Reprogramming natural killer cells for cancer therapy.

The last decade has seen rapid development in the field of cellular immunotherapy, particularly in regard to chimeric antigen receptor (CAR)-modified T cells. However, challenges, such as severe treatment-related toxicities and inconsistent quality of autologous products, have hindered the broader use of CAR-T cell therapy, highlighting the need to explore alternative immune cells for cancer targeting. In this regard, natural killer (NK) cells have been extensively studied in cellular immunotherapy and were found to exert cytotoxic effects without being restricted by human leukocyte antigen and have a lower risk of causing graft-versus-host disease; making them favorable for the development of readily available "off-the-shelf" products. Clinical trials utilizing unedited NK cells or reprogrammed NK cells have shown early signs of their effectiveness against tumors. However, limitations, including limited in vivo persistence and expansion potential, remained. To enhance the antitumor function of NK cells, advanced gene-editing technologies and combination approaches have been explored. In this review, we summarize current clinical trials of antitumor NK cell therapy, provide an overview of innovative strategies for reprogramming NK cells, which include improvements in persistence, cytotoxicity, trafficking and the ability to counteract the immunosuppressive tumor microenvironment, and also discuss some potential combination therapies.

Boron homeostasis affects Longan yield: a study of NIP and BOR boron transporter of two cultivars.

BACKGROUND: Essential micronutrient Boron (B) plays crucial roles in plant survival and reproduction but becomes toxic in higher quantities. Although plant cells have different B transport systems, B homeostasis is mainly maintained by two transporter protein families: B exporters (BOR) and nodulin-26-like intrinsic proteins (NIP). Their diversity and differential expression are responsible for varied B tolerance among plant varieties and species. Longan is a highly admired subtropical fruit with a rising market in China and beyond. In the present study, we cultured Shixia (SX) and Yiduo (YD), two differently characterized Longan cultivars, with foliar B spray. We analyzed their leaf physiology, fruit setting, B content, and boron transporter gene expression of various tissue samples. We also traced some of these genes' subcellular localization and overexpression effects. RESULTS: YD and SX foliage share similar microstructures, except the mesophyll cell wall thickness is double in YD. The B spray differently influenced their cellular constituents and growth regulators. Gene expression analysis showed reduced BOR genes expression and NIP genes differential spatiotemporal expression. Using green fluorescent protein, two high-expressing NIPs, NIP1 and NIP19, were found to translocate in the transformed tobacco leaves' cell membrane. NIPs transformation of SX pollen was confirmed using magnetic beads and quantified using a fluorescence microscope and polymerase chain reaction. An increased seed-setting rate was observed when YD was pollinated using these pollens. Between the DlNIP1 and DlNIP19 transformed SX pollen, the former germinated better with increasing B concentrations and, compared to naturally pollinated plants, had a better seed-setting rate in YD♀ × SX♂. CONCLUSION: SX and YD Longan have different cell wall structures and react differently to foliar B spray, indicating distinct B tolerance and management. Two B transporter NIP genes were traced to localize in the plasma membrane. However, under high B concentrations, their differential expression resulted in differences in Jasmonic acid content, leading to differences in germination rate. Pollination of YD using these NIPs transformed SX pollen also showed NIP1 overexpression might overcome the unilateral cross incompatibility between YD♀ × SX♂ and can be used to increase Longan production.

Management for children and adolescents with overweight and obesity: a recommendations mapping.

BACKGROUND: Childhood obesity is a global public health issue, and the status of clinical practice guidelines (CPGs) as instruction manuals for the management of childhood obesity remains unclear. This study aims to identify and apprise the methodological and reporting quality of CPGs focused on childhood obesity and provide an overview of key recommendations. METHODS: Databases and websites reporting guidelines were searched from January, 2018 to September, 2023. The methodological quality was graded using the AGREE II, and RIGHT was used to assess the reporting completeness. RESULTS: Among the six included CPGs, two were rated as high quality and considered "Recommended" and three were reported no less than 80%. CPGs included 184 recommendations cover diagnosis, assessment and management of complications, interventions and prevention. The diagnostic criteria for children with obesity over 2 years of age are based on normative BMI percentiles, depending on sex and age. CPGs recommended the delivery of multi-component behavior-changed interventions included controlling diet and increasing physical activity. Pharmacological interventions and bariatric surgery are considered as complementary therapies. CONCLUSION: CPGs for childhood obesity should emphasize the impact of psychological factors and consider the provision of interventions from multiple settings, and could consider the role of complementary alternative therapies. IMPACT: Six guidelines have been published in the past 5 years focusing children obesity. Recommendations covered diagnosis, multiple intervention and prevention. Guidelines should focus on the role of complementary alternative therapies. Guidelines should emphasize the impact of psychological factors. Guidelines should consider the provision of interventions from multiple settings.

Discovery of novel FUT8 inhibitors with promising affinity and in vivo efficacy for colorectal cancer therapy.

As a member of glycosyltransferases, fucosyltransferase 8 (FUT8) is essential to core fucosylation and has been considered as a potential therapeutic target for malignant tumors, including colorectal cancer (CRC). Based on the identification of key binding residues and probable conformation of FUT8, an integrated strategy that combines virtual screening and chemical optimization was carried out and compound 15 was identified as a potent FUT8 inhibitor with novel chemical structure and in vitro antitumor activity. Moreover, chemical pulldown experiments and binding assays confirmed that compound 15 selectively bound to FUT8. In vivo, compound 15 showed promising anti-CRC effects in SW480 xenografts. These data support that compound 15 is a potential FUT8 inhibitor for CRC treatment and deserve further optimization studies.

Molecular 14 C evidence for contrasting turnover and temperature sensitivity of soil organic matter components.

Climate projection requires an accurate understanding for soil organic carbon (SOC) decomposition and its response to warming. An emergent view considers that environmental constraints rather than chemical structure alone control SOC turnover and its temperature sensitivity (i.e., Q10 ), but direct long-term evidence is lacking. Here, using compound-specific radiocarbon analysis of soil profiles along a 3300-km grassland transect, we provide direct evidence for the rapid turnover of lignin-derived phenols compared with slower-cycling molecular components of SOC (i.e., long-chain lipids and black carbon). Furthermore, in contrast to the slow-cycling components whose turnover is strongly modulated by mineral association and exhibits low Q10 , lignin turnover is mainly regulated by temperature and has a high Q10 . Such contrasts resemble those between fast-cycling (i.e., light) and mineral-associated slow-cycling fractions from globally distributed soils. Collectively, our results suggest that warming may greatly accelerate the decomposition of lignin, especially in soils with relatively weak mineral associations.

Cytokine profiles are associated with prolonged hematologic toxicities after B-cell maturation antigen targeted chimeric antigen receptor-T-cell therapy.

BACKGROUND AIMS: The considerable efficacy of B-cell maturation antigen-targeted chimeric antigen receptor (CAR)-T-cell therapy has been extensively demonstrated in the treatment of relapsed or refractory multiple myeloma. Nevertheless, in clinical practice, prolonged hematologic toxicity (PHT) extends hospital stay and impairs long-term survival. METHODS: This retrospective study reviewed 99 patients with relapsed or refractory multiple myeloma who underwent B-cell maturation antigen CAR-T-cell therapy at our institution between April 2018 and September 2021 (ChiCTR1800017404). RESULTS: Among 93 evaluable patients, the incidence of prolonged hematologic toxicities was high after CAR-T-cell infusion, including 38.71% (36/93) of patients with prolonged neutropenia, 22.58% (21/93) with prolonged anemia and 59.14% (55/93) with prolonged thrombocytopenia. In addition, 9.68% (9/93) of patients experienced prolonged pancytopenia. Our multivariate analyses identified that cytokine profiles were independent risk factors for PHTs, whereas a sufficient baseline hematopoietic function and high CD4/CD8 ratio of CAR-T cells were protective factors for PHTs after CAR-T-cell infusion. Subgroup analyses found that the kinetics of post-CAR-T hematologic parameters were primarily determined by the collective effects of cytokine release syndrome and baseline hematopoietic functions, and showed influential weights for the three lineages. CONCLUSIONS: Our findings improve the understanding of the impact of cytokines on hematopoietic functions, which could contribute to the mechanism investigation and exploration of potential intervention strategies.

4-Aminopyridine Protects Nigral Dopaminergic Neurons in the MPTP Mouse Model of Parkinson's Disease.

Various pharmacological blockers targeting K+ channel have been identified to be related to the treatment of Parkinson's disease (PD). Previous studies showed that 4-Aminopyridine (4-AP), a wide-spectrum K+ channel blocker, was able to attenuate apomorphine-induced rotation in parkinsonism rats, indicating the possible beneficial effects in attenuation of PD motor symptoms. However, it is unclear whether 4-AP exhibits neuroprotective effects against the neurodegeneration of substantia nigra (SN)-striatum system in PD. In this study, the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse model was employed to evaluate the neuroprotective effects of 4-AP. Results showed that 4-AP inhibited MPTP-induced dopaminergic neuronal loss in the SN as well as dopamine depletion in the striatum. Behavior indexes of open field test and rotarod test confirmed that 4-AP attenuated MPTP-induced motor deficits. We also showed that 4-AP treatment could significantly attenuate the MPTP-induced increase in malonaldehyde (MDA) levels and decrease in superoxide dismutase (SOD) levels. Additionally, MPTP significantly reduced the Bcl-2 expression and promoted the Caspase-3 activation; 4-AP protected dopaminergic neurons against MPTP-induced neurotoxicity by reversing these changes. These results indicate that 4-AP exerts a neuroprotective effect on dopaminergic neurons against MPTP by decreasing oxidative stress and apoptosis. This provides a promising therapeutic target for the treatment of PD.

Serum folate mediates the associations of MTHFR rs1801133 polymorphism with blood glucose levels and gestational diabetes mellitus in Chinese Han pregnant women.

This study aimed to explore the mediation effects of one-carbon metabolism (OCM) related nutrients on the association between MTHFR rs1801133 polymorphism and gestational diabetes mellitus (GDM). Folate, vitamin B12 and homocysteine (Hcy) were measured in the serum of 1254 pregnant women. Linear and logistic regressions were used to estimate the associations of OCM nutrients and MTHFR rs1801133 polymorphism with blood glucose levels and GDM risk. Mediation analysis was applied to test the mediation effects of folate, vitamin B12 and Hcy on the association of MTHFR rs1801133 polymorphism with blood glucose concentrations and GDM. Pregnant women with MTHFR rs1801133 CC genotype had higher serum folate (10·75 v. 8·90 and 9·40 ng/ml) and lower serum Hcy (4·84 v. 4·93 and 5·20 µmol/l) than those with CT and TT genotypes. Folate concentrations were positively associated with fasting plasma glucose (FPG), 1-h plasma glucose (1-h PG), 2-h plasma glucose (2-h PG) and GDM risk. Vitamin B12 levels were negatively correlated with FPG and GDM. Although no direct association was found between MTHFR rs1801133 genotypes and GDM, there were significant indirect effects of MTHFR rs1801133 CC genotype on FPG (ß: 0·005; 95 % CI: 0·001, 0·013), 1-h PG (ß: 0·006; 95 % CI: 0·001, 0·014), 2-h PG (ß: 0·007; 95 % CI: 0·001, 0·015) and GDM (ß: 0·006; 95 % CI: 0·001, 0·014) via folate. In conclusion, serum folate mediates the effect of MTHFR rs1801133 on blood glucose levels and GDM. Our findings potentially provide a feasible GDM prevention strategy via individualised folate supplementation according to the MTHFR genotypes.

Arsenic metabolism, N6AMT1 and AS3MT single nucleotide polymorphisms, and their interaction on gestational diabetes mellitus in Chinese pregnant women.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in N6AMT1 and AS3MT are associated with arsenic (As) metabolism, and efficient As methylation capacity has been associated with diabetes. However, little is known about the gene-As interaction on gestational diabetes mellitus (GDM). OBJECTIVE: This study aimed to explore the individual and combined effects of N6AMT1 and AS3MT SNPs with As metabolism on GDM. METHODS: A cross-sectional study was performed among 385 Chinese pregnant women (86 GDM and 299 Non-GDM). Four SNPs in N6AMT1 (rs1997605 and rs1003671) and AS3MT (rs1046778 and rs11191453) were genotyped. Urinary inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were determined, and the percentages of As species (iAs%, MMA%, and DMA%) were calculated to assess the efficiency of As metabolism. RESULTS: Pregnant women with N6AMT1 rs1997605 AA genotype had lower iAs% (B: 2.11; 95% CI: 4.08, -0.13) and MMA% (B: 0.21; 95% CI: 0.39, -0.04) than pregnant women with GG genotype. The AS3MT rs1046778 and rs11191453 C alleles were negatively associated with iAs% and MMA% but positively associated with DMA%. Higher urinary MMA% was significantly associated with a lower risk of GDM (OR: 0.54; 95% CI: 0.30, 0.97). The A allele in N6AMT1 rs1997605 (OR: 0.46; 95% CI: 0.26, 0.79) was associated with a decreased risk of GDM. The additive interactions between N6AMT1 rs1997605 GG genotypes and lower iAs% (AP: 0.50; 95% CI: 0.01, 0.99) or higher DMA% (AP: 0.52; 95% CI: 0.04, 0.99) were statistically significant. Similar additive interactions were also found between N6AMT1 rs1003671 GG genotypes and lower iAs% or higher DMA%. CONCLUSIONS: Genetic variants in N6AMT1 and efficient As metabolism (indicated by lower iAs% and higher DMA%) can interact to influence GDM occurrence synergistically in Chinese pregnant women.

An artificial intelligence method to assess the tumor microenvironment with treatment outcomes for gastric cancer patients after gastrectomy.

BACKGROUND: The tumor microenvironment (TME) plays an important role in the occurrence and development of gastric cancer (GC) and is widely used to assess the treatment outcomes of GC patients. Immunohistochemistry (IHC) and gene sequencing are the main analysis methods for the TME but are limited due to the subjectivity of observers, the high cost of equipment and the need for professional analysts. METHODS: The ImmunoScore (IS) was developed in the TCGA cohort and validated in GEO cohorts. The Radiomic ImmunoScore (RIS) was developed in the TCGA cohort and validated in the Nanfang cohort. A nomogram was developed and validated in the Nanfang cohort based on RIS and clinical features. RESULTS: For IS, the area under the curves (AUCs) were 0.798 for 2-year overall survival (OS) and 0.873 for 4-year overall survival. For RIS, in the TCGA cohort, the AUCs distinguishing High-IS or Low-IS and predicting prognosis were 0.85 and 0.81, respectively; in the Nanfang cohort, the AUC predicting prognosis was 0.72. The nomogram performed better than the TNM staging system according to the ROC curve (all P < 0.01). Patients with TNM stage II and III in the High-nomogram group were more likely to benefit from adjuvant chemotherapy than Low-nomogram group patients. CONCLUSIONS: The RIS and the nomogram can be used to assess the TME, prognosis and adjuvant chemotherapy benefit of GC patients after radical gastrectomy and are valuable additions to the current TNM staging system. High-nomogram GC patients may benefit more from adjuvant chemotherapy than Low-nomogram GC patients.

Bone-forming perivascular cells: Cellular heterogeneity and use for tissue repair.

Mesenchymal progenitor cells are broadly distributed across perivascular niches-an observation conserved between species. One common histologic zone with a high frequency of mesenchymal progenitor cells within mammalian tissues is the tunica adventitia, the outer layer of blood vessel walls populated by cells with a fibroblastic morphology. The diversity and functions of (re)generative cells present in this outermost perivascular niche are under intense investigation; we have reviewed herein our current knowledge of adventitial cell potential with a somewhat narrow focus on bone formation. Antigens of interest to functionally segregate adventicytes are discussed, including CD10, CD107a, aldehyde dehydrogenase isoforms, and CD140a, among others. Purified adventicytes (such as CD10+ , CD107alow , and CD140a+ cells) have stronger osteogenic potential and promote bone formation in vivo. Recent bone tissue engineering applications of adventitial cells are also presented. A better understanding of perivascular progenitor cell subsets may represent a beneficial advance for future efforts in tissue repair and bioengineering.

Perivascular Fibro-Adipogenic Progenitor Tracing during Post-Traumatic Osteoarthritis.

Perivascular mural cells surround capillaries and microvessels and have diverse regenerative or fibrotic functions after tissue injury. Subsynovial fibrosis is a well-known pathologic feature of osteoarthritis, yet transgenic animals for use in visualizing perivascular cell contribution to fibrosis during arthritic changes have not been developed. Here, inducible Pdgfra-CreERT2 reporter mice were subjected to joint-destabilization surgery to induce arthritic changes, and cell lineage was traced over an 8-week period with a focus on the joint-associated fat pad. Results showed that, at baseline, inducible Pdgfra reporter activity highlighted adventitial and, to a lesser extent, pericytic cells within the infrapatellar fat pad. Joint-destabilization surgery was associated with marked fibrosis of the infrapatellar fat pad, accompanied by an expansion of perivascular Pdgfra-expressing cellular descendants, many of which adopted α-smooth muscle actin expression. Gene expression analysis of microdissected infrapatellar fat pad confirmed enrichment in membrane-bound green fluorescent protein/Pdgfra-expressing cells, along with a gene signature that corresponded with injury-associated fibro-adipogenic progenitors. Our results highlight dynamic changes in joint-associated perivascular fibro-adipogenic progenitors during osteoarthritis.

Impact of Secondary Aneurysmal Bone Cysts on Survival of Patients with Enneking Stage IIB Extremity Osteosarcoma: A Propensity Score Matching Analysis.

BACKGROUND: The clinicopathology of aneurysmal bone cysts (ABCs) secondary to osteosarcoma has not yet been reported. We conduct a retrospective review of ABCs secondary to osteosarcoma to characterize clinicopathology and influence on the survival of patients with Enneking stage IIB extremity osteosarcoma. PATIENTS AND METHODS: A total of 300 patients with Enneking stage IIB extremity osteosarcoma were eligible for analysis. These cases were divided, according to the pathology of biopsy and magnetic resonance imaging (MRI), into ABCs group and no ABCs group. Patients (ABCs versus no ABCs) were compared using a 1:2 propensity score analysis to best match between groups. Clinicopathology and survival data were analyzed. RESULTS: The total occurrence rate of secondary ABCs was 10.3%. A higher prevalence of pathological fractures was observed in the ABCs group (22.6%) compared with the no ABCs group (8.6%) (p = 0.032). Patients with ABCs were more likely to undergo amputation compared with patients without ABCs (p = 0.007). Those with secondary ABCs had poorer response to chemotherapy before and after propensity score matching (p = 0.006 and p = 0.048, respectively). Kaplan-Meier survival analysis showed that EFS and OS distributions were not significantly different between the two patient groups. ABCs were not significantly different in terms of EFS or OS in the multivariate analysis model (p > 0.05). CONCLUSIONS: The presence of secondary ABCs was associated with increased occurrence rate of pathological fracture and high percentage of amputation. Moreover, patients with secondary ABCs had poorer response to chemotherapy. However, the presence of secondary ABCs did not influence survival of patients with Enneking stage IIB extremity osteosarcoma.

PDGFRα marks distinct perivascular populations with different osteogenic potential within adipose tissue.

The perivascular niche within adipose tissue is known to house multipotent cells, including osteoblast precursors. However, the identity of perivascular subpopulations that may mineralize or ossify most readily is not known. Here, we utilize inducible PDGFRα (platelet-derived growth factor alpha) reporter animals to identify subpopulations of perivascular progenitor cells. Results showed that PDGFRα-expressing cells are present in four histologic niches within inguinal fat, including two perivascular locations. PDGFRα+ cells are most frequent within the tunica adventitia of arteries and veins, where PDGFRα+ cells populate the inner aspects of the adventitial layer. Although both PDGFRα+ and PDGFRα- fractions are multipotent progenitor cells, adipose tissue-derived PDGFRα+ stromal cells proliferate faster and mineralize to a greater degree than their PDGFRα- counterparts. Likewise, PDGFRα+ ectopic implants reconstitute the perivascular niche and ossify to a greater degree than PDGFRα- cell fractions. Adventicytes can be further grouped into three distinct groups based on expression of PDGFRα and/or CD34. When further partitioned, adventicytes co-expressing PDGFRα and CD34 represented a cell fraction with the highest mineralization potential. Long-term tracing studies showed that PDGFRα-expressing adventicytes give rise to adipocytes, but not to other cells within the vessel wall under homeostatic conditions. However, upon bone morphogenetic protein 2 (BMP2)-induced ossicle formation, descendants of PDGFRα+ cells gave rise to osteoblasts, adipocytes, and "pericyte-like" cells within the ossicle. In sum, PDGFRα marks distinct perivascular osteoprogenitor cell subpopulations within adipose tissue. The identification of perivascular osteoprogenitors may contribute to our improved understanding of pathologic mineralization/ossification.

Clinical significance of indeterminate pulmonary nodules on the survival of 364 patients with nonmetastatic, high-grade, localized osteosarcoma: A 12-year retrospective cohort study.

BACKGROUND AND OBJECTIVES: We investigated the clinical significance of indeterminate pulmonary nodules (IPNs) in patients diagnosed with nonmetastatic, high-grade localized osteosarcoma. METHODS: We retrospectively analyzed the clinical data of 364 patients with nonmetastatic, high-grade localized osteosarcoma. Based on pulmonary computed tomography findings at presentation, the patients were categorized into the no-nodules and the IPNs group and were further categorized into subgroups based on age (<18 and ≥18 years). We performed an intergroup comparison of event-free survival (EFS) and overall survival (OS). RESULTS: At presentation, 276 (75.8%) patients showed no nodules, and 88 (24.2%) patients showed IPNs. The EFS and OS were similar between adults with IPNs (n = 54 [30.5%]) and without nodules (n = 123 [69.5%]) (p = .200 and p = .609, respectively). No significant intergroup difference in OS was observed in pediatric patients (p = .093). However, pediatric patients with IPNs (n = 34 [18.2%]) had poorer EFS than those without nodules (n = 153 [81.8%]) (p = .016). Multivariate analyses confirmed that IPNs were independently associated with poorer EFS in pediatric patients (hazard ratio 1.788, 95% confidence interval 1.092-2.926, p = .021). CONCLUSIONS: This study showed that IPNs at presentation did not affect the survival of adults with nonmetastatic, high-grade localized osteosarcoma but were associated with poorer EFS in pediatric patients.

Generation of sodium halide endohedral metallofullerenes in the gas phase.

RATIONALE: Recent theoretical calculations show that ionic bond encapsulated endohedral metallofullerenes (EMFs) have great potential in the application of molecular electronic components. However, experimental study of these species is very limited, due to the difficulty in their generation. Thus, it is important to study the possibility and optimized conditions of these species generated in the gas phase. METHODS: Mixtures of graphene and metal halides (MX), where M = Na, K; and X = Cl, Br, I, were used as the precursors for the experiments. Mass spectra were obtained in positive ion mode by laser irradiation of these mixtures of graphene and metal halides using a 7.0 T Fourier transform ion cyclotron resonance (FTICR) mass spectrometer equipped with a 355 nm YAG laser. RESULTS: EMF ions of NaCl@C+ 2n (2n = 120-244), NaBr@C+ 2n (2n = 110-240), and NaI@C+ 2n (2n = 116-198) were observed in the laser ablation mass spectra. However, the encapsulated ion could not be replaced by Li or K in these experiments, indicating that the effects of the metal cation on the EMFs are larger than those of halide anions. CONCLUSIONS: Ionic bond encapsulated EMF ions of NaX@C+ 2n (X = Cl, Br and I, 110 ≤ 2n ≤ 244) were generated by laser ablation of the mixture of graphene and sodium halides, but no species containing lithium or potassium were observed. This work opens the possibilities of using laser ablation for the synthesis of large-sized salt-encaged EMFs. Further study of the mechanism for these processes is important for the generation of the missing species.

Poor Renal and Cardiovascular Outcomes in Patients with Biopsy-Proven Diabetic Nephropathy.

BACKGROUND: Despite the high mortality of cardiovascular disease (CVD) in diabetic patients with renal injury, few studies have compared cardiovascular characteristics and outcomes between patients with diabetic nephropathy (DN) and non-diabetic renal disease (NDRD). METHODS: A total of 326 type 2 diabetes mellitus patients with renal biopsy were assigned to DN and NDRD groups. Echocardiography and Doppler ultrasound were performed to evaluate left ventricular hypertrophy (LVH) and peripheral atherosclerosis disease (PAD). Renal and cardiovascular survival rates were compared between the DN and NDRD groups by Kaplan-Meier analysis. Risk factors for renal and cardiovascular events in DN patients were identified by a Cox proportional hazards model. RESULTS: In total, 179 patients entered the DN group (54.9%) and 147 made up the NDRD group (45.1%). The presence of diabetic retinopathy, family history of diabetes, and dependence on insulin therapy were associated with the presence of DN. DN patients had more CVD with more severe LVH and PAD. Poorer renal (log-rank χ2 = 26.534, p < 0.001) and cardiovascular (log-rank χ2 = 16.257, p < 0.001) prognoses were seen in the DN group. DR (HR 1.539, 95% CI 1.332-1.842), eGFR (HR 0.943, 95% CI 0.919-0.961), and 24-h proteinuria (HR 1.211, 95% CI 1.132-1.387) were identified as risk factors for renal endpoints. Age (HR 1.672, 95% CI 1.487-1.821), HbA1C (HR 1.398, 95% CI 1.197-1.876), and 24-h proteinuria (HR 1.453, 95% CI 1.289-1.672) were associated with cardiovascular endpoints. CONCLUSION: Patients with DN had more severe CVD along with poorer renal and cardiovascular prognoses than those with NDRD.

Multiplexing microelectrodes for dielectrophoretic manipulation and electrical impedance measurement of single particles and cells in a microfluidic device.

This work presents a microfluidic device, which was patterned with (i) microstructures for hydrodynamic capture of single particles and cells, and (ii) multiplexing microelectrodes for selective release via negative dielectrophoretic (nDEP) forces and electrical impedance measurements of immobilized samples. Computational fluid dynamics (CFD) simulations were performed to investigate the fluidic profiles within the microchannels during the hydrodynamic capture of particles and evaluate the performance of single-cell immobilization. Results showed uniform distributions of velocities and pressure differences across all eight trapping sites. The hydrodynamic net force and the nDEP force acting on a 6 µm sphere were calculated in a 3D model. Polystyrene beads with difference diameters (6, 8, and 10 µm) and budding yeast cells were employed to verify multiple functions of the microfluidic device, including reliable capture and selective nDEP-release of particles or cells and sensitive electrical impedance measurements of immobilized samples. The size of immobilized beads and the number of captured yeast cells can be discriminated by analyzing impedance signals at 1 MHz. Results also demonstrated that yeast cells can be immobilized at single-cell resolution by combining the hydrodynamic capture with impedance measurements and nDEP-release of unwanted samples. Therefore, the microfluidic device integrated with multiplexing microelectrodes potentially offers a versatile, reliable, and precise platform for single-cell analysis.

Climate warming alters subsoil but not topsoil carbon dynamics in alpine grassland.

Subsoil contains more than half of soil organic carbon (SOC) globally and is conventionally assumed to be relatively unresponsive to warming compared to the topsoil. Here, we show substantial changes in carbon allocation and dynamics of the subsoil but not topsoil in the Qinghai-Tibetan alpine grasslands over 5 years of warming. Specifically, warming enhanced the accumulation of newly synthesized (14 C-enriched) carbon in the subsoil slow-cycling pool (silt-clay fraction) but promoted the decomposition of plant-derived lignin in the fast-cycling pool (macroaggregates). These changes mirrored an accumulation of lipids and sugars at the expense of lignin in the warmed bulk subsoil, likely associated with shortened soil freezing period and a deepening root system. As warming is accompanied by deepening roots in a wide range of ecosystems, root-driven accrual of slow-cycling pool may represent an important and overlooked mechanism for a potential long-term carbon sink at depth. Moreover, given the contrasting sensitivity of SOC dynamics at varied depths, warming studies focusing only on surface soils may vastly misrepresent shifts in ecosystem carbon storage under climate change.

Encapsulation of an Ionic Bond in Fullerenes: What is the Difference?

Endohedral metallofullerene ions containing an ionic bond of Lu-Cl were observed in a mass spectrum for the first time. A theoretical calculation has been performed on the example of LuCl@C90. The two most stable isomers are LuCl@ C2(99917)-C90 and LuCl@ C2(99914)-C90. Interestingly, both encaged Lu-Cl bonds have potential curves quite different from the Morse curve and have some energy-preferential directions relative to their outside carbon cages.