Custom scoring based on ecological topology of gut microbiota associated with cancer immunotherapy outcome.

The gut microbiota influences the clinical responses of cancer patients to immunecheckpoint inhibitors (ICIs). However, there is no consensus definition of detrimental dysbiosis. Based on metagenomics (MG) sequencing of 245 non-small cell lung cancer (NSCLC) patient feces, we constructed species-level co-abundance networks that were clustered into species-interacting groups (SIGs) correlating with overall survival. Thirty-seven and forty-five MG species (MGSs) were associated with resistance (SIG1) and response (SIG2) to ICIs, respectively. When combined with the quantification of Akkermansia species, this procedure allowed a person-based calculation of a topological score (TOPOSCORE) that was validated in an additional 254 NSCLC patients and in 216 genitourinary cancer patients. Finally, this TOPOSCORE was translated into a 21-bacterial probe set-based qPCR scoring that was validated in a prospective cohort of NSCLC patients as well as in colorectal and melanoma patients. This approach could represent a dynamic diagnosis tool for intestinal dysbiosis to guide personalized microbiota-centered interventions.

Gut Microbiota-Related Biomarkers in Immuno-Oncology.

Carcinogenesis is associated with the emergence of protracted intestinal dysbiosis and metabolic changes. Increasing evidence shows that gut microbiota-related biomarkers and microbiota-centered interventions are promising strategies to overcome resistance to immunotherapy. However, current standard methods for evaluating gut microbiota composition are cost- and time-consuming. The development of routine diagnostic tools for intestinal barrier alterations and dysbiosis constitutes a critical unmet medical need that can guide routine treatment and microbiota-centered intervention decisions in patients with cancer. In this review, we explore the influence of gut microbiota on cancer immunotherapy and highlight gut-associated biomarkers that have the potential to be transformed into simple diagnostic tools, thus guiding standard treatment decisions in the field of immuno-oncology. Mechanistic insights toward leveraging the complex relationship between cancer immunosurveillance, gut microbiota, and metabolism open exciting opportunities for developing novel biomarkers in immuno-oncology.

mRNA-LNP vaccine-induced CD8+ T cells protect mice from lethal SARS-CoV-2 infection in the absence of specific antibodies.

The role of CD8+ T cells in SARS-CoV-2 pathogenesis or mRNA-LNP vaccine-induced protection from lethal COVID-19 is unclear. Using mouse-adapted SARS-CoV-2 virus (MA30) in C57BL/6 mice, we show that CD8+ T cells are unnecessary for the intrinsic resistance of female or the susceptibility of male mice to lethal SARS-CoV-2 infection. Also, mice immunized with a di-proline prefusion-stabilized full-length SARS-CoV-2 Spike (S-2P) mRNA-LNP vaccine, which induces Spike-specific antibodies and CD8+ T cells specific for the Spike-derived VNFNFNGL peptide, are protected from SARS-CoV-2 infection-induced lethality and weight loss, while mice vaccinated with mRNA-LNPs encoding only VNFNFNGL are protected from lethality but not weight loss. CD8+ T cell depletion ablates protection in VNFNFNGL but not in S-2P mRNA-LNP-vaccinated mice. Therefore, mRNA-LNP vaccine-induced CD8+ T cells are dispensable when protective antibodies are present but essential for survival in their absence. Hence, vaccine-induced CD8+ T cells may be critical to protect against SARS-CoV-2 variants that mutate epitopes targeted by protective antibodies.

The dendritic ERGIC: Microtubule and actin cytoskeletons participate in stop-and-go movement of mobile carriers between stable structures.

The endoplasmic reticulum (ER)-to-Golgi intermediate compartment (ERGIC) is a membranous organelle that mediates protein transport between the ER and the Golgi apparatus. In neurons, clusters of these vesiculotubular structures are situated throughout the cell in proximity to the ER, passing cargo to the cis-Golgi cisternae, located mainly in the perinuclear region. Although ERGIC markers have been identified in neurons, the distribution and dynamics of neuronal ERGIC structures have not been characterized yet. Here, we show that long-distance ERGIC transport occurs via an intermittent mechanism in dendrites, with mobile elements moving between stationary structures. Slow and fast live-cell imaging have captured stable ERGIC structures remaining in place over long periods of time, as well as mobile ERGIC structures advancing very short distances along dendrites. These short distances have been consistent with the lengths between the stationary ERGIC structures. Kymography revealed ERGIC elements that moved intermittently, emerging from and fusing with stationary ERGIC structures. Interestingly, this movement apparently depends not only on the integrity of the microtubule cytoskeleton, as previously reported, but on the actin cytoskeleton as well. Our results indicate that the dendritic ERGIC has a dual nature, with both stationary and mobile structures. The neural ERGIC network transports proteins via a stop-and-go movement in which both the microtubule and the actin cytoskeletons participate.

Resistance To Poxvirus Lethality Does Not Require the Necroptosis Proteins RIPK3 or MLKL.

Receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like pseudokinase (MLKL) are proteins that are critical for necroptosis, a mechanism of programmed cell death that is both activated when apoptosis is inhibited and thought to be antiviral. Here, we investigated the role of RIPK3 and MLKL in controlling the Orthopoxvirus ectromelia virus (ECTV), a natural pathogen of the mouse. We found that C57BL/6 (B6) mice deficient in RIPK3 (Ripk3-/-) or MLKL (Mlkl-/-) were as susceptible as wild-type (WT) B6 mice to ECTV lethality after low-dose intraperitoneal infection and were as resistant as WT B6 mice after ECTV infection through the natural footpad route. Additionally, after footpad infection, Mlkl-/- mice, but not Ripk3-/- mice, endured lower viral titers than WT mice in the draining lymph node (dLN) at three days postinfection and in the spleen or in the liver at seven days postinfection. Despite the improved viral control, Mlkl-/- mice did not differ from WT mice in the expression of interferons or interferon-stimulated genes or in the recruitment of natural killer (NK) cells and inflammatory monocytes (iMOs) to the dLN. Additionally, the CD8 T-cell responses in Mlkl-/- and WT mice were similar, even though in the dLNs of Mlkl-/- mice, professional antigen-presenting cells were more heavily infected. Finally, the histopathology in the livers of Mlkl-/- and WT mice at 7 dpi did not differ. Thus, the mechanism of the increased virus control by Mlkl-/- mice remains to be defined. IMPORTANCE The molecules RIPK3 and MLKL are required for necroptotic cell death, which is widely thought of as an antiviral mechanism. Here we show that C57BL/6 (B6) mice deficient in RIPK3 or MLKL are as susceptible as WT B6 mice to ECTV lethality after a low-dose intraperitoneal infection and are as resistant as WT B6 mice after ECTV infection through the natural footpad route. Mice deficient in MLKL are more efficient than WT mice at controlling virus loads in various organs. This improved viral control is not due to enhanced interferon, natural killer cell, or CD8 T-cell responses. Overall, the data indicate that deficiencies in the molecules that are critical to necroptosis do not necessarily result in worse outcomes following viral infection and may improve virus control.

Infection increases activity via Toll dependent and independent mechanisms in Drosophila melanogaster.

Host behavioural changes are among the most apparent effects of infection. 'Sickness behaviour' can involve a variety of symptoms, including anorexia, depression, and changed activity levels. Here, using a real-time tracking and behavioural profiling platform, we show that in Drosophila melanogaster, several systemic bacterial infections cause significant increases in physical activity, and that the extent of this activity increase is a predictor of survival time in some lethal infections. Using multiple bacteria and D. melanogaster immune and activity mutants, we show that increased activity is driven by at least two different mechanisms. Increased activity after infection with Micrococcus luteus, a Gram-positive bacterium rapidly cleared by the immune response, strictly requires the Toll ligand spätzle. In contrast, increased activity after infection with Francisella novicida, a Gram-negative bacterium that cannot be cleared by the immune response, is entirely independent of both Toll and the parallel IMD pathway. The existence of multiple signalling mechanisms by which bacterial infections drive increases in physical activity implies that this effect may be an important aspect of the host response.

Oenothein B from Eugenia uniflora leaves exerts pro-angiogenic effects by increasing VEGF and TNF-α levels.

Oenothein B (OeB), a dimeric ellagitannin with a macrocyclic structure, is reported to have beneficial effects, including antioxidant, antitumor, antiviral, and antimutagenic effects, on human health. Despite the remarkable properties of OeB, its role in neovascularization process has not yet been evaluated. Thus, this study aimed to evaluate the angiogenic activity of OeB using a chorioallantoic membrane (CAM) assay at different concentrations (6.25, 12.5, and 25 µg/µL), employing digital imaging and histological analysis. Furthermore, to elucidate the mechanisms by which OeB influences angiogenesis, we assessed the levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α) in CAM using immunohistochemical analysis. All concentrations of OeB significantly increased (p < 0.05) the percentage of vascularization as well as the levels of all the angiogenesis-associated parameters evaluated, indicating the pronounced pro-angiogenic activity of OeB. Our results showed that inflammation was one of the most relevant phenomena observed in CAM histology along with angiogenesis. In addition, a significant increase in VEGF and TNF-α levels was observed in all the CAMs compared to the negative control (p < 0.05). We suggest that OeB may induce the presence of inflammatory cells in CAM, leading to increased VEGF and TNF-α levels that result in the induction of angiogenesis. Therefore, OeB presents a favorable profile that could be further explored for the development of drugs for pro-angiogenic and tissue repair therapies.

ß-enaminoester derivatives exhibit promising in vitro and in silico antiviral potential against Mayaro virus.

Mayaro virus (MAYV) is the causative agent of Mayaro fever, which is characterized mainly by acute fever and long-term severe arthralgia, common manifestations of other arbovirus infections, making the correct diagnosis a challenge. Besides, MAYV infections have been reported in South America, especially in Brazil. However, the lack of vaccines or specific antiviral drugs to control these infections makes the search for new antivirals an urgent need. Herein, we evaluated the antiviral potential of synthetic ß-enaminoesters derivatives against MAYV replication and their pharmacokinetic and toxicological (ADMET) properties using in vitro and in silico strategies. For this purpose, Vero cells were infected with MAYV at an MOI of 0.1, treated with compounds (50 µM) for 24 h, and virus titers were quantified by plaque reduction assays. Compounds 2b (83.33%) and 2d (77.53%) exhibited the highest activity with inhibition rates of 83.33% and 77.53%, respectively. The most active compounds 2b (EC50 = 18.92 µM; SI > 52.85), and 2d (EC50 = 14.52 µM; SI > 68.87) exhibited higher potency and selectivity than the control drug suramin (EC50 = 38.97 µM; SI > 25.66). Then, we investigated the mechanism of action of the most active compounds. None of the compounds showed virucidal activity, neither inhibited virus adsorption, but compound 2b inhibited virus entry (62.64%). Also, compounds 2b and 2d inhibited some processes involved with the release of new virus particles. Finally, in silico results indicated good ADMET parameters of the most active compounds and reinforced their promising profile as drug candidates against MAYV.

Effectiveness of Interventions for Changing More Than One Behavior at a Time to Manage Chronic Conditions: A Systematic Review and Meta-analysis.

BACKGROUND: Health behaviors play a significant role in chronic disease management. Rather than being independent of one another, health behaviors often co-occur, suggesting that targeting more than one health behavior in an intervention has the potential to be more effective in promoting better health outcomes. PURPOSE: We aimed to conduct a systematic review and meta-analysis of randomized trials of interventions that target more than one behavior to examine the effectiveness of multiple health behavior change interventions in patients with chronic conditions. METHODS: Five electronic databases (Web of Science, PubMed, CINAHL, EMBASE, and Cochrane) were systematically searched in November 2023, and studies included in previous reviews were also consulted. We included randomized trials of interventions aiming to change more than one health behavior in individuals with chronic conditions. Two independent reviewers screened and extracted data, and used Cochrane's Risk of Bias 2 tool. Meta-analyses were conducted to estimate the effects of interventions on change in health behaviors. Results were presented as Cohen's d for continuous data, and risk ratio for dichotomous data. RESULTS: Sixty-one studies were included spanning a range of chronic diseases: cardiovascular (k = 25), type 2 diabetes (k = 15), hypertension (k = 10), cancer (k = 7), one or more chronic conditions (k = 3), and multiple conditions (k = 1). Most interventions aimed to change more than one behavior simultaneously (rather than in sequence) and most targeted three particular behaviors at once: "physical activity, diet and smoking" (k = 20). Meta-analysis of 43 eligible studies showed for continuous data (k = 29) a small to substantial positive effect on behavior change for all health behaviors (d = 0.081-2.003) except for smoking (d = -0.019). For dichotomous data (k = 23) all analyses showed positive effects of targeting more than one behavior on all behaviors (RR = 1.026-2.247). CONCLUSIONS: Targeting more than one behavior at a time is effective in chronic disease management and more research should be directed into developing the science of multiple behavior change.

Many recommendations suggest engaging in more than one health behavior to manage a chronic disease; however, most research trying to understand or support health behavior tends to focus on only one behavior. We wanted to clarify if interventions aiming to support people in changing more than one health behavior are effective and promote better health outcomes. We aimed to conduct a systematic review to summarize the effects of studies reporting randomized trials of interventions that target more than one behavior in people with a chronic condition. We found and analyzed 61 studies published up to November 2023 covering people with a variety of chronic diseases: cardiovascular conditions, type 2 diabetes, hypertension, cancer, and, in some studies, people with multiple conditions. Most interventions tried to change three particular behaviors at once (physical activity, diet, and smoking) and, overall, interventions that tried to change more than one behavior had positive effects on diet, physical activity, medication adherence, and alcohol consumption, but not smoking cessation. Findings highlight the benefits of targeting more than one behavior in health behavior change interventions. Future research could seek to identify if findings are similar across settings and populations and how they can inform routine healthcare and self-management interventions.

Efficacy and threshold dose of intensive training targeting mobility for children with cerebral palsy: A systematic review and meta-analysis.

AIM: To systematically review the evidence for intensive mobility training in cerebral palsy (CP) and to determine the minimum effective dose to improve mobility. METHOD: Randomized controlled trials (RCTs) or quasi-RCTs that included participants with CP, and which used intensive task-oriented training (TOT) mobility interventions and reported mobility outcomes, were included. Five databases were searched; two independent reviewers selected studies and extracted data. The Grading of Recommendations Assessment, Development, and Evaluation system and the Cochrane Risk of Bias 2 tool were used to rate the certainty of evidence at the outcomes level and to determine the risk of bias respectively. Meta-analyses were conducted with clinically homogeneous studies. Threshold dose was analysed through meta-regression. RESULTS: Forty-six RCTs with 1449 participants (mean age range 1 year 2 months to 16 years 4 months) were included. TOT had statistically and clinically significant effects on walking speed (p = 0.001), cadence (p = 0.02), gross motor function (p = 0.03), and functional mobility (p = 0.009) compared with control interventions. The threshold dose was undeterminable owing to the high heterogeneity of studies. INTERPRETATION: TOT may improve walking speed, walking endurance, and balance. Studies with homogeneous samples and outcomes are needed to support clinical recommendations for intensive mobility interventions.

The rs2018736 fibulin-5 polymorphism as a determinant for pelvic organ prolapse: a case-control study.

OBJECTIVE: Fibulin-5 is a connective tissue component and may play a role in pelvic organ prolapse (POP) pathogenesis. This study aimed to verify the association of the rs2018736 polymorphism of the fibulin-5 gene with POP in postmenopausal Brazilian women, and to determine the risk factors for POP. METHOD: This observational, cross-sectional, case-control study assessed postmenopausal women with advanced POP (stages III and IV) and control women (stages 0 and I) by examination and peripheral blood sample collection. DNA sequences were analyzed by real-time reverse-transcriptase polymerase chain reaction. A logistic regression model was used with p < 0.05 for significance. RESULTS: A total of 565 participants were evaluated (325 POP and 240 control). The homozygous C allele of rs2018736 (CC) was protective against POP (odds ratio [OR] 0.49, 95% confidence interval [CI] 0.26-0.91). Age (OR 1.09, 95% CI 1.05-1.13), number of pregnancies (OR 1.14, 95% CI 1.01-1.28), vaginal delivery (OR 5.32, 95% CI 2.58-11.01), forceps delivery (OR 3.34, 95% CI 1.72-6.47), weight of newborn (OR 1.0007, 95% CI 1.0002-1.0011), family history of POP (OR 2.35, 95% CI 1.24-4.44), hypertension (OR 1.74, 95% CI 1.01-3.00) and diabetes (OR 2.19, 95% CI 1.07-4.48)] were independent predictors for POP; cesarean (OR 0.02, 95% CI 0.005-0.09) was protective. CONCLUSION: The rs2018736-CC genotype of the fibulin-5 gene has a protective role against POP.

Taxonomy of Candida parapsilosis complex isolated from neonates and the role of Hsp90 inhibitors to enhanced the antifungal activity of micafungin.

Species from Candida parapsilosis complex are frequently found in neonatal candidemia. The antifungal agents to treat this infection are limited and the occurrence of low in vitro susceptibility to echinocandins such as micafungin has been observed. In this context, the chaperone Hsp90 could be a target to reduce resistance. Thus, the objective of this research was to identify isolates from the C. parapsilosis complex and verify the action of Hsp90 inhibitors associated with micafungin. The fungal identification was based on genetic sequencing and mass spectrometry. Minimal inhibitory concentrations were determined by broth microdilution method according to Clinical Laboratory and Standards Institute. The evaluation of the interaction between micafungin with Hsp90 inhibitors was realized using the checkerboard methodology. According to the polyphasic taxonomy, C. parapsilosis sensu stricto was the most frequently identified, followed by C. orthopsilosis and C. metapsilosis, and one isolate of Lodderomyces elongisporus was identified by genetic sequencing. The Hsp90 inhibitor geladanamycin associated with micafungin showed a synergic effect in 31.25% of the isolates, a better result was observed with radicicol, which shows synergic effect in 56.25% tested yeasts. The results obtained demonstrate that blocking Hsp90 could be effective to reduce antifungal resistance to echinocandins.

Association of low pregnancy associated plasma protein-A with increased umbilical artery pulsatility index in cases of fetal weight between the 3rd and 10th percentiles: a retrospective cohort study.

OBJECTIVES: This study aims to evaluate if low levels of serum maternal pregnancy associated plasma protein-A (PAPP-A) during the first trimester are related to increased umbilical artery pulsatility index (UA PI) later in pregnancy, in cases of estimated fetal weight between the 3rd and 10th percentiles, in order to establish PAPP-A as a predictor of this particular cases of fetal growth restriction (FGR). METHODS: An observational, retrospective cohort study, conducted at a tertiary University Hospital located in Oporto, Portugal. Pregnant women who did the first trimester combined screening, between May 2013 and June 2020 and gave birth in the same hospital, with an estimated fetal weight (EFW) between the 3rd and 10th percentiles were included. The primary outcome is the difference in increased UA PI prevalence between two groups: PAPP-A<0.45 MoM and PAPP-A≥0.45 MoM. As secondary outcomes were evaluated differences in neonatal weight, gestational age at delivery, cesarean delivery, neonatal intensive care unit hospitalization, 5-min Apgar score below 7 and live birth rate between the same two groups. RESULTS: We included 664 pregnancies: 110 cases of PAPP-A<0.45 MoM and 554 cases with PAPP-A≥0.45 MoM. Increased UA PI prevalence, which was the primary outcome of this study, was significantly different between the two groups (p=0.005), as the PAPP-A<0.45 MoM group presents a higher prevalence (12.7 %) when compared to the PAPP-A≥0.45 MoM group (5.4 %). The secondary outcome cesarean delivery rate was significantly different between the groups (p=0.014), as the PAPP-A<0.45 MoM group presents a higher prevalence (42.7 %) than the PAPP-A≥0.45 MoM group (30.1 %). No other secondary outcomes showed differences between the two groups. CONCLUSIONS: There is an association of low serum maternal PAPP-A (<0.45 MoM) during the first trimester and increased UA PI (>95th percentile) later in pregnancy, in cases of EFW between the 3rd and 10th percentiles. However, this association is not strong enough alone for low PAPP-A to be a reliable predictor of increased UA PI in this population.

Intraoperative 3D fluoroscopy accurately predicts final electrode position in deep brain stimulation surgery.

PURPOSE: In the absence of an intraoperative CT or MRI setup, post-implantation confirmation of electrode position in deep brain stimulation (DBS) requires patient transportation to the radiology unit, prolonging surgery time. This project aims to validate intraoperative 3D fluoroscopy (3DF), a widely available tool in Neurosurgical units, as a method to determine final electrode position. METHODS: We performed a retrospective study including 64 patients (124 electrodes) who underwent DBS at our institution. Intraoperative 3DF after electrode implantation and postoperative volumetric CT were acquired. The Euclidean coordinates of the electrode tip displayed in both imaging modalities were determined and inter-method deviations were assessed. Pneumocephalus was quantified and its potential impact in determining the electrode position analyzed. Finally, 3DF and CT-imposed exposure to radiation was compared. RESULTS: The difference between the electrode tip estimated by 3DF and CT was 0.85 ± 0.03 mm, and not significantly different (p = 0.11 for the distance to MCP assessed by both methods), but was, instead, highly correlated (p = 0.91; p < 0.0001). Even though pneumocephalus was larger in 3DF (6.89 ± 1.76 vs 5.18 ± 1.37 mm3 in the CT group, p < 0.001), it was not correlated with the difference in electrode position measured by both techniques (p = 0.17; p = 0.06). Radiation exposure from 3DF is significantly lower than CT (0.36 ± 0.03 vs 2.08 ± 0.05 mSv; p < 0.0001). CONCLUSIONS: Intraoperative 3DF is comparable to CT in determining the final DBS electrode position. Being a method with fewer radiation exposure, less expensive, faster and that avoids patient transportation outside the operation room, it is a valid tool to replace postoperative CT.

Is use of flowable resin composite an option for occluso-proximal restorations in primary teeth? A fracture strength analysis.

BACKGROUND: Use of flowable resin composites for ocluso-proximal restorations in primary molars could improve cervical adaptation, and reduce the failure risk. AIM: To investigate the fracture strength of occluso-proximal restorations in primary teeth using different flowable resin composites (as an intermediate layer or entire cavity) and a conventional resin composite (incremental technique). DESIGN: Two standardized occluso-proximal cavities were prepared on mesial and distal surfaces of 50 sound primary molars. The teeth were randomly assigned into five groups (n = 10): 2 mm Filtek Bulk Fill Flow + Z350 XT; 4 mm Filtek Bulk Fill Flow; 2 mm Z350 XT Flow + Z350 XT; 4 mm Z350 XT Flow; and Z350 XT inserted by incremental technique. All restored teeth were subjected to cariogenic challenge and then submitted to fracture strength test. The failure pattern of each specimen was categorized as reparable or irreparable/need for replacement based on the World Dental Federation (FDI) criteria. Fracture strength means were submitted to one-way ANOVA and Tukey's post hoc tests. Failure pattern was analyzed descriptively. RESULTS: There was no statistically significant difference on fracture strength among groups (p = .48). A similar distribution of reparable (35%-40%) and irreparable (60%-65%) failures was observed among groups. CONCLUSION: Based on a laboratorial setting, the use of different flowable resin composites (as an intermediate layer or entire cavity) may be an option to restore occluso-proximal cavities in primary molars.

Resistance to lethal ectromelia virus infection requires Type I interferon receptor in natural killer cells and monocytes but not in adaptive immune or parenchymal cells.

Type I interferons (IFN-I) are antiviral cytokines that signal through the ubiquitous IFN-I receptor (IFNAR). Following footpad infection with ectromelia virus (ECTV), a mouse-specific pathogen, C57BL/6 (B6) mice survive without disease, while B6 mice broadly deficient in IFNAR succumb rapidly. We now show that for survival to ECTV, only hematopoietic cells require IFNAR expression. Survival to ECTV specifically requires IFNAR in both natural killer (NK) cells and monocytes. However, intrinsic IFNAR signaling is not essential for adaptive immune cell responses or to directly protect non-hematopoietic cells such as hepatocytes, which are principal ECTV targets. Mechanistically, IFNAR-deficient NK cells have reduced cytolytic function, while lack of IFNAR in monocytes dampens IFN-I production and hastens virus dissemination. Thus, during a pathogenic viral infection, IFN-I coordinates innate immunity by stimulating monocytes in a positive feedback loop and by inducing NK cell cytolytic function.

Alpha-Synuclein RT-QuIC in Idiopathic Normal Pressure Hydrocephalus.

This study quantified the occurrence of an underlying synucleinopathy in 50 patients with idiopathic normal pressure hydrocephalus by means of real-time quaking-induced conversion, a highly sensitive and specific technique capable of detecting and amplifying misfolded aggregated forms of α-synuclein in the cerebrospinal fluid. Seven patients were positive and they did not differ from negative cases, except for a more frequent L-dopa responsiveness and gait characterized by a wider base. The two groups did not differ in terms of response rate to tap test or shunt surgery, although step length and gait velocity improved by a lesser extent in positive cases. ANN NEUROL 2022;92:985-991.

Tomato miR156-targeted SlSBP15 represses shoot branching by modulating hormone dynamics and interacting with GOBLET and BRANCHED1b.

The miRNA156 (miR156)/SQUAMOSA PROMOTER-BINDING PROTEIN-LIKE (SPL/SBP) regulatory hub is highly conserved among phylogenetically distinct species, but how it interconnects multiple pathways to converge to common integrators controlling shoot architecture is still unclear. Here, we demonstrated that the miR156/SlSBP15 node modulates tomato shoot branching by connecting multiple phytohormones with classical genetic pathways regulating both axillary bud development and outgrowth. miR156-overexpressing plants (156-OE) displayed high shoot branching, whereas plants overexpressing a miR156-resistant SlSBP15 allele (rSBP15) showed arrested shoot branching. Importantly, the rSBP15 allele was able to partially restore the wild-type shoot branching phenotype in the 156-OE background. rSBP15 plants have tiny axillary buds, and their activation is dependent on shoot apex-derived auxin transport inhibition. Hormonal measurements revealed that indole-3-acetic acid (IAA) and abscisic acid (ABA) concentrations were lower in 156-OE and higher in rSBP15 axillary buds, respectively. Genetic and molecular data indicated that SlSBP15 regulates axillary bud development and outgrowth by inhibiting auxin transport and GOBLET (GOB) activity, and by interacting with tomato BRANCHED1b (SlBRC1b) to control ABA levels within axillary buds. Collectively, our data provide a new mechanism by which the miR156/SPL/SBP hub regulates shoot branching, and suggest that modulating SlSBP15 activity might have potential applications in shaping tomato shoot architecture.

Fetal and infant growth patterns, sleep, and 24-h activity rhythms: a population-based prospective cohort study in school-age children.

The study objective was to explore associations of fetal and infant weight patterns and preterm birth with sleep and 24-h activity rhythm parameters at school-age. In our prospective population-based study, 1327 children were followed from birth to age 10-15 years. Fetal weight was estimated using ultrasound in the second and third trimester of pregnancy. Birth weight and gestational age were available from midwife registries. Infant weight was measured at 6, 12 and 24 months. Fetal and infant weight acceleration or deceleration were defined as a change of >0.67 standard deviation between the corresponding age intervals. At school-age, sleep duration, sleep efficiency, wake after sleep onset, social jetlag, inter-daily stability, and intra-daily variability were assessed using tri-axial wrist actigraphy for 9 consecutive nights. We observed that low birth weight (<2500 g) was associated with 0.24 standard deviation (95% confidence interval [CI] 0.04; 0.43) longer sleep duration compared to normal weight. Compared to normal growth, growth deceleration in fetal life and infancy was associated with 0.40 standard deviation (95% CI 0.07; 0.73) longer sleep duration, 0.44 standard deviation (95% CI 0.14; 0.73) higher sleep efficiency, and -0.41 standard deviation (95% CI -0.76; -0.07) shorter wake after sleep onset. A pattern of normal fetal growth followed by infant growth acceleration was associated with -0.40 standard deviation (95% CI -0.61; -0.19) lower inter-daily stability. Preterm birth was not associated with any sleep or 24-h rhythm parameters. Our findings showed that children with fetal and infant growth restriction had longer and more efficient sleep at school-age, which may be indicative of an increased need for sleep for maturational processes and development after a difficult start in life.

Designing a large-scale track-based monitoring program to detect changes in species distributions in arid Australia.

Monitoring trends in animal populations in arid regions is challenging due to remoteness and low population densities. However, detecting species' tracks or signs is an effective survey technique for monitoring population trends across large spatial and temporal scales. In this study, we developed a simulation framework to evaluate the performance of alternative track-based monitoring designs at detecting change in species distributions in arid Australia. We collated presence-absence records from 550 2-ha track-based plots for 11 vertebrates over 13 years and fitted ensemble species distribution models to predict occupancy in 2018. We simulated plausible changes in species' distributions over the next 15 years and, with estimates of detectability, simulated monitoring to evaluate the statistical power of three alternative monitoring scenarios: (1) where surveys were restricted to existing 2-ha plots, (2) where surveys were optimized to target all species equally, and (3) where surveys were optimized to target two species of conservation concern. Across all monitoring designs and scenarios, we found that power was higher when detecting increasing occupancy trends compared to decreasing trends owing to the relatively low levels of initial occupancy. Our results suggest that surveying 200 of the existing plots annually (with a small subset resurveyed twice within a year) will have at least an 80% chance of detecting 30% declines in occupancy for four of the five invasive species modeled and one of the six native species. This increased to 10 of the 11 species assuming larger (50%) declines. When plots were positioned to target all species equally, power improved slightly for most compared to the existing survey network. When plots were positioned to target two species of conservation concern (crest-tailed mulgara and dusky hopping mouse), power to detect 30% declines increased by 29% and 31% for these species, respectively, at the cost of reduced power for the remaining species. The effect of varying survey frequency depended on its trade-off with the number of sites sampled and requires further consideration. Nonetheless, our research suggests that track-based surveying is an effective and logistically feasible approach to monitoring broad-scale occupancy trends in desert species with both widespread and restricted distributions.