Applications of nanobodies in brain diseases.

Nanobodies are antibody fragments derived from camelids, naturally endowed with properties like low molecular weight, high affinity and low immunogenicity, which contribute to their effective use as research tools, but also as diagnostic and therapeutic agents in a wide range of diseases, including brain diseases. Also, with the success of Caplacizumab, the first approved nanobody drug which was established as a first-in-class medication to treat acquired thrombotic thrombocytopenic purpura, nanobody-based therapy has received increasing attention. In the current review, we first briefly introduce the characterization and manufacturing of nanobodies. Then, we discuss the issue of crossing of the brain-blood-barrier (BBB) by nanobodies, making use of natural methods of BBB penetration, including passive diffusion, active efflux carriers (ATP-binding cassette transporters), carrier-mediated influx via solute carriers and transcytosis (including receptor-mediated transport, and adsorptive mediated transport) as well as various physical and chemical methods or even more complicated methods such as genetic methods via viral vectors to deliver nanobodies to the brain. Next, we give an extensive overview of research, diagnostic and therapeutic applications of nanobodies in brain-related diseases, with emphasis on Alzheimer's disease, Parkinson's disease, and brain tumors. Thanks to the advance of nanobody engineering and modification technologies, nanobodies can be linked to toxins or conjugated with radionuclides, photosensitizers and nanoparticles, according to different requirements. Finally, we provide several perspectives that may facilitate future studies and whereby the versatile nanobodies offer promising perspectives for advancing our knowledge about brain disorders, as well as hopefully yielding diagnostic and therapeutic solutions.

An update on Ym1 and its immunoregulatory role in diseases.

Ym1 is a rodent-specific chitinase-like protein (CLP) lacking catalytic activity, whose cellular origins are mainly macrophages, neutrophils and other cells. Although the detailed function of Ym1 remains poorly understood, Ym1 has been generally recognized as a fundamental feature of alternative activation of macrophages in mice and hence one of the prevalent detecting targets in macrophage phenotype distinguishment. Studies have pointed out that Ym1 may have regulatory effects, which are multifaceted and even contradictory, far more than just a mere marker. Allergic lung inflammation, parasite infection, autoimmune diseases, and central nervous system diseases have been found associations with Ym1 to varying degrees. Thus, insights into Ym1's role in diseases would help us understand the pathogenesis of different diseases and clarify the genuine roles of CLPs in mammals. This review summarizes the information on Ym1 from the gene to its expression and regulation and focuses on the association between Ym1 and diseases.

Mental health of new undergraduate students before and after COVID-19 in China.

The purpose of this study was to examine the changes in severity of anxiety and depression symptoms, stress and sleeping quality after three months of mass quarantine for COVID-19 among undergraduate fresh students compared to their pre-COVID-19 measures. We used participants from the Chinese Undergraduate Cohort (CUC), a national prospective longitudinal study to examine the changes in anxiety and depression symptoms severity, stress and sleep quality after being under mass quarantine for three months. Wilcoxon matched pair signed-rank test was used to compare the lifestyle indicators. Severity of anxiety, depression symptoms, stress and sleep quality were compared with Wilcoxon signed-rank test. We used generalized estimating equation (GEE) to further quantify the change in mental health indicators and sleep quality after the COVID-19 mass quarantine compared to baseline. This study found that there was no deterioration in mental health status among Chinese new undergraduate students in 2020 after COVID-19 mass quarantine compared with the baseline measures in 2019. There was an improvement in sleep quality and anxiety symptoms. After adjusting for age, sex, exercise habit, time spent on mobile gadgets, and time spent outdoors, year 2020 was significantly associated with severity of depression symptoms in males (OR:1.52. 95%CI:1.05-2.20, p-value = 0.027). Year 2020 was significantly associated with the improvement of sleeping quality in total (OR:0.45, 95%CI:0.38-0.52, p < 0.001) and in all the subgroups. This longitudinal study found no deterioration in mental health status among Chinese new undergraduate students after three months of mass quarantine for COVID-19.

Structure-Activity Relationship Studies Using Natural and Synthetic Okadaic Acid/Dinophysistoxin Toxins.

Okadaic acid (OA) and the closely related dinophysistoxins (DTXs) are algal toxins that accumulate in shellfish and are known serine/threonine protein phosphatase (ser/thr PP) inhibitors. Phosphatases are important modulators of enzyme activity and cell signaling pathways. However, the interactions between the OA/DTX toxins and phosphatases are not fully understood. This study sought to identify phosphatase targets and characterize their structure-activity relationships (SAR) with these algal toxins using a combination of phosphatase activity and cytotoxicity assays. Preliminary screening of 21 human and yeast phosphatases indicated that only three ser/thr PPs (PP2a, PP1, PP5) were inhibited by physiologically saturating concentrations of DTX2 (200 nM). SAR studies employed naturally-isolated OA, DTX1, and DTX2, which vary in degree and/or position of methylation, in addition to synthetic 2-epi-DTX2. OA/DTX analogs induced cytotoxicity and inhibited PP activity with a relatively conserved order of potency: OA = DTX1 ≥ DTX2 >> 2-epi-DTX. The PPs were also differentially inhibited with sensitivities of PP2a > PP5 > PP1. These findings demonstrate that small variations in OA/DTX toxin structures, particularly at the head region (i.e., C1/C2), result in significant changes in toxicological potency, whereas changes in methylation at C31 and C35 (tail region) only mildly affect potency. In addition to this being the first study to extensively test OA/DTX analogs' activities towards PP5, these data will be helpful for accurately determining toxic equivalence factors (TEFs), facilitating molecular modeling efforts, and developing highly selective phosphatase inhibitors.

Formal total synthesis of okadaic acid via regiocontrolled gold(I)-catalyzed spiroketalizations.

Both C19 and C34 spiroketal domains of okadaic acid were assembled using gold(I) chloride catalyzed spiroketalizations, and the two resulting fragments were coupled to give the C15-C38 fragment of okadaic acid, a known intermediate for the total synthesis of this important natural product.

Versatile synthesis of the C3-C14 domain of 7-deoxyokadaic acid.

Described is a flexible synthesis of the C3-C14 domain of 7-deoxyokadaic acid that is amenable to facile structural diversification. Treatment of ynone 10 under acidic conditions led to net bis-conjugate addition of the latent diol to give the thermodynamically favored spiroketal 27, a versatile intermediate, en route to 7-deoxyokadaic acid and analogs.

Selective synthesis of monazite- and zircon-type LaVO(4) nanocrystals.

Pure monoclinic (m-) and tetragonal phased (t-) LaVO(4) nanocrystals could be obtained by a hydrothermal method in a controllable way with additives. It is found that chelating ligands, such as ethylenediaminetetraacetic acid [EDTA or H(4)L, where L(4-) = (CH(2)COO)(2)N(CH(2))(2)N(CH(2)COO)(2)(4-)], favor the formation of t-LaVO(4) and can induce the polymorph transformation from stable m-LaVO(4) to metastable t-LaVO(4). Further studies demonstrated the important roles of chelating ligands in this transformation process. Careful investigation over the phase transition from t- to m-LaVO(4) was also conducted with high-temperature X-ray diffraction (HTXRD) studies. The phase transition occurred at 850 degrees C, which is about 250 degrees C higher than for the bulk. The enhanced thermal stability of the nanosized metastable t-LaVO(4) may come from the small size effect. Our capability of obtaining and stabilizing t-LaVO(4) not only benefits the wider applications based on LaVO(4) due to the improved luminescent and catalytic performance but also provides a new idea in the studies of polymorph control and selective synthesis of inorganic materials.