and transient electronics. It explores potential transient and biodegradable materials and fabrication technologies, emphasizing sustainable electronics with low-energy consumption and low-carbon footprint techniques, particularly favoring printing methods. The review highlights examples of necessary electronic components containing biodegradable materials for electrochemical PoC devices and discusses their role in device sustainability. Finally, it examines the feasibility of integrating these components and technologies into comprehensive biodegradable PoC devices, addressing the imminent need for eco-friendly solutions in diagnostic testing. This comprehensive discussion serves as a guide for researchers and developers striving to mitigate the environmental impact of PoC testing in the era of IoMT and personalized medicine.

Mutations in colony stimulating factor 1 receptor (CSF1R) result in CSF1R-related disorder (CSF1R-RD). Our previous study demonstrated a proteolytic generation of a soluble CSF1R (sCSF1R) that could potentially serve as a diagnostic biomarker of CSF1R-RD. Herein, we observed that sCSF1R is released into peripheral serum as a highly glycosylated monomer in Csf1r^+/- mice that mimic the clinical symptoms of CSF1R-RD patients. Notably, we found that serum sCSF1R could distinguish CSF1R-RD cohorts from controls with high accuracy as evaluated by receiver operating characteristic (ROC) curves. This study demonstrates that reduced sCSF1R in serum may serve as a diagnostic biomarker for CSF1R-RD. ANN NEUROL 2024.

Acenes are notable for their optoelectronic properties and applications in organic electronics. Starphenes are structurally related molecules possessing three acene arms that radiate linearly from a central benzene ring (i. e., linearly annellated triphenylenes). Large starphenes have been prepared using convergent syntheses involving transition metal catalyzed cyclotrimerizations of either preformed acenes or arynes. Here, we report a one-pot divergent synthesis of a 13-ring triquinone that is readily converted to a [4.4.4]tridecastarphene derivative. The one-pot procedure involves the sequential reactions of three 1,4-anthraquinones with o-quinodimethane derivatives that are generated sequentially from a stable, trisulfone precursor. The resulting [4.4.4]tridecastarphene derivative bearing p-(t-butyl)phenyl substituents was characterized by ¹H NMR, ¹³C NMR and UV-vis spectroscopies, as well as mass spectrometry, cyclic voltammetry and differential pulse voltammetry. Theoretical and experimental studies reveal a relatively high-lying HOMO orbital (about -4.70 to -4.86 eV) and a relatively small HOMO-LUMO gap (2.1 eV), suggesting utility as a p-type organic semiconductor. Our [4.4.4]tridecastarphene derivative photooxidizes in a CH₂Cl₂ solution exposed to ambient light and air with a half-life of 150 minutes at room temperature, but shows no sign of degradation after 12 months in the solid-state. Our [4.4.4]tridecastarphene derivative also shows excellent solubility in a number of organic solvents including dichloromethane, chloroform and toluene, potentially enabling printed electronic applications.

Over the past two decades, microglia and astrocytes have emerged as critical mediators of neural circuit formation. Particularly during the postnatal period, both glial subtypes play essential roles in orchestrating nervous system development through communication with neurons. These functions include regulating synapse elimination, modulating neuronal density and activity, mediating synaptogenesis, facilitating axon guidance and organization, and actively promoting neuronal survival. Despite the vital roles of both microglia and astrocytes in ensuring homeostatic brain development, the extent to which the postnatal functions of these cells are regulated by sex and the manner in which these glial cells communicate with one another to coordinate nervous system development remain less well understood. Here, we review the critical functions of both microglia and astrocytes independently and synergistically in mediating neural circuit formation, focusing our exploration on the postnatal period from birth to early adulthood.