Search Results (26)

The Santa Barbara Sense of Direction scale (SBSoD) is a self-report scale that assesses the ability to orient oneself in the environment. With the current study, we validated the Danish version of the SBSoD (SBSoDDK) and compared performance on the SBSoD across samples with different nationalities. We collected data for a Danish sample consisting of 119 Danish university students and received data from studies validating other versions of the SBSoD using American, German, Japanese, Chinese, Turkish, and British samples. The internal consistency and convergent and discriminant validity of the SBSoDDK, which exhibited a two-factor structure, were affirmed, and differences in performance on the SBSoD across samples with different nationalities were identified and may be linked to cultural variations in the sense of direction. The current study has certain weaknesses, including using nationality as a proxy for culture and variations in the gender compositions of the samples. Future studies should focus on addressing the current study’s weaknesses and revising and further validating the SBSoD. Full article

In this review, we summarize the processes of the assembly of multi-protein replisomes at the origins of replication. Replication licensing, the loading of inactive minichromosome maintenance double hexamers (dhMCM2-7) during the G1 phase, is followed by origin firing triggered by two serine–threonine kinases, Cdc7 (DDK) and CDK, leading to the assembly and activation of Cdc45/MCM2-7/GINS (CMG) helicases at the entry into the S phase and the formation of replisomes for bidirectional DNA synthesis. Biochemical and structural analyses of the recruitment of initiation or firing factors to the dhMCM2-7 for the formation of an active helicase and those of origin melting and DNA unwinding support the steric exclusion unwinding model of the CMG helicase. Full article

Background: The number of kidney transplant recipients over 70 years of age is increasing but detailed data on patient and graft survival in the modern era of immune suppression are few. Methods: A single-center cohort of patients of 70 years and older (n = 349) at time of kidney transplantation from 2010–2020 were followed until January 2023. Results: The median age was 73 years with a median follow-up of 4.3 years. Fifty percent of recipients of a living donor kidney (LDK, n = 143) received their graft pre-emptively. Cumulative death-censored graft survival was excellent in the LDK group and reached 98% at 5 years vs. 85% in the deceased donor kidney (DDK) group. Primary non-function (38%) and rejection (43%) were the major causes of graft loss in the first year after DDK transplantation. Rejection-related graft loss was 4.6% during follow-up. Median recipient survival was superior in the subgroup of pre-emptively transplanted LDK patients compared to non-pre-emptively LDK transplanted patients (11.1 versus 6.2 years). Non-pre-emptively transplanted patients had a significantly increased incidence of infection (HR 3.81, 1.46–9.96) and cardiovascular-related causes of death (HR 3.35, 1.16–9.71). Pre-emptive transplantation was also associated with a significantly improved graft survival in the DDK recipients but this result was confounded by significantly better HLA matching and younger donor age in this group. Conclusions: Pre-emptive LDK transplantation in patients of 70 years or older confers superior graft and recipient survival. Full article

This experiment was conducted to study the effects of different skinning seasons on the fur quality and hair follicle development of Rex rabbits. A total of 80,150-day-old Rex rabbits were slaughtered on 15 July 2022 (summer), 15 October 2022 (autumn), 15 January 2023 (winter), and 15 April 2023 (spring) in Shandong Province (10 males and 10 females in each season). The results show that the skin weight, skin area, skin thickness, and hair follicle density of the Rex rabbits (at 150 days of age) were lower in summer than in winter (p < 0.05). Moreover, the coat length was shorter in summer than in spring, autumn, and winter (p < 0.05). The shoulder fat weight, perirenal fat weight, and perigastric fat weight of the Rex rabbits in winter were higher than those in summer (p < 0.05). Furthermore, the leptin levels in serum were higher in winter than in summer in the Rex rabbits (p < 0.05). In terms of serum biochemistry, the glucose levels were higher in autumn and winter than in spring and summer (p < 0.05). The cholesterol, high-density lipoprotein cholesterol (HDL), and low-density lipoprotein cholesterol (LDL) in summer had higher values than in winter in the Rex rabbits (p < 0.05). In winter, the expression of the Wnt10b, catenin beta 1 (CTNNB1), glycogen synthase kinase 3 beta (GSK3β), insulin like growth factor I (IGF-I), Type I insulin-like growth factor receptor (IGF-IR), and epidermal growth factor (EGF) genes was higher (p < 0.05), and the expression of the dickkopf-1 (DDK1), transforming growth factor beta 1 (TGFβ-1), bone morphogenetic protein 2 (BMP2), and bone morphogenetic protein 4 (BMP4) genes was lower than in summer (p < 0.05). In summer, the heat shock 70 kDa protein (HSP70) expression and CTNNB1 protein phosphorylation levels in skin tissue were higher than in spring, autumn, and winter (p < 0.05). In winter, Wnt10b protein expression was higher (p < 0.05), and GSK-3β protein phosphorylation levels were lower than in spring, autumn, and winter (p < 0.05). These results show that the skinning season can affect the production performance and hair follicle development of Rex rabbits. Compared with other seasons, the quality of skin from rabbits slaughtered in winter is better. Seasons may regulate hair follicle development via the Wnt10b/β-catenin, TGFβ-BMP, IGF1, and EGF signaling pathways in Rex rabbits. Full article

Oral diadochokinetic (DDK) tasks are common research and clinical tools used to test oromotor skills across different age groups. They include alternating motion rate (AMR) and sequential motion rate (SMR) tasks. AMR tasks involve repeating a single syllable, whereas SMR tasks involve repeating varying syllables. DDK performance is mostly discussed regarding the increasing rates of AMR and SMR tasks from childhood to adulthood, although less attention is given to the performance differences between SMR and AMR tasks across age groups. Here, AMR and SMR syllabic rates were contrasted in three populations: 7–9-year-old children, 14–16-year-old adolescents and 20–30-year-old adults. The results revealed similar syllabic rates for the two DDK tasks in children, whereas adolescents and adults achieved faster SMR rates. Acoustic analyses showed similarities in prosodic features between AMR and SMR sequences and in anticipatory coarticulation in the SMR sequences in all age groups. However, a lower degree of coarticulation was observed in children relative to adults. Adolescents, on the contrary, showed an adult-like pattern. These findings suggest that SMR tasks may be more sensitive to age-related changes in oromotor skills than AMR tasks and that greater gestural overlap across varying syllables may be a factor in achieving higher rates in SMR tasks. Full article

Histone deacetylases (HDACs) play a key role in the control of transcription, cell proliferation, and migration. FDA-approved histone deacetylase inhibitors (HDACi) demonstrate clinical efficacy in the treatment of different T-cell lymphomas and multiple myeloma. However, due to unselective inhibition, they display a wide range of adverse effects. One approach to avoiding off-target effects is the use of prodrugs enabling a controlled release of the inhibitor in the target tissue. Herein, we describe the synthesis and biological evaluation of HDACi prodrugs with photo-cleavable protecting groups masking the zinc-binding group of the established HDACi DDK137 (I) and VK1 (II). Initial decaging experiments confirmed that the photocaged HDACi pc-I could be deprotected to its parent inhibitor I. In HDAC inhibition assays, pc-I displayed only low inhibitory activity against HDAC1 and HDAC6. After irradiation with light, the inhibitory activity of pc-I strongly increased. Subsequent MTT viability assays, whole-cell HDAC inhibition assays, and immunoblot analysis confirmed the inactivity of pc-I at the cellular level. Upon irradiation, pc-I demonstrated pronounced HDAC inhibitory and antiproliferative activities which were comparable to the parent inhibitor I. Additionally, only phototreated pc-I was able to induce apoptosis in Annexin V/PI and caspase-Glo 3/7 assays, making pc-I a valuable tool for the development of light-activatable HDACi. Full article

Nonspeech (or paraspeech) parameters are widely used in clinical assessment of speech impairment in persons with dysarthria (PWD). Virtually every standard clinical instrument used in dysarthria diagnostics includes nonspeech parameters, often in considerable numbers. While theoretical considerations have challenged the validity of these measures as markers of speech impairment, only a few studies have directly examined their relationship to speech parameters on a broader scale. This study was designed to investigate how nonspeech parameters commonly used in clinical dysarthria assessment relate to speech characteristics of dysarthria in individuals with movement disorders. Maximum syllable repetition rates, accuracies, and rates of isolated and repetitive nonspeech oral–facial movements and maximum phonation times were compared with auditory–perceptual and acoustic speech parameters. Overall, 23 diagnostic parameters were assessed in a sample of 130 patients with movement disorders of six etiologies. Each variable was standardized for its distribution and for age and sex effects in 130 neurotypical speakers. Exploratory Graph Analysis (EGA) and Confirmatory Factor Analysis (CFA) were used to examine the factor structure underlying the diagnostic parameters. In the first analysis, we tested the hypothesis that nonspeech parameters combine with speech parameters within diagnostic dimensions representing domain–general motor control principles. In a second analysis, we tested the more specific hypotheses that diagnostic parameters split along effector (lip vs. tongue) or functional (speed vs. accuracy) rather than task boundaries. Our findings contradict the view that nonspeech parameters currently used in dysarthria diagnostics are congruent with diagnostic measures of speech characteristics in PWD. Full article

Spot blotch is a highly destructive disease in wheat caused by the fungal pathogen Bipolaris sorokiniana (teleomorph, Cochliobolus sativus). It is prevalent in warm and humid areas, including Africa, Asia, Latin America, and the USA. In the present study, twelve isolates of B. sorokiniana were collected from wheat fields in three different geographical locations in India. The pathogenicity of seven sporulating isolates was assessed on ‘DDK 1025’, a spot blotch-susceptible wheat variety under greenhouse conditions. The isolate ‘D2’ illustrated the highest virulence, followed by ‘SI’ and ‘BS52’. These three isolates were sequenced using the Illumina HiSeq1000 platform. The estimated genome sizes of the isolates BS52, D2, and SI were 35.19 MB, 39.32 MB, and 32.76 MB, with GC contents of 48.48%, 50.43%, and 49.42%, respectively. The numbers of pathogenicity genes identified in BS52, D2, and SI isolates were 2015, 2476, and 2018, respectively. Notably, the isolate D2 exhibited a relatively larger genome with expanded arsenals of Biosynthetic Gene Clusters (BGCs), CAZymes, secretome, and pathogenicity genes, which could have contributed to its higher virulence among the tested isolates. This study provides the first comparative genome analysis of the Indian isolates of B. sorokiniana using whole genome sequencing. Full article

The aqueous extract of kava (Piper methysticum) root is known as a traditional beverage for daily intake in the Western Pacific Islands, such as Fiji, Tonga, and Vanuatu, to induce relaxation and health-beneficial effects. In this study, the antioxidant, anti-hyperuricemia, and antibacterial properties of kava root were investigated through the isolation and purification of bioactive compounds in ten fractions separated by column chromatography (CC). They included six flavonoids, 5-hydroxy-4′,7-dimethoxyflavanone (C1), matteucinol (C2), isosakuranetin (C3), 5,7- dimethoxyflavanone (C4), 2′,4′-dihydroxy-6′-methoxydihydrochalcone (in MC5) and alpinetin (C10), and seven kavalactones, 5,6-dehydrokawain (DK) (in MC5 and C6), kavain (in MC7), yangonin (in MC7 and C8), dihydro-5,6-dehydrokavain (DDK) (in MC9), 7,8-dihydromethysticin (in MC9), dihydromethysticin (in MC9), methysticin (in MC9). The chemical structures of the compounds were illustrated by the analyses of gas chromatography–mass spectrometry (GC–MS), electrospray ionization–mass spectrometry (ESI–MS), nuclear magnetic resonance (¹H and ¹³C-NMR), and X-ray diffraction. The evaluation of the free radical scavenging activity of the isolated substances via the DPPH and ABTS assays revealed that C3 (IC₅₀: ABTS = 76.5; DPPH = 74.8 µg/mL) possessed the strongest antioxidant property. In terms of anti-hyperuricemia activity evaluated via the xanthine oxidase inhibitory in vitro assay, the compound C10 was the most promising inhibitor, revealing an IC₅₀ of 134.52 µg/mL. The two kavalactone mixtures in MC5 and a pure compound C6 inhibited the growth of bacteria Listeria monocytogenes, while MC7 can constrain the development of Klebsiella pneumoniae. This is the first study to isolate, purify, and identify the flavonoids isosakuranetin, 2′,4′-dihydroxy-6′-methoxydihydrochalcone and alpinetin in kava root and report their pharmaceutical potential. The identified bioactive compounds showed potent antioxidant, anti-hyperuricemia, and antibacterial activity and thus can enhance the value of beverages and foods derived from kava root. Full article

Changes in the terrestrial total water storage (TWS) have been estimated at both global and river basin scales from the Gravity Recovery and Climate Experiment (GRACE) mission and are still being detected from its GRACE Follow-On (GRACE-FO) mission. In this contribution, the sixth release of GRACE-FO (RL06) level-2 products applying DDK5 (decorrelation filter) were used to detect water mass variations for the Nile River Basin (NRB) in Africa and the Mega Aquifer System (MAS) in Asia. The following approach was implemented to detect the mass variation over the NRB and MAS: (1) TWS mass (June 2018–June 2021) was estimated by converting the spherical harmonic coefficients from the decorrelation filter DDK 5 of the GRACE-FO Level-2 RL06 products into equivalent water heights, where the TWS had been re-produced after removing the mean temporal signal (2) Precipitation data from Global Precipitation Climatology Project was used to investigate the pattern of change over the study area. Our findings include: (1) during the GRACE-FO period, the mass variations extracted from the RL06-DDK5 solutions from the three official centers—CSR, JPL, and GFZ—were found to be consistent with each other, (2) The NRB showed substantial temporal TWS variations, given a basin average of about 6 cm in 2019 and about 12 cm in 2020 between September and November and a lower basin average of about −9 cm in 2019 and −6 cm in 2020 in the wet seasons between March and May, while mass variations for the MAS had a relatively weaker temporal TWS magnitude, (3) the observed seasonal signal over the NRB was attributed to the high intensity of the precipitation events over the NRB (AAP: 1000–1800 mm yr⁻¹), whereas the lack of the seasonal TWS signal over the MAS was due to the low intensity of the precipitation events over the MAS (AAP:180–500 mm yr⁻¹). Full article

Eukaryotic genomes are replicated in spatiotemporal patterns that are stereotypical for individual genomes and developmental profiles. In the model system Saccharomyces cerevisiae, two primary mechanisms determine the preferential activation of replication origins during early S phase, thereby largely defining the consequent replication profiles of these cells. Both mechanisms are thought to act through specific recruitment of a rate-limiting initiation factor, Dbf4-dependent kinase (DDK), to a subset of licensed replication origins. Fkh1/2 is responsible for stimulation of most early-firing origins, except for centromere (CEN)-proximal origins that recruit DDK via the kinetochore protein Ctf19, which is required for their early firing. The C-terminus of Dbf4 has been implicated in its recruitment to origins via both the Fkh1/2 and Ctf19 mechanisms. Here, we show that the Zn-finger motif within the C-terminus is specifically required for Dbf4 recruitment to CENs to stimulate CEN-proximal/Ctf19-dependent origins, whereas stimulation of origins via the Fkh1/2 pathway remains largely intact. These findings re-open the question of exactly how Fkh1/2 and DDK act together to stimulate replication origin initiation. Full article

Precise regulation of DNA replication complex assembly requires cyclin-dependent kinase (CDK) and Dbf4-dependent kinase (DDK) activities to activate the replicative helicase complex and initiate DNA replication. Chemical probes have been essential in the molecular analysis of DDK-mediated regulation of MCM2-7 activation and the initiation phase of DNA replication. Here, the inhibitory activity of two distinct DDK inhibitor chemotypes, PHA-767491 and XL-413, were assessed in cell-free and cell-based proliferation assays. PHA-767491 and XL-413 show distinct effects at the level of cellular proliferation, initiation of DNA replication and replisome activity. XL-413 and PHA-767491 both reduce DDK-specific phosphorylation of MCM2 but show differential potency in prevention of S-phase entry. DNA combing and DNA replication assays show that PHA-767491 is a potent inhibitor of the initiation phase of DNA replication but XL413 has weak activity. Importantly, PHA-767491 decreased E2F-mediated transcription of the G1/S regulators cyclin A2, cyclin E1 and cyclin E2, and this effect was independent of CDK9 inhibition. Significantly, the enhanced inhibitory profile of PHA-767491 is mediated by potent inhibition of both DDK and the CDK2-Rb-E2F transcriptional network, that provides the molecular basis for its increased anti-proliferative effects in RB⁺ cancer cell lines. Full article

Filtering for GRACE temporal gravity fields is a necessary step before calculating surface mass anomalies. In this study, we propose a new denoising and decorrelation kernel (DDK) filtering scheme called adaptive DDK filter. The involved error covariance matrix (ECM) adopts nothing but the monthly time-variable released by several data centers. The signal covariance matrix (SCM) involved is monthly time-variable also. Specifically, it is parameterized into two parameters, namely the regularization coefficient and the power index of signal covariances, which are adaptively determined from the data themselves according to the generalized cross validation (GCV) criterion. The regularization coefficient controls the global constraint on the signal variances of all degrees, while the power index adjusts the attenuation of the signal variances from low to high degrees, namely local constraint. By tuning these two parameters for the monthly SCM, the adaptability to the data and the optimality of filtering strength can be expected. In addition, we also devise a half-weight polygon area (HWPA) of the filter kernel to measure the filtering strength of the anisotropic filter more reasonably. The proposed adaptive DDK filter and filtering strength metric are tested based on CSR GRACE temporal gravity solutions with their ECMs from January 2004 to December 2010. Results show that the selected optimal power indices range from 3.5 to 6.9, with the corresponding regularization parameters range from 1 × 10¹⁴ to 5 × 10¹⁹. The adaptive DDK filter can retain comparable/more signal amplitude and suppress more high-degree noise than the conventional DDK filters. Compared with the equivalent smoothing radius (ESR) of filtering strength, the HWPA has stronger a distinguishing ability, especially when the filtering strength is similar. Full article

High-frequency and correlated noise filtering is one of the important preprocessing steps for GRACE level-2 products before calculating mass anomaly. Decorrelation and denoising kernel (DDK) filters are usually considered as such optimal filters to solve this problem. In this work, a sparse DDK filter is proposed. This is achieved by replacing Tikhonov regularization in traditional DDK filters with weighted L1 norm regularization. The proposed sparse DDK filter adopts a time-varying error covariance matrix, while the equivalent signal covariance matrix is adaptively determined by the Gravity Recovery and Climate Experiment (GRACE) monthly solution. The covariance matrix of the sparse DDK filtered solution is also developed from the Bayesian and error-propagation perspectives, respectively. Furthermore, we also compare and discuss the properties of different filters. The proposed sparse DDK has all the advantages of traditional filters, such as time-varying, location inhomogeneity, and anisotropy, etc. In addition, the filtered solution is sparse; that is, some high-degree and high-order terms are strictly zeros. This sparsity is beneficial in the following sense: high-degree and high-order sparsity mean that the dominating noise in high-degree and high-order terms is completely suppressed, at a slight cost that the tiny signals of these terms are also discarded. The Center for Space Research (CSR) GRACE monthly solutions and their error covariance matrices, from January 2004 to December 2010, are used to test the performance of the proposed sparse DDK filter. The results show that the sparse DDK can effectively decorrelate and denoise these data. Full article

The maintenance of genomic stability during the mitotic cell-cycle not only demands that the DNA is duplicated and repaired with high fidelity, but that following DNA replication the chromatin composition is perpetuated and that the duplicated chromatids remain tethered until their anaphase segregation. The coordination of these processes during S phase is achieved by both cyclin-dependent kinase, CDK, and Dbf4-dependent kinase, DDK. CDK orchestrates the activation of DDK at the G1-to-S transition, acting as the ‘global’ regulator of S phase and cell-cycle progression, whilst ‘local’ control of the initiation of DNA replication and repair and their coordination with the re-formation of local chromatin environments and the establishment of chromatid cohesion are delegated to DDK. Here, we discuss the regulation and the multiple roles of DDK in ensuring chromosome maintenance. Regulation of replication initiation by DDK has long been known to involve phosphorylation of MCM2-7 subunits, but more recent results have indicated that Treslin:MTBP might also be important substrates. Molecular mechanisms by which DDK regulates replisome stability and replicated chromatid cohesion are less well understood, though important new insights have been reported recently. We discuss how the ‘outsourcing’ of activities required for chromosome maintenance to DDK allows CDK to maintain outright control of S phase progression and the cell-cycle phase transitions whilst permitting ongoing chromatin replication and cohesion establishment to be completed and achieved faithfully. Full article