Frequent disturbances enhanced the resilience of past human populations.

The record of past human adaptations provides crucial lessons for guiding responses to crises in the future1-3. To date, there have been no systematic global comparisons of humans' ability to absorb and recover from disturbances through time4,5. Here we synthesized resilience across a broad sample of prehistoric population time-frequency data, spanning 30,000 years of human history. Cross-sectional and longitudinal analyses of population decline show that frequent disturbances enhance a population's capacity to resist and recover from later downturns. Land-use patterns are important mediators of the strength of this positive association: farming and herding societies are more vulnerable but also more resilient overall. The results show that important trade-offs exist when adopting new or alternative land-use strategies.

Cytokinin-responsive MdTCP17 interacts with MdWOX11 to repress adventitious root primordium formation in apple rootstocks.

Adventitious root (AR) formation plays an important role in vegetatively propagated plants. Cytokinin (CK) inhibits AR formation, but the molecular mechanisms driving this process remain unknown. In this study, we confirmed that CK content is related to AR formation and further revealed that a high auxin/CK ratio was beneficial to AR formation in apple (Malus domestica). A correlation between expression of CK-responsive TEOSINTE BRANCHED1, CYCLOIDEA, and PCF17 (MdTCP17) and AR formation in response to CK was identified, and overexpression of MdTCP17 in transgenic apple inhibited AR formation. Yeast two-hybrid, bimolecular fluorescence complementation, and co-immunoprecipitation assays revealed an interaction between MdTCP17 and WUSCHEL-RELATED HOMEOBOX11 (MdWOX11), and a significant correlation between the expression of MdWOX11 and AR ability. Overexpression of MdWOX11 promoted AR primordium formation in apple, while interference of MdWOX11 inhibited AR primordium production. Moreover, a positive correlation was found between MdWOX11 and LATERAL ORGAN BOUNDARIES DOMAIN29 (MdLBD29) expression, and yeast one-hybrid, dual luciferase reporter, and ChIP-qPCR assays verified the binding of MdWOX11 to the MdLBD29 promoter with a WOX-box element in the binding sequence. Furthermore, MdTCP17 reduced the binding of MdWOX11 and MdLBD29 promoters, and coexpression of MdTCP17 and MdWOX11 reduced MdLBD29 expression. Together, these results explain the function and molecular mechanism of MdTCP17-mediated CK inhibition of AR primordium formation, which could be used to improve apple rootstocks genetically.

A method for Porphyromonas gingivalis based on recombinase polymerase amplification and lateral flow strip technology.

OBJECTIVE: A practical visual detection method was established to detect Porphyromonas gingivalis (P. gingivalis) by employing a combination of recombinase polymerase amplification and lateral flow strips (RPA-LF) assay, designed for conducting point-of-care testing in clinical settings. METHODS: Primers and probes targeting the P. gingivalis pepO gene were designed. The RPA-LF assay was established by optimising reaction temperature and time, determining the limit of detection (LOD). The specificity of the method was determined by assessing its cross-reactivity with deoxyribonucleic acid from 23 pathogenic bacteria. Finally, the clinical samples from healthy controls (n = 30) and individuals with periodontitis (n = 31) were analysed. The results were compared with those obtained using real-time polymerase chain reaction (PCR). RESULTS: The optimal reaction temperature and time were 39 °C and 12 min. The method exhibited a LOD at 6.40 × 10-4 µg/mL and demonstrated high specificity and sensitivity during cross-reactivity assessment. The RPA-LF assay achieved a P. gingivalis detection rate of 84 % in individuals with periodontitis and 3 % in healthy controls. The results were consistent with those obtained through real-time PCR. CONCLUSION: An RPA-LF assay was developed for detecting P. gingivalis, characterised by its high sensitivity, high specificity, simple operational procedure, and rapid reaction time.

Circ_0000011 promotes cerebral ischemia/reperfusion injury via miR-27a-3p-dependent regulation of NRIP1.

BACKGROUND: Cerebral ischemia/reperfusion (I/R) can result in brain function impairments. Circular RNAs (circRNAs) have emerged as vital regulators in cerebral I/R injury. However, the functions of mmu_circ_0000011 in cerebral I/R injury are still unclear. Thus, in this study, we aimed to explore the effect of mmu_circ_0000011 on cerebral I/R injury. METHODS: Oxygen-glucose deprivation and reperfusion (OGD/R)-induced HT-22 cells were used to mimic the condition of cerebral I/R injury in vitro. Cell Counting Kit-8 (CCK-8) assay, lactate dehydrogenase (LDH) assay, 5'-ethynyl-2'-deoxyuridine (EdU) assay and flow cytometry analysis were utilized to assess cell viability, LDH release, proliferation and apoptosis, respectively. qRT-PCR and western blot were performed to determined the levels of circ_0000011, miR-27a-3p and NRIP1. Dual-luciferase reporter assay and RNA pull-down assay were utilized to analyze the targeting relation of circ_0000011, miR-27a-3p and NRIP1. RESULTS: OGD/R treatment inhibited HT-22 cell viability and promoted LDH release, cell apoptosis and inflammation. Circ_0000011 level was increased in OGD/R-induced HT-22 cells. Silencing of circ_0000011 promoted cell proliferation and inhibited LDH release, apoptosis and inflammation in OGD/R-treated HT-22 cells. For mechanism analysis, circ_0000011 was demonstrated to sponge miR-27a-3p, which directly targeted NRIP1. MiR-27a-3p inhibition or NRIP1 overexpression ameliorated the impacts of circ_0000011 silencing on cell proliferation, LDH release, apoptosis and inflammation in OGD/R-treated HT-22 cells. CONCLUSIONS: Circ_0000011 promotes OGD/R-induced HT-22 cell impairments by elevating NRIP1 through sponging miR-27a-3p.

The efficacy of mouthwashes on oral microorganisms and gingivitis in patients undergoing orthodontic treatment: a systematic review and meta-analysis.

BACKGROUND: Mouthwashes were convenient adjuncts to mechanical cleaning procedures. This review aimed to evaluate the efficacy of mouthwashes on oral microorganisms and gingivitis in orthodontic patients. METHODS: By April 16, 2022, multiple databases and grey literature were searched based on the PICOS strategy. Randomized controlled trials in orthodontic patients evaluating the efficacy of mouthwashes with at least one microbial parameter and/or plaque- and/or gingival inflammation-related index were included. Relevant data were extracted, and the risk of bias was evaluated using Cochrane's tool. Individual mean and standard deviation of the outcomes in mouthwashes and placebos/blank controls were pooled to estimate the weighted mean differences (WMDs) and 95% confidence intervals (95%CIs). Sensitivity analysis, and certainty of evidence were evaluated. RESULTS: Of 1684 articles, 32 studies satisfied the eligibility criteria, and nine were included for meta-analysis. Missing outcome data was the primary source of bias. Compared to blank controls, the short-term application of fluoride mouthwashes significantly reduced the colony counts of Mutans streptococci (MS), while the long-term application may not be effective. Compared to placebos or blank controls, Chlorhexidine mouthwashes significantly reduced the colony counts of multiple microorganisms in the short-term. Compared to placebos or blank controls, herbal mouthwashes showed the inhibitory effect of MS in the short-term, with some results lacking statistical significance. After meta-analysis, significant lower plaque- and gingival inflammation-related indexes were observed in the Chlorhexidine mouthwashes groups [Gingival Index: WMD = -0.45, 95%CI = -0.70 to -0.20 (placebos as control); WMD = -0.54, 95%CI = -0.96 to -0.13 (blank controls); Plaque Index: WMD = -0.70, 95%CI = -1.12 to -0.27 (blank controls)]. Significant lower gingival inflammation-related indexes were observed in the herbal mouthwashes groups [Gingival Index: WMD = -0.20, 95%CI = -0.32 to -0.09 (blank controls)]. CONCLUSIONS: The short-term application of fluoride mouthwashes may reduce the colony counts of cariogenic bacteria, but the long-term effect is not evident. Chlorhexidine may reduce the colony counts of multiple microorganisms in the short-term. Short-term application Chlorhexidine and herbal mouthwashes may effectively reduce plaque- and gingival inflammation-related indexes. However, the risk of bias, inconsistency, and imprecision in the included studies may reduce the certainty of the evidence.

MdNup62 interactions with MdHSFs involved in flowering and heat-stress tolerance in apple.

Because of global warming, the apple flowering period is occurring significantly earlier, increasing the probability and degree of freezing injury. Moreover, extreme hot weather has also seriously affected the development of apple industry. Nuclear pore complexes (NPCs) are main channels controlling nucleocytoplasmic transport, but their roles in regulating plant development and stress responses are still unknown. Here, we analysed the components of the apple NPC and found that MdNup62 interacts with MdNup54, forming the central NPC channel. MdNup62 was localized to the nuclear pore, and its expression was significantly up-regulated in 'Nagafu No. 2' tissue-cultured seedlings subjected to heat treatments. To determine MdNup62's function, we obtained MdNup62-overexpressed (OE) Arabidopsis and tomato lines that showed significantly reduced high-temperature resistance. Additionally, OE-MdNup62 Arabidopsis lines showed significantly earlier flowering compared with wild-type. Furthermore, we identified 62 putative MdNup62-interacting proteins and confirmed MdNup62 interactions with multiple MdHSFs. The OE-MdHSFA1d and OE-MdHSFA9b Arabidopsis lines also showed significantly earlier flowering phenotypes than wild-type, but had enhanced high-temperature resistance levels. Thus, MdNUP62 interacts with multiple MdHSFs during nucleocytoplasmic transport to regulate flowering and heat resistance in apple. The data provide a new theoretical reference for managing the impact of global warming on the apple industry.

[Recent Developments and Future Directions of Oral Healthcare System and Dental Public Health System in China in Light of the Current Global Emergency].

The study is aimed to help promote the development of the oral healthcare system and dental public health system in China and to help achieve the goal of improving the nation's oral health. We herein provided an overview and critical evaluation of recent developments in oral healthcare systems and dental public health systems in China and other countries, and discussed a number of potential directions for the future development of dental public health. The current global public health emergency of the coronavirus disease 2019 (COVID-19) pandemic was also taken into account in our discussions. Thus, to facilitate the accomplishment of the goals of the Healthy China 2030 Program, we suggested the establishment of a community-based, prevention-oriented model for the oral healthcare system and dental public health system. The model we proposed features the integration of oral and general health services, the utilization of technological innovations and big data concerning health, and a forceful promotion of remote dental services focused on prevention and early diagnosis and treatment. Furthermore, under the background of COVID-19 becoming a normal part of people's lives, we should adopt differentiated prevention and protection measures and emergency response preplans appropriate for the actual epidemic situation of a particular region so that clinical services are strengthened while unnecessary wastes of resources are avoided. We should actively explore for alternative approaches to care in the face of special circumstances.

Molecular mechanism of MdWUS2-MdTCP12 interaction in mediating cytokinin signaling to control axillary bud outgrowth.

Shoot branching is an important factor that influences the architecture of apple trees and cytokinin is known to promote axillary bud outgrowth. The cultivar 'Fuji', which is grown on ~75% of the apple-producing area in China, exhibits poor natural branching. The TEOSINTE BRANCHED1/CYCLOIDEA/PCF (TCP) family genes BRANCHED1/2 (BRC1/2) are involved in integrating diverse factors that function locally to inhibit shoot branching; however, the molecular mechanism underlying the cytokinin-mediated promotion of branching that involves the repression of BRC1/2 remains unclear. In this study, we found that apple WUSCHEL2 (MdWUS2), which interacts with the co-repressor TOPLESS-RELATED9 (MdTPR9), is activated by cytokinin and regulates branching by inhibiting the activity of MdTCP12 (a BRC2 homolog). Overexpressing MdWUS2 in Arabidopsis or Nicotiana benthamiana resulted in enhanced branching. Overexpression of MdTCP12 inhibited axillary bud outgrowth in Arabidopsis, indicating that it contributes to the regulation of branching. In addition, we found that MdWUS2 interacted with MdTCP12 in vivo and in vitro and suppressed the ability of MdTCP12 to activate the transcription of its target gene, HOMEOBOX PROTEIN 53b (MdHB53b). Our results therefore suggest that MdWUS2 is involved in the cytokinin-mediated inhibition of MdTCP12 that controls bud outgrowth, and hence provide new insights into the regulation of shoot branching by cytokinin.

Molecular cloning and functional characterization of AcGST1, an anthocyanin-related glutathione S-transferase gene in kiwifruit (Actinidia chinensis).

KEY MESSAGE: AcGST1, an anthocyanin-related GST, may functions as a carrier to transport anthocyanins from ER to tonoplast in kiwifruit. It was positively regulated by AcMYBF110 through directly binding to its promoter. Anthocyanins are synthesized in the cytoplasmic surface of the endoplasmic reticulum but accumulate predominantly in the vacuole. Previous studies in model and ornamental plants have suggested that a member of the glutathione S-transferase (GST) gene family is involved in sequestration of anthocyanins into the vacuole. However, little is known about anthocyanin-related GST protein in kiwifruit. Here, four putative AcGSTs were identified from the genome of the red-fleshed Actinidia chinensis cv 'Hongyang'. Expression analyses reveal only the expression of AcGST1 was highly consistent with anthocyanin accumulation. Molecular complementation of Arabidopsis tt19 demonstrates AcGST1 can complement the anthocyanin-less phenotype of tt19. Transient expression in Actinidia arguta fruits further confirms that AcGST1 is functional in anthocyanin accumulation in kiwifruit. In vitro assays show the recombinant AcGST1 increases the water solubility of cyanidin-3-O-galactoside (C3Gal) and cyanidin-3-O-xylo-galactoside (C3XG). We further show that AcGST1 protein is localized not only in the ER but also on the tonoplast, indicating AcGST1 (like AtTT19) may functions as a carrier protein to transport anthocyanins to the tonoplast in kiwifruit. Moreover, the promoter of AcGST1 can be activated by AcMYBF110, based on results from transient dual-luciferase assays and yeast one-hybrid assays. EMSAs show that AcMYBF110 binds directly to CAGTTG and CCGTTG motifs in the AcGST1 promoter. These results indicate that AcMYBF110 plays an important role in transcriptional regulation of AcGST1 and, therefore, in controlling accumulation of anthocyanins in kiwifruit.

Investigation of the optimal suspension culture time for the osteoblastic differentiation of human induced pluripotent stem cells using the embryoid body method.

The differentiation of human induced pluripotent stem cells (hiPSCs) into osteoblasts provides a new paradigm in the field of bone tissue regeneration. The embryoid body (EB) differentiation method is commonly used for the osteogenic differentiation of hiPSCs. However, the spontaneous differentiation process of EBs is poorly understood, as evidenced by the inconsistency of the suspension time among previously reported studies as well as the low osteoblastic differentiation efficiency of hiPSCs. In the present study, we investigated the effects of the suspension culture time of EBs on the osteogenic differentiation of hiPSCs. Under chemically defined conditions, the expression of key genes related to presomitic mesoderm, neural crest, mesenchymal and pre-osteoblast cells in EBs derived from hiPSCs was examined daily by quantitative RT-PCR. Then, EBs with varying times in suspension (3, 5, 7 or 10 days) were attached onto gelatine surfaces, and their osteoblastic differentiation efficiencies after 14 days of culture in osteogenic induction medium were determined. Our results showed that EBs derived from hiPSCs subjected to 4 days of suspension culture produced the most mesenchymal stem cells, and exhibited the best osteogenic differentiation efficiency. Our research is valuable to standardizing, the time in suspension for the osteogenic differentiation of hiPSCs through the EB method, and facilitated the development of a high-efficiency in vitro osteogenic differentiation system for hiPSCs.

Biochemical and functional characterization of AcUFGT3a, a galactosyltransferase involved in anthocyanin biosynthesis in the red-fleshed kiwifruit (Actinidia chinensis).

Much of the diversity of anthocyanin pigmentation in plant tissues is due to the action of glycosyltransferases, which attach sugar moieties to the anthocyanin aglycone. This step can increase both their solubility and stability. We investigated the pigmentation of the outer and inner pericarps of developing fruits of the red-fleshed kiwifruit Actinidia chinensis cv. 'Hongyang'. The results show that the red color of the inner pericarp is due to anthocyanin. Based on expression analyses of structural genes, AcUFGT was shown to be the key gene involved in the anthocyanin biosynthetic pathway. Expression of AcUFGT in developing fruit paralleled changes in anthocyanin concentration. Thirteen putative UFGT genes, including different transcripts, were identified in the genome of 'Hongyang'. Among these, only the expression of AcUFGT3a was found to be highly consistent with anthocyanin accumulation. Fruit infiltrated with virus-induced gene silencing showed delayed red colorations, lower anthocyanin contents and lower expressions of AcUFGT3a. At the same time, transient overexpression of AcUFGT3a in both Actinidia arguta and green apple fruit resulted in higher anthocyanin contents and deeper red coloration. In vitro biochemical assays revealed that recombinant AcUFGT3a recognized only anthocyanidins as substrate but not flavonols. Also, UDP-galactose was used preferentially as the sugar donor. These results indicate AcUFGT3a is the key enzyme regulating anthocyanin accumulation in red-fleshed kiwifruit.

MdHB1 down-regulation activates anthocyanin biosynthesis in the white-fleshed apple cultivar 'Granny Smith'.

Coloration in apple (Malus×domestica) flesh is mainly caused by the accumulation of anthocyanin. Anthocyanin is biosynthesized through the flavonoid pathway and regulated by MYB, bHLH, and WD40 transcription factors (TFs). Here, we report that the HD-Zip I TF MdHB1 was also involved in the regulation of anthocyanin accumulation. MdHB1 silencing caused the accumulation of anthocyanin in 'Granny Smith' flesh, whereas its overexpression reduced the flesh content of anthocyanin in 'Ballerina' (red-fleshed apple). Moreover, flowers of transgenic tobacco (Nicotiana tabacum 'NC89') overexpressing MdHB1 showed a remarkable reduction in pigmentation. Transient promoter activation assays and yeast one-hybrid results indicated that MdHB1 indirectly inhibited expression of the anthocyanin biosynthetic genes encoding dihydroflavonol-4-reductase (DFR) and UDP-glucose:flavonoid 3-O-glycosyltransferase (UFGT). Yeast two-hybrid and bimolecular fluorescence complementation determined that MdHB1 acted as a homodimer and could interact with MYB, bHLH, and WD40 in the cytoplasm, consistent with its cytoplasmic localization by green fluorescent protein fluorescence observations. Together, these results suggest that MdHB1 constrains MdMYB10, MdbHLH3, and MdTTG1 to the cytoplasm, and then represses the transcription of MdDFR and MdUFGT indirectly. When MdHB1 is silenced, these TFs are released to activate the expression of MdDFR and MdUFGT and also anthocyanin biosynthesis, resulting in red flesh in 'Granny Smith'.

S100a8/NF-κB signal pathway is involved in the 800-nm diode laser-induced skin collagen remodeling.

The 800-nm diode laser is widely used for hair removal and also promotes collagen synthesis, but the molecular mechanism by which dermis responses to the thermal damage induced by the 800-nm diode laser is still unclear. Ten 2-month-old mice were irradiated with the 800-nm diode laser at 20, 40, and 60 J/cm(2), respectively. Skin samples were taken for PCR, Western blot analysis, and histological study at day 3 or 30 after laser irradiation. The expression of S100a8 and its two receptors (advanced glycosylation end product-specific receptor, RAGE and toll-like receptor 4, TRL4) was upregulated at day 3 after laser treatments. P-p65 levels were also elevated, causing the increase of cytokine (tumor necrosis factor, TNF-α and interleukin 6, IL-6) and MMPs (MMP1a, MMP9). At day 30, PCR and Western blot analysis showed significant increase of type I and III procollagen in the dermis treated with laser. Importantly, skin structure was markedly improved in the laser-irradiated skin compared with the control. Thus, it seemed that S100a8 upregulation triggered NF-κB signal pathway through RAGE and TLR4, responding to laser-induced dermis wound healing. The involvement of the NF-κB pathway in MMP gene transcription promoted the turnover of collagen in the skin, accelerating new collagen synthesis.

The FOUR LIPS and MYB88 transcription factor genes are widely expressed in Arabidopsis thaliana during development.

PREMISE OF THE STUDY: The FOUR LIPS (FLP) and MYB88 transcription factors, which are closely related in structure and function, control the development of stomata, as well as entry into megasporogenesis in Arabidopsis thaliana. However, other locations where these transcription factors are expressed are poorly described. Documenting additional locations where these genes are expressed might define new functions for these genes. METHODS: Expression patterns were examined throughout vegetative and reproductive development. The expression from two transcriptional-reporter fusions were visualized with either ß-glucuronidase (GUS) or green fluorescence protein (GFP). KEY RESULTS: Both flp and myb88 genes were expressed in many, previously unreported locations, consistent with the possibility of additional functions for FLP and MYB88. Moreover, expression domains especially of FLP display sharp cutoffs or boundaries. CONCLUSIONS: In addition to stomatal and reproductive development, FLP and MYB88, which are R2R3 MYB transcription factor genes, are expressed in many locations in cells, tissues, and organs.

Discovering treatment pattern in Traditional Chinese Medicine clinical cases by exploiting supervised topic model and domain knowledge.

In Traditional Chinese Medicine (TCM), the prescription is the crystallization of clinical experience of doctors, which is the main way to cure diseases in China for thousands of years. Clinical cases, on the other hand, describe how doctors diagnose and prescribe. In this paper, we propose a framework which mines treatment patterns in TCM clinical cases by exploiting supervised topic model and TCM domain knowledge. The framework can reflect principle rules in TCM and improve function prediction of a new prescription. We evaluate our method on 3090 real world TCM clinical cases. The experiment validates the effectiveness of our method.

Non-destructive measurement of fracturability and chewiness of apple by FT-NIRS.

In order to assess quickly and non-destructively the fracturability and chewiness of apple fruit by FT-NIR spectra in the wavelength range of 4000 cm(-1)-12000 cm(-1), multivariate models were built using multiple linear regression (MLR), partial least squares regression (PLSR), and principal component regression (PCR). Fracturability and chewiness reference data were instrumentally measured using a Texture Profile Analysis (TPA) test. The effects of various pre-processing methods of the spectroscopic data on the performance of the multivariate models were analyzed. Standard normal variate transformation (SNV), multiplicative scatter correction (MSC), Min-Max normalization(MMN) and first derivative (FD) were tested. The performance of the fracturability prediction models was better for the PLSR model (R(2) = 0.91, RMSEP = 101.90) than for the PCR and MLR models. With regard to chewiness, the performance of the PCR model (R(2) = 0.88, RMSEP = 13.46) was similar to the one of the PLSR model but better than the one of the MLR model. The results demonstrated that NIR spectra together with stoichiometry could determine precisely fracturability and chewiness of apple, and the predictive ability of the models developed by other methods may be improved in the future.

Chronic myeloid leukemia drug evaluation using a multisignal amplified photoelectrochemical sensing platform.

Chronic myeloid leukemia (CML) is a malignant clone disease of hematopoietic stem cells. At present, the most effective therapy for CML is bone marrow transplantation, but this procedure is expensive, and it is often difficult to find appropriately matched bone marrow donors. As an alternative to marrow transplantation, a more effective anticancer drug should be developed to cure the disease; in addition, an effective system to evaluate the activity of the drug needs to be developed. Herein, we present a novel antileukemia drug evaluation method based on a multisignal amplified photoelectrochemical sensing platform that monitors the activity of caspase-3, a known marker of cell apoptosis. Manganese-doped CdS@ZnS core-shell nanoparticles (Mn:CdS@ZnS) were synthesized via a simple wet chemical method, which provided a stable photocurrent signal. A DEVD-biotin peptide and streptavidin-labeled alkaline phosphatise (SA-ALP) were immobilized successively at these nanoparticles through amide bonding and through specific interaction between biotin and streptavidin, respectively. The photocurrent of this sensing platform improved as the ALP hydrolyzed the substrate 2-phospho-l-ascorbic acid (AAP) to ascorbic acid (AA), a more efficient electron donor. The activity of caspase-3 was detected using this sensing platform, and thus, the efficacy of nilotinib for targeting K562 CML cells could be evaluated. The results indicate that nilotinib can effectively induce apoptosis of the K562 cells. This sensing platform exhibited sensitive, reproductive, and stable performance in studying the nilotinib-induced apoptosis of K562 CML cells, and the platform could be utilized to evaluate other anticancer drugs.

Effects of Parkinson's disease on optic flow perception for heading direction during navigation.

Visuoperceptual disorders have been identified in individuals with Parkinson's disease (PD) and may affect the perception of optic flow for heading direction during navigation. Studies in healthy subjects have confirmed that heading direction can be determined by equalizing the optic flow speed (OS) between visual fields. The present study investigated the effects of PD on the use of optic flow for heading direction, walking parameters, and interlimb coordination during navigation, examining the contributions of OS and spatial frequency (dot density). Twelve individuals with PD without dementia, 18 age-matched normal control adults (NC), and 23 young control adults (YC) walked through a virtual hallway at about 0.8 m/s. The hallway was created by random dots on side walls. Three levels of OS (0.8, 1.2, and 1.8 m/s) and dot density (1, 2, and 3 dots/m(2)) were presented on one wall while on the other wall, OS and dot density were fixed at 0.8 m/s and 3 dots/m(2), respectively. Three-dimensional kinematic data were collected, and lateral drift, walking speed, stride frequency and length, and frequency, and phase relations between arms and legs were calculated. A significant linear effect was observed on lateral drift to the wall with lower OS for YC and NC, but not for PD. Compared to YC and NC, PD veered more to the left under OS and dot density conditions. The results suggest that healthy adults perceive optic flow for heading direction. Heading direction in PD may be more affected by the asymmetry of dopamine levels between the hemispheres and by motor lateralization as indexed by handedness.

Case report: Response to Savolitinib/EGFR-TKI combination in NSCLC patients harboring concurrent primary MET amplification/overexpression and EGFR mutation.

Lung cancer is the leading cause of cancer death, accounting for one-third of all cancer deaths worldwide. The MET (c-MET) gene, as one of the therapeutic target spots of NSCLC, has become increasingly more important. MET amplification/overexpression was divided into primary (intrinsic) and secondary (acquired). Studies indicated that the combination of Osimertinib and Savolitinib was safe and showed promising antitumor effect in NSCLC patients with secondary MET amplification after EGFR mutations. However, NSCLC patients with primary MET amplification/overexpression and EGFR mutations are rare in clinics, and the efficacy of dual-target therapy combined with EGFR-TKI and Savolitinib for them has not been studied yet. Here, we reported two NSCLC patients with primary MET amplification/overexpression and EGFR mutation, who benefited from T+S therapy (the dual-target therapy of EGFR-TKI plus Savolitinib) and achieved a progression-free survival (PFS) of approximately 5 months. The two cases indicated that T+S therapy has an acceptable safety profile and encouraging antitumor efficacy in NSCLC patients harboring concurrent primary MET amplification/overexpression and EGFR mutation. Meanwhile, the observation stresses the importance of genetic testing, and the MET gene needs to be detected at first diagnosis for the best choice of targeted therapies.