Search

Background/ObjectivesThe timely diagnosis of inherited metabolic disorders (IMD) is essential for initiating treatment, prognostication and genetic testing of relatives. Recognition of IMD in adults is difficult, because phenotypes are different from those in children and influenced by symptoms from acquired conditions. This systematic literature review aims to answer the following questions: (1) What is the diagnostic yield of exome/genome sequencing (ES/GS) for IMD in adults with unsolved phenotypes? (2) What characteristics do adult patients diagnosed with IMD through ES/GS have?MethodsA systematic search was conducted using the following search terms (simplified): “Whole exome sequencing (WES),” “Whole genome sequencing (WGS),” “IMD,” “diagnostics” and the 1,450 known metabolic genes derived from ICIMD. Data from 695 articles, including 27,702 patients, were analyzed using two different methods. First, the diagnostic yield for IMD in patients presenting with a similar phenotype was calculated. Secondly, the characteristics of patients diagnosed with IMD through ES/GS in adulthood were established.ResultsThe diagnostic yield of ES and/or GS for adult patients presenting with unexplained neurological symptoms is 11% and for those presenting with dyslipidemia, diabetes, auditory and cardiovascular symptoms 10, 9, 8 and 7%, respectively. IMD patients diagnosed in adulthood (n = 1,426), most frequently portray neurological symptoms (65%), specifically extrapyramidal/cerebellar symptoms (57%), intellectual disability/dementia/psychiatric symptoms (41%), pyramidal tract symptoms/myelopathy (37%), peripheral neuropathy (18%), and epileptic seizures (16%). The second most frequently observed symptoms were ophthalmological (21%). In 47% of the IMD diagnosed patients, symptoms from multiple organ systems were reported. On average, adult patients are diagnosed 15 years after first presenting symptoms. Disease-related abnormalities in metabolites in plasma, urine or cerebral spinal fluid were identified in 40% of all patients whom underwent metabolic screening. In 52% the diagnosis led to identification of affected family members with the same IMD.ConclusionES and/or GS is likely to yield an IMD diagnosis in adult patients presenting with an unexplained neurological phenotype, as well as in patients with a phenotype involving multiple organ systems. If a gene panel does not yield a conclusive diagnosis, it is worthwhile to analyze all known disease genes. Further prospective research is needed to establish the best diagnostic approach (type and sequence of metabolic and genetic test) in adult patients presenting with a wide range of symptoms, suspected of having an IMD.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier: CRD42021295156.

BackgroundVitamin D supplementation improves colorectal cancer (CRC) survival outcomes in randomized trials. The aim of this study was to test the feasibility, safety and efficacy of vitamin D supplementation in the pre- and perioperative period in patients undergoing CRC surgery.MethodsPatients were given 3200IU oral cholecalciferol (D3) per day perioperatively. Serial serum 25-hydroxyvitamin (25OHD) was measured by liquid chromatography tandem mass spectrometry and compared to untreated CRC controls. 25OHD and C-reactive protein (CRP) levels were compared using adjusted generalized linear mixed-effects models.ResultsA total of 122 patients underwent serial perioperative sampling, including 41 patients given high-dose perioperative supplementation. Supplementation was well-tolerated with no adverse or serious adverse events related to supplementation reported. Pre-operative supplementation increased 25OHD levels on the day of surgery (103.9 vs. 42.5 nmol/l, P = 8.2E–12). Supplementation increased 25OHD levels at all post-operative timepoints (P < 0.001) and attenuated the post-operative drop in 25OHD (46 vs. 24% drop, P = 3.0E–4). Rate of vitamin D peri-operative insufficiency was significantly less in those on supplementation (e.g., day 3–5, 14 vs. 84%, P = 1.41E–08), with multivariate modeling across all timepoints indicating a ∼59 nmol/l higher 25OHD compared to control patients (P = 3.7E–21). Post-operative CRP was lower in patients taking supplementation (e.g., day 3–5 timepoint; 129 vs. 81 mg/l, P = 0.04).ConclusionHigh dose pre-operative vitamin D supplementation is associated with higher perioperative 25OHD levels, lower rates of vitamin D insufficiency and reduced early post-operative CRP. Alongside published evidence for a beneficial effect of vitamin D on CRC survival outcomes, these novel findings provide strong rationale for early initiation of vitamin D supplementation after a diagnosis of CRC.

Light at night is an emergent problem for modern society. Rodents exposed to light at night develop a loss of circadian rhythms, which leads to increased adiposity, altered immune response, and increased growth of tumors. In female rats, constant light (LL) eliminates the estrous cycle leading to a state of persistent estrus. The suprachiasmatic nucleus (SCN) drives circadian rhythms, and it interacts with the neuroendocrine network necessary for reproductive function. Timed restricted feeding (RF) exerts a powerful entraining influence on the circadian system, and it can influence the SCN activity and can restore rhythmicity or accelerate re-entrainment in experimental conditions of shift work or jet lag. The present study explored RF in female rats exposed to LL, with the hypothesis that this cyclic condition can rescue or prevent the loss of daily rhythms and benefit the expression of the estrous cycle. Two different feeding schedules were explored: 1. A 12-h food/12-h fasting schedule applied to arrhythmic rats after 3 weeks in LL, visualized as a rescue strategy (LL + RFR, 3 weeks), or applied simultaneously with the first day of LL as a preventive strategy (LL + RFP, 6 weeks). 2. A 12-h window of food intake with food given in four distributed pulses (every 3 h), applied after 3 weeks in LL, as a rescue strategy (LL + PR, 3 weeks) or applied simultaneously with the first day of LL as a preventive strategy (LL + PP, 6 weeks). Here, we present evidence that scheduled feeding can drive daily rhythms of activity and temperature in rats exposed to LL. However, the protocol of distributed feeding pulses was more efficient to restore the day–night activity and core temperature as well as the c-Fos day–night change in the SCN. Likewise, the distributed feeding partially restored the estrous cycle and the ovary morphology under LL condition. Data here provided indicate that the 12-h feeding/12-h fasting window determines the rest-activity cycle and can benefit directly the circadian and reproductive function. Moreover, this effect is stronger when food is distributed along the 12 h of subjective night.

IntroductionIn the current study, we evaluated the effectiveness of two well-defined probiotic strains, Lactobacillus paracasei LPc-G110 (CCTCC M 2013691) and Lactobacillus plantarum GOS42 (DSM 32131), during an experimental gingivitis challenge. The primary objective was to evaluate clinically the effectiveness of lozenges containing one of the two oral probiotic strains, compared with placebo lozenges, on the gingival bleeding (bleeding on marginal probing; BOMP change) after a two-week experimental gingivitis period. The secondary objectives were to assess the effects of the test products on gingival health (Modified Gingival Index; MGI), dental plaque accumulation and fluorescence, and the dynamics of immunological and microbiological aspects after the wash-in phase, followed by a two-week period refraining from oral hygiene and a two-week wash-out phase.MethodsThis single-center challenge intervention study was a triple-blind randomized placebo-controlled clinical trial with three parallel groups. The full study population consisted of 117 healthy 18–55 years old human volunteers. Subjects were instructed to use one lozenge, 3 times daily after each meal, containing either L. plantarum, L. paracasei, or lozenges without probiotics (placebo group). After a 2-week wash-in period, the subjects were requested to refrain from any form of oral hygiene for 2 weeks.ResultsThere were no differences in the primary outcome (BOMP change) among the groups. However, gingival health (MGI) in individuals from the groups exposed to the test products recovered better from experimental gingivitis than the individuals in the placebo group (p = 0.021, one-way ANOVA). The two test products inhibited pro-inflammatory cytokine IL-1ß production, measured in saliva, during the experimental gingivitis period. Both test strains significantly reduced bacterial DNA in tongue samples and L. paracasei strain showed stronger microbiome-modulating potential than the L. plantarum strain.ConclusionsThe two tested lozenges with the L. paracasei or L. plantarum strains did show potential for beneficial effects for the oral health of the host during experimental gingivitis to the oral ecosystem.

Water ferns of the genus Azolla and the filamentous cyanobacteria Nostoc azollae constitute a model symbiosis that enabled the colonization of the water surface with traits highly desirable for the development of more sustainable crops: their floating mats capture CO2 and fix N2 at high rates using light energy. Their mode of sexual reproduction is heterosporous. The regulation of the transition from the vegetative phase to the spore forming phase in ferns is largely unknown, yet a prerequisite for Azolla domestication, and of particular interest as ferns represent the sister lineage of seed plants. Sporocarps induced with far red light could be crossed so as to verify species attribution of strains from the Netherlands but not of the strain from the Anzali lagoon in Iran; the latter strain was assigned to a novel species cluster from South America. Red-dominated light suppresses the formation of dissemination stages in both gametophyte- and sporophyte-dominated lineages of plants, the response likely is a convergent ecological strategy to open fields. FR-responsive transcripts included those from MIKCC homologues of CMADS1 and miR319-controlled GAMYB transcription factors in the fern, transporters in N. azollae, and ycf2 in chloroplasts. Loci of conserved microRNA (miRNA) in the fern lineage included miR172, yet FR only induced miR529 and miR535, and reduced miR319 and miR159. Phylogenomic analyses of MIKCC TFs suggested that the control of flowering and flower organ specification may have originated from the diploid to haploid phase transition in the homosporous common ancestor of ferns and seed plants.

The desalination of seawater using reverse osmosis membranes is an attractive solution to global freshwater scarcity. However, membrane performance is reduced by (bio)fouling. Membrane autopsies are essential for identifying the type of fouling material, and applying corrective measures to minimize membrane fouling. Information from full-scale membrane autopsies guiding improved plant operations is scant in the formal literature. In this case-study, a reverse osmosis membrane from a full-scale seawater desalination plant with a feed channel pressure drop increase of about 218% over the pressure vessel was autopsied. The simultaneous determination of microbial cells, ATP, and total organic carbon (TOC) abundances per membrane area allowed estimating the contributions of biofouling and organic fouling. The abundance of microbial cells determined by flow cytometry (up to 7 × 108 cells/cm2), and ATP (up to 21,000 pg/cm2) as well as TOC (up to 98 μg/cm2) were homogeneously distributed on the membrane. Inorganic fouling was also measured, and followed a similar coverage distribution to that of biofouling. Iron (∼150 μg/cm2, estimated by ICP-MS) was the main inorganic foulant. ATR-FTIR spectra supported that membrane fouling was both organic/biological and inorganic. High-resolution SEM-EDS imaging of cross-sectioned membranes allowed assessing the thickness of the fouling layer (up to 20 μm) and its elemental composition. Imaging results further supported the results of homogeneous fouling coverage. Moreover, imaging revealed both zones with and without compression of the polysulfone membrane layer, suggesting that the stress due to operating pressure was heterogeneous. The procedure for this membrane autopsy provided a reasonable overview of the diverse contributors of fouling and might be a starting point to building a consensus autopsy protocol. Next, it would be valuable to build a RO membrane autopsy database, which can be used as a guidance and diagnostic tool to improve the management and operation of RO desalination plants.

Background/Objectives: The timely diagnosis of inherited metabolic disorders (IMD) is essential for initiating treatment, prognostication and genetic testing of relatives. Recognition of IMD in adults is diffcult, because phenotypes are different fromthose in children and influenced by symptoms fromacquired conditions. This systematic literature review aims to answer the following questions: (1) What is the diagnostic yield of exome/genome sequencing (ES/GS) for IMD in adults with unsolved phenotypes? (2) What characteristics do adult patients diagnosed with IMD through ES/GS have? Methods: A systematic search was conducted using the following search terms (simplified): "Whole exome sequencing (WES)," "Whole genome sequencing (WGS)," "IMD," "diagnostics" and the 1,450 known metabolic genes derived from ICIMD. Data from 695 articles, including 27,702 patients, were analyzed using two different methods. First, the diagnostic yield for IMD in patients presenting with a similar phenotype was calculated. Secondly, the characteristics of patients diagnosed with IMD through ES/GS in adulthood were established. Results: The diagnostic yield of ES and/or GS for adult patients presenting with unexplained neurological symptoms is 11% and for those presenting with dyslipidemia, diabetes, auditory and cardiovascular symptoms 10, 9, 8 and 7%, respectively. IMD patients diagnosed in adulthood (n = 1,426), most frequently portray neurological symptoms (65%), specifically extrapyramidal/cerebellar symptoms (57%), intellectual disability/dementia/psychiatric symptoms (41%), pyramidal tract symptoms/myelopathy (37%), peripheral neuropathy (18%), and epileptic seizures (16%). The second most frequently observed symptoms were ophthalmological (21%). In 47% of the IMD diagnosed patients, symptoms from multiple organ systems were reported. On average, adult patients are diagnosed 15 years after first presenting symptoms. Disease-related abnormalities inmetabolites in plasma, urine or cerebral spinal fluid were identified in 40% of all patients whom underwent metabolic screening. In 52% the diagnosis led to identification of affected family members with the same IMD. Conclusion: ES and/or GS is likely to yield an IMD diagnosis in adult patients presenting with an unexplained neurological phenotype, as well as in patients with a phenotype involving multiple organ systems. If a gene panel does not yield a conclusive diagnosis, it is worthwhile to analyze all known disease genes. Further prospective research is needed to establish the best diagnostic approach (type and sequence of metabolic and genetic test) in adult patients presenting with a wide range of symptoms, suspected of having an IMD. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies directed against the CD20 surface antigen on B cells are widely used in the therapy of B cell malignancies. Upon administration, the antibodies bind to CD20 expressing B cells and induce their depletion via cell- and complement-dependent cytotoxicity or by induction of direct cell killing. The three antibodies currently most often used in the clinic are Rituximab (RTX), Ofatumumab (OFA) and Obinutuzumab (OBI). Even though these antibodies are all of the human IgG1 subclass, they have previously been described to vary considerably in the effector functions involved in therapeutic B cell depletion, especially in regards to complement activation. Whereas OFA is known to strongly induce complement-dependent cytotoxicity, OBI is described to be far less efficient. In contrast, the role of complement in RTX-induced B cell depletion is still under debate. Some of this dissent might come from the use of different in vitro systems for characterization of antibody effector functions. We therefore set out to systematically compare antibody as well as C1q binding and complement-activation by RTX, OFA and OBI on human B cell lines that differ in expression levels of CD20 and complement-regulatory proteins as well as human primary B cells. Applying real-time interaction analysis, we show that the overall strength of C1q binding to live target cells coated with antibodies positively correlated with the degree of bivalent binding for the antibodies to CD20. Kinetic analysis revealed that C1q exhibits two binding modes with distinct affinities and binding stabilities, with exact numbers varying both between antibodies and cell lines. Furthermore, complement-dependent cell killing by RTX and OBI was highly cell-line dependent, whereas the superior complement-dependent cytotoxicity by OFA was independent of the target B cells. All three antibodies were able to initiate deposition of C3b on the B cell surface, although to varying extent. This suggests that complement activation occurs but might not necessarily lead to induction of complement-dependent cytotoxicity. This activation could, however, initiate complement-dependent phagocytosis as an alternative mechanism of therapeutic B cell depletion.

The development and spread of multidrug resistant pathogens have reinforced the urgency to find novel natural products with antibiotic activity. In bacteria, orphan biosynthetic gene clusters (BGCs) far outnumber the BGCs for which chemistry is known, possibly because they are transcriptionally silent under laboratory conditions. A strategy to trigger the production of this biosynthetic potential is to challenge the microorganism with low concentrations of antibiotics, and by using a Burkholderia genetic reporter strain (Seyedsayamdost, Proc Natl Acad Sci 111:7266–7271), we found BGC unsilencing activity for the antimicrobial andrimid, produced by the marine bacterium Vibrio coralliilyticus. Next, we challenged another marine Vibrionaceae, Photobacterium galatheae, carrier of seven orphan BGCs with sub-inhibitory concentrations of andrimid. A combined approach of transcriptional and chemical measurements of andrimid-treated P. galatheae cultures revealed a 10-fold upregulation of an orphan BGC and, amongst others, a 1.6–2.2-fold upregulation of the gene encoding the core enzyme for biosynthesis of holomycin. Also, addition of andrimid caused an increase, based on UV-Vis peak area, of 4-fold in production of the antibiotic holomycin. Transcriptional measurements of stress response related genes in P. galatheae showed a co-occurrence of increased transcript levels of rpoS (general stress response) and andrimid induced holomycin overproduction, while in trimethoprim treated cultures attenuation of holomycin production coincided with a transcriptional increase of recA (SOS stress response). This study shows that using antimicrobial compounds as activators of secondary metabolism can be a useful strategy in eliciting biosynthetic gene clusters and facilitate natural product discovery. Potentially, such interactions could also have ecological relevant implications.

The detection of ambient cold is critical for mammals, who use this information to avoid tissue damage by cold and to maintain stable body temperature. The transduction of information about the environmental cold is mediated by cold-sensitive ion channels expressed in peripheral sensory nerve endings in the skin. Most transduction mechanisms for detecting temperature changes identified to date depend on transient receptor potential (TRP) ion channels. Mild cooling is detected by the menthol-sensitive TRPM8 ion channel, but how painful cold is detected remains unclear. The TRPA1 ion channel, which is activated by cold in expression systems, seemed to provide an answer to this question, but whether TRPA1 is activated by cold in neurons and contributes to the sensation of cold pain continues to be a matter of debate. Recent advances have been made in this area of investigation with the identification of several potential cold-sensitive ion channels in thermosensory neurons, including two-pore domain potassium channels (K2P), GluK2 glutamate receptors, and CNGA3 cyclic nucleotide-gated ion channels. This mini-review gives a brief overview of the way by which ion channels contribute to cold sensation, discusses the controversy around the cold-sensitivity of TRPA1, and provides an assessment of some recently-proposed novel cold-transduction mechanisms. Evidence for another unidentified cold-transduction mechanism is also presented.

Over the past years vlogs rapidly have become an attractive platform for food industries, sponsoring social media influencers to promote their products. As with more traditional media, social media influencers predominantly promote unhealthy drinks and foods that are high in sugar, fat, and salt – consumption of which may increase the risk of overweight, obesity, and non-communicable diseases. The aim of the current Brief Research Report is to examine the impact of vlogs on children’s unhealthy dietary behaviors. Drawing on longitudinal survey data from 453 8- to 12-year-old children, we analyzed the longitudinal relations between children’s frequency of watching vlogs and their consumption of unhealthy beverages and snacks. Structural path modeling analyses of three waves of data with 1-year intervals showed that children’s self-reported frequency of watching vlogs influenced consumption of unhealthy beverages 2 years later. The analyses did not yield significant relations for Unhealthy Snacks Consumption. The strength of the observed longitudinal relation between children’s Frequency of Watching Vlogs and Consumption of unhealthy beverages was comparable to previous findings regarding more traditional types of food marketing.

There is a need to stimulate physical activity among adolescents, but unfortunately, they are hard to reach with traditional mass media interventions. A promising alternative is to carry out social network interventions. In social network interventions, a small group of individuals (influence agents) is selected to promote health-related behaviors within their social network. This study investigates whether a social network intervention is more effective to promote physical activity, compared to a mass media intervention and no intervention. Adolescents (N = 446; Mage = 11.35, SDage = 1.34; 47% male) were randomly allocated by classroom (N = 26, in 11 schools) to one of three conditions: social network intervention, mass media intervention, or control condition. In the social network intervention, 15% of the participants (based on peer nominations) was approached to become an influence agent, who created vlogs about physical activity that were shown during the intervention. In the mass media intervention, participants were exposed to vlogs made by unfamiliar peers (i.e., vlogs of the social network intervention). The control condition did not receive vlogs about physical activity. All participants received a research smartphone to complete questionnaires and a wrist-worn accelerometer to measure physical activity. The trial was registered a priori in the Dutch Trial Registry (NTR6903). There were no differences in objectively measured physical activity between this social network intervention and the control condition in the short-term, but there was an unexpected increase in the control condition compared to the social network intervention in the long-term. No differences between the social network intervention and mass media intervention were observed. The current study does not provide evidence that this social network intervention is effective in increasing physical activity in adolescents. Exploratory analyses suggest that this social network intervention increased the perceived social norm toward physical activity and responses to the vlogs were more positive in the social network intervention than in the mass media intervention. These initial results warrant further research to investigate the role of the social norms and the added benefit of using influence agents for social network interventions.Clinical Trial Registration:https://www.trialregister.nl/, identifier NTR6903.

Objectives: Our aim of this work was to investigate the regrowth of implant-related biofilms after various antimicrobial treatments in vitro.Methods: Saliva-derived microcosm biofilms were grown on titanium discs in an active attachment model. Treatments including hydrogen peroxide (HP), citric acid (CA), chlorhexidine (CHX), and distilled water (control), at different concentrations, were applied to 2-day biofilms for 1 or 5 min. The viability, lactic acid production, and composition of the biofilms were followed for 3 days. The biofilm composition was analyzed by 16S rDNA amplicon sequencing.Results: The short treatments of CA, CHX, and HP resulted in a 2–3 log reduction in biofilm viability and lactic acid production immediately. However, both parameters returned to the pre-treatment level within 2 days due to biofilm regrowth. The alpha diversity of the regrown biofilms in antimicrobial-treated groups tended to decrease, whereas the diversity of those in water-treated group increased. The composition of the regrown biofilms altered compared to those before treatments. Streptococcus and Enterobacteriaceae were enriched in the regrown biofilms.Conclusions: Although the antimicrobial treatments were efficient, the multi-species biofilms were indeed able to regrow within 2 days. The regrown biofilms display an altered microbial diversity and composition, which in the oral cavity may lead to an aggressive infection.

Understanding molecular interactions on immune cells is crucial for drug development to treat cancer and autoimmune diseases. When characterizing molecular interactions, the use of a relevant living model system is important, as processes such as receptor oligomerization and clustering can influence binding patterns. We developed a protocol to enable time-resolved analysis of ligand binding to receptors on living suspension cells. Different suspension cell lines and weakly adhering cells were tethered to Petri dishes with the help of a biomolecular anchor molecule, and antibody binding was analyzed using LigandTracer. The protocol and assay described in this report were used to characterize interactions involving eight cell lines. Experiments were successfully conducted in three different laboratories, demonstrating the robustness of the protocol. For various antibodies, affinities and kinetic rate constants were obtained for binding to CD20 on both Daudi and Ramos B-cells, the T-cell co-receptor CD3 on Jurkat cells, and the Fcγ receptor CD32 on transfected HEK293 cells, respectively. Analyzing the binding of Rituximab to B-cells resulted in an affinity of 0.7–0.9 nM, which is similar to values reported previously for living B-cells. However, we observed a heterogeneous behavior for Rituximab interacting with B-cells, which to our knowledge has not been described previously. The understanding of complex interactions will be facilitated with the possibility to characterize binding processes in real-time on living immune cells. This provides the chance to broaden the understanding of how binding kinetics relate to biological function.

This study investigated whether a forewarning of advertising’s intent can increase children’s (N = 159, 8-10 years old) defenses against television commercials to lower their desire for advertised products. Two different forewarnings were tested, one for advertising’s commercial intent or warning for the promotional nature, and one for advertising’s manipulative intent or warning for the deceptive nature. Results showed that only the warning of manipulative intent prior to advertising exposure was successful in increasing children’s advertising defenses. This forewarning activated children’s attitudinal advertising literacy (i.e., skepticism towards the commercial), which in turn led to lower advertised product desire. The forewarning of commercial intent was not effective in strengthening children’s advertising defenses. These findings have important implications for interventions that aim to lower children’s desire for (unhealthy) advertised products by activating their advertising literacy.

Volatile energy costs and environmental concerns have spurred interest in the development of alternative, renewable, sustainable and cost-effective energy resources. Advanced biofuels have potential to replace fossil fuels in supporting high-power demanding machinery such as aircrafts and trucks. Microbial biosynthesis is generally considered as an environmental friendly refinery process, and fatty acid biosynthesis is an attractive route to synthesize chemicals and especially drop-in biofuels due to the high degree of reduction of fatty acids. The robustness and excellent accessibility to molecular genetics make the yeast S. cerevisiae a suitable host for the production of biofuels, chemicals and pharmaceuticals, and recent advances in metabolic engineering as well as systems and synthetic biology allow us to engineer the yeast fatty acid metabolism and modification pathways for production of advanced biofuels and chemicals.

Monoclonal antibodies directed against the CD20 surface antigen on B cells are widely used in the therapy of B cell malignancies. Upon administration, the antibodies bind to CD20 expressing B cells and induce their depletion via cell- and complement-dependent cytotoxicity or by induction of direct cell killing. The three antibodies currently most often used in the clinic are Rituximab (RTX), Ofatumumab (OFA) and Obinutuzumab (OBI). Even though these antibodies are all of the human IgG1 subclass, they have previously been described to vary considerably in the effector functions involved in therapeutic B cell depletion, especially in regards to complement activation. Whereas OFA is known to strongly induce complement-dependent cytotoxicity, OBI is described to be far less efficient. In contrast, the role of complement in RTX-induced B cell depletion is still under debate. Some of this dissent might come from the use of different in vitro systems for characterization of antibody effector functions. We therefore set out to systematically compare antibody as well as C1q binding and complement-activation by RTX, OFA and OBI on human B cell lines that differ in expression levels of CD20 and complement-regulatory proteins as well as human primary B cells. Applying real-time interaction analysis, we show that the overall strength of C1q binding to live target cells coated with antibodies positively correlated with the degree of bivalent binding for the antibodies to CD20. Kinetic analysis revealed that C1q exhibits two binding modes with distinct affinities and binding stabilities, with exact numbers varying both between antibodies and cell lines. Furthermore, complement-dependent cell killing by RTX and OBI was highly cell-line dependent, whereas the superior complement-dependent cytotoxicity by OFA was independent of the target B cells. All three antibodies were able to initiate deposition of C3b on the B cell surface, although to varying extent. This suggests that complement activation occurs but might not necessarily lead to induction of complement-dependent cytotoxicity. This activation could, however, initiate complement-dependent phagocytosis as an alternative mechanism of therapeutic B cell depletion. [ABSTRACT FROM AUTHOR]

The development and spread of multidrug resistant pathogens have reinforced the urgency to find novel natural products with antibiotic activity. In bacteria, orphan biosynthetic gene clusters (BGCs) far outnumber the BGCs for which chemistry is known, possibly because they are transcriptionally silent under laboratory conditions. A strategy to trigger the production of this biosynthetic potential is to challenge the microorganism with low concentrations of antibiotics, and by using a Burkholderia genetic reporter strain (Seyedsayamdost, Proc Natl Acad Sci 111:7266–7271), we found BGC unsilencing activity for the antimicrobial andrimid, produced by the marine bacterium Vibrio coralliilyticus. Next, we challenged another marine Vibrionaceae, Photobacterium galatheae , carrier of seven orphan BGCs with sub-inhibitory concentrations of andrimid. A combined approach of transcriptional and chemical measurements of andrimid-treated P. galatheae cultures revealed a 10-fold upregulation of an orphan BGC and, amongst others, a 1.6–2.2-fold upregulation of the gene encoding the core enzyme for biosynthesis of holomycin. Also, addition of andrimid caused an increase, based on UV-Vis peak area, of 4-fold in production of the antibiotic holomycin. Transcriptional measurements of stress response related genes in P. galatheae showed a co-occurrence of increased transcript levels of rpoS (general stress response) and andrimid induced holomycin overproduction, while in trimethoprim treated cultures attenuation of holomycin production coincided with a transcriptional increase of recA (SOS stress response). This study shows that using antimicrobial compounds as activators of secondary metabolism can be a useful strategy in eliciting biosynthetic gene clusters and facilitate natural product discovery. Potentially, such interactions could also have ecological relevant implications. [ABSTRACT FROM AUTHOR]

The detection of ambient cold is critical for mammals, who use this information to avoid tissue damage by cold and to maintain stable body temperature. The transduction of information about the environmental cold is mediated by cold-sensitive ion channels expressed in peripheral sensory nerve endings in the skin. Most transduction mechanisms for detecting temperature changes identified to date depend on transient receptor potential (TRP) ion channels. Mild cooling is detected by the menthol-sensitive TRPM8 ion channel, but how painful cold is detected remains unclear. The TRPA1 ion channel, which is activated by cold in expression systems, seemed to provide an answer to this question, but whether TRPA1 is activated by cold in neurons and contributes to the sensation of cold pain continues to be a matter of debate. Recent advances have been made in this area of investigation with the identification of several potential cold-sensitive ion channels in thermosensory neurons, including two-pore domain potassium channels (K2P), GluK2 glutamate receptors, and CNGA3 cyclic nucleotide-gated ion channels. This mini-review gives a brief overview of the way by which ion channels contribute to cold sensation, discusses the controversy around the cold-sensitivity of TRPA1, and provides an assessment of some recently-proposed novel cold-transduction mechanisms. Evidence for another unidentified cold-transduction mechanism is also presented. [ABSTRACT FROM AUTHOR]

Over the past years vlogs rapidly have become an attractive platform for food industries, sponsoring social media influencers to promote their products. As with more traditional media, social media influencers predominantly promote unhealthy drinks and foods that are high in sugar, fat, and salt – consumption of which may increase the risk of overweight, obesity, and non-communicable diseases. The aim of the current Brief Research Report is to examine the impact of vlogs on children's unhealthy dietary behaviors. Drawing on longitudinal survey data from 453 8- to 12-year-old children, we analyzed the longitudinal relations between children's frequency of watching vlogs and their consumption of unhealthy beverages and snacks. Structural path modeling analyses of three waves of data with 1-year intervals showed that children's self-reported frequency of watching vlogs influenced consumption of unhealthy beverages 2 years later. The analyses did not yield significant relations for Unhealthy Snacks Consumption. The strength of the observed longitudinal relation between children's Frequency of Watching Vlogs and Consumption of unhealthy beverages was comparable to previous findings regarding more traditional types of food marketing. [ABSTRACT FROM AUTHOR]

There is a need to stimulate physical activity among adolescents, but unfortunately, they are hard to reach with traditional mass media interventions. A promising alternative is to carry out social network interventions. In social network interventions, a small group of individuals (influence agents) is selected to promote health-related behaviors within their social network. This study investigates whether a social network intervention is more effective to promote physical activity, compared to a mass media intervention and no intervention. Adolescents (N = 446; M age = 11.35, SD age = 1.34; 47% male) were randomly allocated by classroom (N = 26, in 11 schools) to one of three conditions: social network intervention, mass media intervention, or control condition. In the social network intervention, 15% of the participants (based on peer nominations) was approached to become an influence agent, who created vlogs about physical activity that were shown during the intervention. In the mass media intervention, participants were exposed to vlogs made by unfamiliar peers (i.e., vlogs of the social network intervention). The control condition did not receive vlogs about physical activity. All participants received a research smartphone to complete questionnaires and a wrist-worn accelerometer to measure physical activity. The trial was registered a priori in the Dutch Trial Registry (NTR6903). There were no differences in objectively measured physical activity between this social network intervention and the control condition in the short-term, but there was an unexpected increase in the control condition compared to the social network intervention in the long-term. No differences between the social network intervention and mass media intervention were observed. The current study does not provide evidence that this social network intervention is effective in increasing physical activity in adolescents. Exploratory analyses suggest that this social network intervention increased the perceived social norm toward physical activity and responses to the vlogs were more positive in the social network intervention than in the mass media intervention. These initial results warrant further research to investigate the role of the social norms and the added benefit of using influence agents for social network interventions. Clinical Trial Registration: https://www.trialregister.nl/, identifier NTR6903. [ABSTRACT FROM AUTHOR]

Objectives: Our aim of this work was to investigate the regrowth of implant-related biofilms after various antimicrobial treatments in vitro. Methods: Saliva-derived microcosm biofilms were grown on titanium discs in an active attachment model. Treatments including hydrogen peroxide (HP), citric acid (CA), chlorhexidine (CHX), and distilled water (control), at different concentrations, were applied to 2-day biofilms for 1 or 5 min. The viability, lactic acid production, and composition of the biofilms were followed for 3 days. The biofilm composition was analyzed by 16S rDNA amplicon sequencing. Results: The short treatments of CA, CHX, and HP resulted in a 2–3 log reduction in biofilm viability and lactic acid production immediately. However, both parameters returned to the pre-treatment level within 2 days due to biofilm regrowth. The alpha diversity of the regrown biofilms in antimicrobial-treated groups tended to decrease, whereas the diversity of those in water-treated group increased. The composition of the regrown biofilms altered compared to those before treatments. Streptococcus and Enterobacteriaceae were enriched in the regrown biofilms. Conclusions: Although the antimicrobial treatments were efficient, the multi-species biofilms were indeed able to regrow within 2 days. The regrown biofilms display an altered microbial diversity and composition, which in the oral cavity may lead to an aggressive infection. [ABSTRACT FROM AUTHOR]

One evolutionary adaptation in motor activity control of animals is the anticipation of food that drives foraging under natural conditions and is mimicked in laboratory with daily scheduled food availability. Food anticipation is characterized by increased activity a few hours before the feeding period. Here we report that 2-h food availability during the normal inactive phase of rats not only increases activity levels before the feeding period but also alters the temporal organization of motor activity fluctuations over a wide range of time scales from minutes up to 24 h. We demonstrate this multiscale alteration by assessing fractal patterns in motor activity fluctuations--similar fluctuation structure at different time scales--that are robust in intact animals with ad libitum food access but are disrupted under food restriction. In addition, we show that fractal activity patterns in rats with ad libitum food access are also perturbed by lesion of the dorsomedial hypothalamic (DMH)--a neural node that is involved in food anticipatory behavior. Instead of further disrupting fractal regulation, food restriction restores the disrupted fractal patterns in these animals after the DMH lesion despite the persistence of the 24-h rhythms. This compensatory effect of food restriction is more clearly pronounced in the same animals after the additional lesion of the suprachiasmatic nucleus (SCN)--the central master clock in the circadian system that generates and orchestrates circadian rhythms in behavior and physiological functions in synchrony with day-night cycles. Moreover, all observed influences of food restriction persist even when data during the food anticipatory and feeding period are excluded. These results indicate that food restriction impacts dynamics of motor activity at different time scales across the entire circadian/daily cycle, which is likely caused by the competition between the food-induced time cue and the light-entrained circadian rhythm of the SCN. The differential impacts of food restriction on fractal activity control in intact and DMH-lesioned animals suggest that the DMH plays a crucial role in integrating these different time cues to the circadian network for multiscale regulation of motor activity. [ABSTRACT FROM AUTHOR]

Understanding molecular interactions on immune cells is crucial for drug development to treat cancer and autoimmune diseases. When characterizing molecular interactions, the use of a relevant living model system is important, as processes such as receptor oligomerization and clustering can influence binding patterns. We developed a protocol to enable time-resolved analysis of ligand binding to receptors on living suspension cells. Different suspension cell lines and weakly adhering cells were tethered to Petri dishes with the help of a biomolecular anchor molecule, and antibody binding was analyzed using LigandTracer. The protocol and assay described in this report were used to characterize interactions involving eight cell lines. Experiments were successfully conducted in three different laboratories, demonstrating the robustness of the protocol. For various antibodies, affinities and kinetic rate constants were obtained for binding to CD20 on both Daudi and Ramos B-cells, the T-cell co-receptor CD3 on Jurkat cells, and the Fcγ receptor CD32 on transfected HEK293 cells, respectively. Analyzing the binding of Rituximab to B-cells resulted in an affinity of 0.7--0.9 nM, which is similar to values reported previously for living B-cells. However, we observed a heterogeneous behavior for Rituximab interacting with B-cells, which to our knowledge has not been described previously. The understanding of complex interactions will be facilitated with the possibility to characterize binding processes in real-time on living immune cells. This provides the chance to broaden the understanding of how binding kinetics relate to biological function. [ABSTRACT FROM AUTHOR]

Sustainable agriculture demands reduced input of man-made nitrogen (N) fertilizer, yet N2 fixation limits the productivity of crops with heterotrophic diazotrophic bacterial symbionts. We investigated floating ferns from the genus Azolla that host phototrophic diazotrophic Nostoc azollae in leaf pockets and belong to the fastest growing plants. Experimental production reported here demonstrated N-fertilizer independent production of nitrogen-rich biomass with an annual yield potential per ha of 1200 kg-1 N fixed and 35 t dry biomass. 15N2 fixation peaked at noon, reaching 0.4 mg N g-1 dry weight h-1. Azolla ferns therefore merit consideration as protein crops in spite of the fact that little is known about the fern's physiology to enable domestication. To gain an understanding of their nitrogen physiology, analyses of fern diel transcript profiles under differing nitrogen fertilizer regimes were combined with microscopic observations. Results established that the ferns adapted to the phototrophic N2-fixing symbionts N. azollae by (1) adjusting metabolically to nightly absence of N supply using responses ancestral to ferns and seed plants; (2) developing a specialized xylem-rich vasculature surrounding the leaf-pocket organ; (3) responding to N-supply by controlling transcripts of genes mediating nutrient transport, allocation and vasculature development. Unlike other non-seed plants, the Azolla fern clock is shown to contain both the morning and evening loops; the evening loop is known to control rhythmic gene expression in the vasculature of seed plants and therefore may have evolved along with the vasculature in the ancestor of ferns and seed plants. [ABSTRACT FROM AUTHOR]

This study investigated whether a forewarning of advertising's intent can increase children's (N D 159, 8-10 years old) defenses against television commercials to lower their desire for advertised products. Two different forewarnings were tested, one for advertising's commercial intent or warning for the promotional nature, and one for advertising's manipulative intent or warning for the deceptive nature. Results showed that only the warning of manipulative intent prior to advertising exposure was successful in increasing children's advertising defenses. This forewarning activated children's attitudinal advertising literacy (i.e., skepticism toward the commercial), which in turn led to lower advertised product desire. The forewarning of commercial intent was not effective in strengthening children's advertising defenses. These findings have important implications for interventions that aim to lower children's desire for (unhealthy) advertised products by activating their advertising literacy. [ABSTRACT FROM AUTHOR]

One evolutionary adaptation in motor activity control of animals is the anticipation of food that drives foraging under natural conditions and is mimicked in laboratory with daily scheduled food availability. Food anticipation is characterized by increased activity a few hours before the feeding period. Here we report that 2-h food availability during the normal inactive phase of rats not only increases activity levels before the feeding period but also alters the temporal organization of motor activity fluctuations over a wide range of time scales from minutes up to 24 h. We demonstrate this multiscale alteration by assessing fractal patterns in motor activity fluctuations—similar fluctuation structure at different time scales—that are robust in intact animals with ad libitum food access but are disrupted under food restriction. In addition, we show that fractal activity patterns in rats with ad libitum food access are also perturbed by lesion of the dorsomedial hypothalamic (DMH)—a neural node that is involved in food anticipatory behavior. Instead of further disrupting fractal regulation, food restriction restores the disrupted fractal patterns in these animals after the DMH lesion despite the persistence of the 24-h rhythms. This compensatory effect of food restriction is more clearly pronounced in the same animals after the additional lesion of the suprachiasmatic nucleus (SCN)—the central master clock in the circadian system that generates and orchestrates circadian rhythms in behavior and physiological functions in synchrony with day-night cycles. Moreover, all observed influences of food restriction persist even when data during the food anticipatory and feeding period are excluded. These results indicate that food restriction impacts dynamics of motor activity at different time scales across the entire circadian/daily cycle, which is likely caused by the competition between the food-induced time cue and the light-entrained circadian rhythm of the SCN. The differential impacts of food restriction on fractal activity control in intact and DMH-lesioned animals suggest that the DMH plays a crucial role in integrating these different time cues to the circadian network for multiscale regulation of motor activity.

Oral bacteria live in symbiosis with the host. Therefore, when mouthwashes are indicated, selective inhibition of taxa contributing to disease is preferred instead of broad-spectrum antimicrobials. The potential selectivity of an oxygenating mouthwash, Ardox-X® (AX), has not been assessed. The aim of this study was to determine the antimicrobial potential of AX and the effects of a twice-daily oral rinse on dental plaque composition. Material and methods: In vitro, 16 oral bacterial strains were tested using agar diffusion susceptibility, minimum inhibitory and minimum bactericidal concentration tests. A pilot clinical study was performed with 25 healthy volunteers. Clinical assessments and microbiological sampling of supragingival plaque were performed at 1 month before the experiment (Pre-exp), at the start of the experiment (Baseline) and after the one-week experimental period (Post-exp). During the experiment individuals used AX mouthwash twice daily in absence of other oral hygiene measures. The microbiological composition of plaque was assessed by 16S rRNA gene amplicon sequencing. Results: AX showed high inter-species variation in microbial growth inhibition. The tested Prevotella strains and Fusobacterium nucleatum showed the highest sensitivity, while streptococci and Lactobacillus acidophilus were most resistant to AX. Plaque scores at Pre-exp and Baseline visits did not differ significantly (p = 0.193), nor did the microbial composition of plaque. During a period of 7-days non-brushing but twice daily rinsing plaque scores increased from 2.21 (0.31) at Baseline to 2.43 (0.39) Post-exp. A significant microbial shift in composition was observed: genus Streptococcus and Veillonella increased while Corynebacterium, Haemophilus, Leptotrichia, Cardiobacterium and Capnocytophaga decreased (p ≤ 0.001). Conclusion: AX has the potential for selective inhibition of oral bacteria. The shift in oral microbiome after 1 week of rinsing deserves further research. [ABSTRACT FROM AUTHOR]

The bottled drinking water market has seen significant growth and diversification, yet the selection criteria lack scientific basis, as all must adhere to stringent health standards. Prior studies predominantly focused on chemical quality, with limited assessments of microbial quality using methods prone to underestimation. Moreover, insufficient research explores the impact of packaging materials and temperatures optimal for mesophilic growth on microbial quality. To understand the unique characteristics and justify the distinction among different types of bottled waters, a comprehensive analysis encompassing both chemical and microbiological aspects is imperative. Addressing these gaps, our study examines 19 diverse bottled water brands comprising purified, mineral, artesian, and sparkling water types from Saudi Arabia and abroad. Our findings reveal distinct chemical compositions among bottled waters, with notable variations across types. Flow cytometry analysis reveals significant differences in bacterial content among water types, with natural mineral waters having the highest concentrations and treated purified waters the lowest. Bacterial content in plastic-bottled mineral water suggests it may be higher than in glass-bottled water. Flow cytometry fingerprints highlight separate microbial communities for purified and mineral waters. Additionally, temperatures favorable for mesophilic growth reveal varying microbial responses among different types of bottled waters. Some variation is also observed in mineral water bottled in plastic versus glass, suggesting potential differences that warrant further investigation. 16S rRNA gene sequencing identifies unique microbial taxa among different mineral waters. Overall, our study underscores that all bottled waters meet health regulations. Furthermore, the combined chemical and microbial profiles may serve as authenticity indicators for distinct bottled water types. This study can serve as a basis for future research on the environmental impact of bottled water transportation, suggesting that locally produced water may offer a more sustainable option. [ABSTRACT FROM AUTHOR]

Background: Higher rates of physical inactivity and comorbid conditions are reported in Hispanic/Latinx and Black cancer patients receiving chemotherapy compared to their White counterparts. Despite the beneficial effect of exercise training for cancer patients, rates of participation in exercise oncology clinical trials are low among disadvantaged and racial and ethnic minority groups. Here, we will examine the effect of an exercise intervention using a novel, accessible, and cost-effective home-based exercise approach among Hispanic/Latinx and Black cancer patients receiving chemotherapy on exercise participation and cardiovascular disease risk. Methods: The THRIVE trial is an 8-month prospective, three-arm study of 45 patients who are randomized in a 1:1:1 fashion to a supervised exercise intervention (SUP), unsupervised exercise (UNSUP), or an attention control (AC) group. Eligible patients include those with breast, colorectal, or prostate cancer, who are sedentary, overweight or obese, self-identify as Hispanic/Latinx or Black, and plan to receive chemotherapy. Patients randomized to the SUP group participate in a home-based 16-week periodized aerobic and resistance exercise program performed three days per week, supervised through video conference technology. Patients randomized to the UNSUP group participate in an unsupervised 16-week, telehealth-based, periodized aerobic and resistance exercise program performed three days per week using the same exercise prescription parameters as the SUP group. Patients randomized to the AC group receive a 16-week home-based stretching program. The primary outcome is changes in minutes of physical activity assessed by 7-day accelerometry at postintervention. Secondary outcomes include cardiovascular risk factors, patientreported outcomes, and physical function. Outcome measures are tested at baseline, post-intervention at month 4, and after a non-intervention follow-up period at month 8. Discussion: The THRIVE trial is the first study to employ a novel and potentially achievable exercise intervention for a minority population receiving chemotherapy. In addition, this study utilizes an intervention approach to investigate the biological and behavioral mechanisms underlying exercise participation in these cancer patients. Results will guide and inform large randomized controlled trials to test the effect of home-based exercise on treatment outcomes and comorbid disease risk in minority patients with cancer undergoing chemotherapy. [ABSTRACT FROM AUTHOR]

Microglia are highly dynamic cells that have been mainly studied under pathological conditions. The present review discusses the possible implication of microglia as modulators of neuronal electrical responses in physiological conditions and hypothesizes how these cells might modulate hypothalamic circuits in health and during obesity. Microglial cells studied under physiological conditions are highly diverse, depending on the developmental stage and brain region. The evidence also suggests that neuronal electrical activity modulates microglial motility to control neuronal excitability. Additionally, we show that the expression of genes associated with neuronmicroglia interaction is down-regulated in obese mice compared to control-fed mice, suggesting an alteration in the contact-dependent mechanisms that sustain hypothalamic arcuate-median eminence neuronal function. We also discuss the possible implication of microglial-derived signals for the excitability of hypothalamic neurons during homeostasis and obesity. This review emphasizes the importance of studying the physiological interplay between microglia and neurons to maintain proper neuronal circuit function. It aims to elucidate how disruptions in the normal activities of microglia can adversely affect neuronal health. [ABSTRACT FROM AUTHOR]

Prior research on social media influencers (SMIs) often examined questions such as their model of communication with followers, ethical concerns, motivations, and ways of gaining capital. How influencers curate intense and intimate relations and strategize their content creation, and how the influencer industry takes a toll on their physical and psychological wellbeing should be carefully addressed. To fill in this gap, we conducted in-depth interviews with 20 SMIs. The findings advance the literature on influencers and influencer advertising by explicating the ways through which influencers maintain intimate and engaged relations with followers, including providing value, creating emotional bond, interacting and co-creating with followers, and disclosing personal life. Second, this research identifies and theorizes four principles - authenticity, topic sensitivity, fact-checking, and strategic sharing of privacy - under which influencers strategize content creations in building human brands. Last, our findings add to the ongoing literature on digital labor by expounding the downsides of influencers being digital labor. This research contributes to the understudied aspect regarding influencers' wellbeing and strategies employed in content creation and relation management in the current influencer literature. [ABSTRACT FROM AUTHOR]

The exponential increase in global population continues to present an ongoing challenge for livestock producers worldwide to consistently provide a safe, highquality, and affordable source of protein for consumers. In the last 50 years, the poultry industry has spearheaded this effort thanks to focused genetic and genomic selection for feed-efficient, high-yielding broilers. However, such intense selection for productive traits, along with conventional industry farming practices, has also presented the industry with a myriad of serious issues that negatively impacted animal health, welfare, and productivity-such as woody breast and virulent diseases commonly associated with poultry farming. Bacterial chondronecrosis with osteomyelitis (BCO) lameness is one such issue, having rapidly become a key issue affecting the poultry industry with serious impacts on broiler welfare, meat quality, production, food safety, and economic losses since its discovery in 1972. This review focuses on hallmark clinical symptoms, diagnosis, etiology, and impact of BCO lameness on key issues facing the poultry industry. [ABSTRACT FROM AUTHOR]

Vasopressin (VP) plays a crucial role in social memory even at the level of the olfactory bulb (OB), where OB VP cells are activated during social interactions. However, it remains unclear how VP modulates olfactory processing to enable enhanced discrimination of very similar odors, e.g., rat body odors. Thus far, it has been shown that VP reduces firing rates in mitral cells (MCs) during odor presentation in vivo and decreases the amplitudes of olfactory nerve-evoked excitatory postsynaptic potentials (ON-evoked EPSPs) in external tufted cells in vitro. We performed whole-cell patch-clamp recordings and population Ca2+ imaging on acute rat OB slices. We recorded ON-evoked EPSPs as well as spontaneous inhibitory postsynaptic currents (IPSCs) from two types of projection neurons: middle tufted cells (mTCs) and MCs. VP bath application reduced the amplitudes of ON-evoked EPSPs and the frequencies of spontaneous IPSCs in mTCs but did not change those in MCs. Therefore, we analyzed ON-evoked EPSPs in inhibitory interneurons, i.e., periglomerular cells (PGCs) and granule cells (GCs), to search for the origin of increased inhibition in mTCs. However, VP did not increase the amplitudes of evoked EPSPs in either type of interneurons. We next performed two-photon population Ca2+ imaging in the glomerular layer and the superficial GC layer of responses to stronger ON stimulation than during patch-clamp experiments that should evoke action potentials in the measured cells. We observed that VP application increased ON-evoked Ca2+ influx in juxtaglomerular cells and GC somata. Thus, our findings indicate inhibition by VP on projection neurons via strong ON input-mediated inhibitory interneuron activity. This neural modulation could improve representation of odors, hence, better discriminability of similar odors, e.g., conspecific body odors. [ABSTRACT FROM AUTHOR]

Hypertensive disorders of pregnancy (HDP) are severe complications of pregnancy with high morbidity and are a major cause of increased maternal and infant morbidity and mortality. Currently, there is a lack of effective early diagnostic indicators and safe and effective preventive strategies for HDP in clinical practice, except for monitoring maternal blood pressure levels, the degree of proteinuria, organ involvement and fetal conditions. The intestinal microbiota consists of the gut flora and intestinal environment, which is the largest microecosystem of the human body and participates in material and energy metabolism, gene expression regulation, immunity regulation, and other functions. During pregnancy, due to changes in hormone levels and altered immune function, the intestinal microecological balance is affected, triggering HDP. A dysregulated intestinal microenvironment influences the composition and distribution of the gut flora and changes the intestinal barrier, driving beneficial or harmful bacterial metabolites and inflammatory responses to participate in the development of HDP and promote its malignant development. When the gut flora is dysbiotic and affects blood pressure, supplementation with probiotics and dietary fiber can be used to intervene. In this review, the interaction between the intestinal microbiota and HDP was investigated to explore the feasibility of the gut flora as a novel biomarker of HDP and to provide a new strategy and basis for the prevention and treatment of clinical HDP. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia (ALL) is a prevalent malignancy affecting the hematopoietic system, encompassing both B-cell ALL (B-ALL) and T-cell ALL (T-ALL). T-ALL, characterized by the proliferation of T-cell progenitors in the bone marrow, presents significant treatment challenges, with patients often experiencing high relapse rates and poor long-term survival despite advances in chemotherapy and hematopoietic stem cell transplantation (HSCT). This review explores the pathogenesis and traditional treatment strategies of T-ALL, emphasizing the promising potential of chimeric antigen receptor (CAR) technology in overcoming current therapeutic limitations. CAR therapy, leveraging genetically modified immune cells to target leukemia-specific antigens, offers a novel and precise approach to T-ALL treatment. The review critically analyzes recent developments in CAR-T and CAR-NK cell therapies, their common targets, optimization strategies, clinical outcomes, and the associated challenges, providing a comprehensive overview of their clinical prospects in T-ALL treatment. [ABSTRACT FROM AUTHOR]

Introduction: Cities globally, including Tokyo, face challenges in managing small urban green spaces due to limited land, aging infrastructure, and rising maintenance costs. This study explores effective community engagement strategies for park revitalization as cities focus on improving existing green spaces rather than expanding them. Methods: This research investigates community park revitalization in Toshima Ward, Tokyo, using a case study approach involving three parks. Data were collected through interviews with seven park management stakeholders and a survey of 176 residents. The study aimed to identify key factors for successful community participation, evaluate perceptions of engagement activities, and assess residents' willingness to participate. Results: Key factors for effective park revitalization include public buildings inside and outside the parks, sufficient greenery and open spaces, and local responsible persons. Despite these conditions, challenges such as high maintenance costs and low resident engagement persist. Among 176 respondents, 55 had participated in park events. Both genders noted increased use by parents and children and enhanced motivation to visit as significant impacts, with mean ratings of 4.36 and 4.37, respectively. Age differences were observed: respondents aged 18-39 emphasized increased use by parents and children (mean 4.75), while those aged 40-59 and over 60 valued motivation to visit (means 4.64 and 4.00). Long-term residents (over 10 years) reported lower impact ratings than newer residents, and larger families rated activities more positively than smaller or single-person households. Key issues included insufficient publicity (60%), restriction of normal use (20%), increased waste (14.5%), and noise (12.7%). Discussion: The study highlights the need to address demographic differences in engagement preferences and barriers. Tailoring activities to diverse groups, including seniors and single-person households, can improve participation and effectiveness. These findings can guide localized park management strategies and foster more inclusive urban green space initiatives. [ABSTRACT FROM AUTHOR]

Organoid technology has been developed rapidly in the past decade, which involves the exploration of the mechanism of development, regeneration and various diseases, and intersects among multiple disciplines. Thousands of literature on 3D-culture or organoids have been published in the research areas of cell biology tissue engineering, nanoscience, oncology and so on, resulting in it being challenging for researchers to timely summarize these studies. Bibliometric statistics is a helpfulway to help researchers clarify the above issues efficiently andmanage the whole landscape systematically. In our study, all original articles on organoids were included in the Web of Science database from January 2009 to May 2024, and related information was collected and analyzed using Excel software, "bibliometrix" packages of the R software, VOSviewer and CiteSpace. As results, a total of 6222 papers were included to classify the status quo of the organoids and predict future research areas. Our findings highlight a growing trend in publications related to organoids, with the United States and Netherlands leading in this field. The University of California System, Harvard University, Utrecht University and Utrecht University Medical Center have emerged as pivotal contributors and the key authors in the field include Clevers, H, Beekman, JM and Spence JR. Our results also revealed that the research hotspots and trends of organoids mainly focused on clinical treatment, drug screening, and the application of materials and technologies such as "hydrogel" and "microfluidic technology" in organoids. Next, we had an in-depth interpretation of the development process of organoid research area, including the emergence of technology, the translation from bench to bedsides, the profiles of the most widely studied types of organoids, the application of materials and technologies, and the emerging organoid-immune co-cultures trends. Furthermore,we also discussed the pitfalls, challenges and prospects of organoid technology. In conclusion, this study provides readers straightforward and convenient access to the organoid research field. [ABSTRACT FROM AUTHOR]

Introduction: Facial expressions conveying an emotion may a ect social interactions, such as approach- or avoidance-related behaviors. A specific facial feature is the gaze direction. An emotional facial expression such as anger will elicit distinct behavioral tendencies, depending on whether the angry gaze is directed toward the onlooker, or in a di erent direction. We tested whether facial expressions of anger and fear, combined with direct or averted gaze, elicit approach- or avoidance tendencies, using a go/no-go variant of thewhole-body stepping task. Method: Healthy adults stood on a force plate, recording the center of pressure (COP). Participants were presented with angry or fearful faces; either with direct or averted gaze. Participants had to identify the emotion, and "depending on instructions- eithermake a single step forward, or remain in a quiet stance. From the COP of the forward steps, we derived parameters such as reaction time and step size. From the quiet standing trials we derived parameters of postural sway, indicative of postural "freeze." We used analysis of variance to analyze the outcomes. Results and discussion: First, we found that steps were initiated faster with angry faces than with fearful faces, in line with existing literature. Second, we did not observe a significant e ect of gaze direction. Forward steps with direct and averted gaze had similar COP characteristics. Finally,we had expected to find freeze (postural immobility) with fearful faces, but this was also not observed.We discuss various explanations for the finding, and implications for research into the motoric grounding of social interactions. [ABSTRACT FROM AUTHOR]

Introduction: Type 2 diabetes (T2D) is the predominant form of diabetes mellitus and is among the leading causes of death with an increasing prevalence worldwide. However, the pathological mechanism underlying T2D remains complex and unclear. An increasing number of studies have suggested an association between circadian clock disruption and high T2D prevalence. Method: This review explores the physiological and genetic evidence underlying T2D symptoms associated with circadian clock disturbances, including insulin secretion and glucose metabolism. Results and Discussion: Notably, circadian clock disruption reduces insulin secretion and insulin sensitivity and negatively affects glucose homeostasis. The circadian clock regulates the hypothalamic-pituitary-adrenal axis, an important factor that regulates glucose metabolism and influences T2D progression. Therefore, circadian clock regulation is an attractive, novel therapeutic approach for T2D, and various circadian clock stabilizers play therapeutic roles in T2D. Lastly, this review suggests novel therapeutic and preventive approaches using circadian clock regulators for T2D. [ABSTRACT FROM AUTHOR]

Circadian fluctuations in physiological setpoints are determined by the suprachiasmatic nucleus (SCN) which exerts control over many target structures within and beyond the hypothalamus via projections. The SCN, or central pacemaker, orchestrates synchrony between the external environment and the internal circadian mechanism. The resulting cycles in hormone levels and autonomic nervous system (ANS) activity provide precise messages to specific organs, adjusting, for example, their sensitivity to approaching hormones or metabolites. The SCN responds to both photic (light) and non-photic input. Circadian patterns are found in both heart rate and blood pressure, which are linked to daily variations in activity and autonomic nervous system activity. Variations in blood pressure are of great interest as several cardiovascular diseases such as stroke, arrhythmias, and hypertension are linked to circadian rhythm dysregulation. The disruption of normal day-night cycles, such as in shift work, social jetlag, or eating outside of normal hours leads to desynchronization of the central and peripheral clocks. This desynchronization leads to disorganization of the cellular processes that are normally driven by the interactions of the SCN and photic input. Here, we review autonomic system function and dysfunction due to regulation and interaction between different cardiorespiratory brain centers and the SCN, as well as social, lifestyle, and external factors that may impact the circadian control of blood pressure. [ABSTRACT FROM AUTHOR]

Sleep disturbances are common features of neurodegenerative disorders including Huntington's disease (HD). Sleep and circadian disruptions are recapitulated in animal models, providing the opportunity to evaluate the effectiveness of circadian interventions as countermeasures for neurodegenerative disease. For instance, time restricted feeding (TRF) successfully improved activity rhythms, sleep behavior and motor performance in mouse models of HD. Seeking to determine if these benefits extend to physiological measures of sleep, electroencephalography (EEG) was used to measure sleep/wake states and polysomnographic patterns in male and female wild-type (WT) and bacterial artificial chromosome transgenic (BACHD) adult mice, under TRF and ad lib feeding (ALF). Our findings show that male, but not female, BACHD mice exhibited significant changes in the temporal patterning of wake and non-rapid eye movement (NREM) sleep. The TRF intervention reduced the inappropriate early morning activity by increasing NREM sleep in the male BACHD mice. In addition, the scheduled feeding reduced sleep fragmentation (# bouts) in the male BACHD mice. The phase of the rhythm in rapid-eye movement (REM) sleep was significantly altered by the scheduled feeding in a sex-dependent manner. The treatment did impact the power spectral curves during the day in male but not female mice regardless of the genotype. Sleep homeostasis, as measured by the response to six hours of gentle handling, was not altered by the diet. Thus, TRF improves the temporal patterning and fragmentation of NREM sleep without impacting sleep homeostasis. This work adds critical support to the view that sleep is a modifiable risk factor in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

The forage grass factory could break through the restrictions of land resources, region and climate to achieve efficient production throughout the year by accurate and intelligent management. However, due to its closed environment, mold outbreaks in the forage grass factory were severe, significantly affecting barley production. In this study, 9 contaminated barley tissues were collected and 45 strains were isolated in forage grass factory. After ITS sequencing, 45 strains were all identified as Rhizopus oryzae. Through stress factor assays, R. oryzae growth was seriously hindered by low concentration of sodium nitrate, high pH value and ozone water treatment. High pH and ozone water affected growth mainly by altering membrane integrity of R. oryzae. Sodium nitrate inhibited the growth of R. oryzae mainly by affecting the amount of sporulation. Low concentration of sodium nitrate and ozone water did not affect the growth of barley. High concentrations of sodium nitrate (100mM) and pH values (8-8.5) inhibited barley growth. Among them, ozone water had the most obvious inhibition effect on R. oryzae. Large-scale ozone water treatment in the forage grass factory had also played a role in restoring barley production. Taken together, the green techonology to controlmold disease andmaintain the safety of forage through different physicochemical methods was selected, which was of considerable application value in animal husbandry. [ABSTRACT FROM AUTHOR]