[Research progress of traditional Chinese and Western medicine non-pharmacological prevention strategies for acute high altitude disease].

Acute high altitude disease (AHAD) is a general term for a series of clinical reactions that occur when the body fails to adapt to the low-pressure hypoxic environment of high altitudes. Mild cases can cause symptoms such as headache, nausea and vomiting, while more severe cases can lead to life-threatening conditions such as pulmonary edema, cerebral edema and other critical conditions that can be fatal. With the increasing demand for high altitudes deployment, understanding the common preventive measures of AHAD can reduce its morbidity or mortality to a certain extent, which is of great benefit to those who reside temporarily at high altitudes. In recent years, as people's health awareness has improved, there has been a growing attention towards non-pharmacological methods of disease prevention. At the same time, non-pharmacological therapy has significant therapeutic effects in preventing and treating high-altitude diseases, which has attracted the attention of researchers in this field. This review summarizes the major non-pharmacological preventive components of modern medicine and outlines the current non-pharmacological approaches to AHAD from the perspective of traditional Chinese medicine, intending to serve clinical purposes and improve the onset and prognosis of AHAD.

Molecular and cellular mechanisms of teneurin signaling in synaptic partner matching.

In developing brains, axons exhibit remarkable precision in selecting synaptic partners among many non-partner cells. Evolutionarily conserved teneurins are transmembrane proteins that instruct synaptic partner matching. However, how intracellular signaling pathways execute teneurins' functions is unclear. Here, we use in situ proximity labeling to obtain the intracellular interactome of a teneurin (Ten-m) in the Drosophila brain. Genetic interaction studies using quantitative partner matching assays in both olfactory receptor neurons (ORNs) and projection neurons (PNs) reveal a common pathway: Ten-m binds to and negatively regulates a RhoGAP, thus activating the Rac1 small GTPases to promote synaptic partner matching. Developmental analyses with single-axon resolution identify the cellular mechanism of synaptic partner matching: Ten-m signaling promotes local F-actin levels and stabilizes ORN axon branches that contact partner PN dendrites. Combining spatial proteomics and high-resolution phenotypic analyses, this study advanced our understanding of both cellular and molecular mechanisms of synaptic partner matching.

Modified Zhenwu Decoction improved intestinal barrier function of experimental colitis through activation of sGC-mediated cGMP/PKG signaling.

BACKGROUND: The invasion of luminal antigens and an aberrant immune response resulting from a disrupted physical epithelial barrier are the key characteristics of ulcerative colitis (UC). The restoration of damaged epithelial function is crucial for maintaining mucosal homeostasis and disease quiescence. Current therapies for UC primarily focus on suppressing inflammation. However, most patients fail to respond to therapy or develop secondary resistance over time, emphasizing the need to develop novel therapeutic targets for UC. Our study aimed to identify the potential targets of a novel modified herbal formula from the Zhen Wu Decoction, namely CDD-2103, which has demonstrated promising efficacy in treating chronic colitis. METHODS: The effect of CDD-2103 on epithelial barrier function was examined using in vitro and ex vivo models of tissue injury, as well as a chronic colitis C57BL/6 mouse model. Transcriptomic analysis was employed to profile gene expression changes in colonic tissues following treatment with CDD-2103. RESULTS: Our in vivo experiments demonstrated that CDD-2103 dose-dependently reduced disease severity in mice with chronic colitis. The efficacy of CDD-2103 was mediated by a reduction in goblet cell loss and the enhancement of tight junction protein integrity. Mechanistically, CDD-2103 suppressed epithelial cell apoptosis and tight junction protein breakdown by activating the soluble guanynyl cyclase (sGC)-mediated cyclic guanosine monophosphate (cGMP)/PKG signaling cascade. Molecular docking analysis revealed strong sGC ligand recognition by the CDD-2103-derived molecules, warranting further investigation. CONCLUSION: Our study revealed a novel formulation CDD-2103 that restores intestinal barrier function through the activation of sGC-regulated cGMP/PKG signaling. Furthermore, our findings suggest that targeting sGC can be an effective approach for promoting mucosal healing in the management of UC.

Pharmacokinetics and safety of mavacamten in healthy Chinese participants with different CYP2C19 phenotypes.

Obstructive hypertrophic cardiomyopathy (oHCM) is a subtype of HCM characterized by left ventricular outflow tract obstruction resulting from cardiac muscle hypertrophy and anatomic alterations in the mitral valve and apparatus. Mavacamten, a cardiac myosin inhibitor metabolized primarily by CYP2C19 in the liver, is the first and only targeted medication approved for the treatment of symptomatic New York Heart Association (NYHA) class II-III oHCM. Previous pharmacokinetic (PK) results of mavacamten in healthy Caucasian, Japanese, and Asian participants demonstrated that mavacamten exposure was affected by CYP2C19 metabolism status. This open-label, parallel-group, phase I trial aimed to determine the PK and safety of mavacamten in healthy Chinese participants with different CYP2C19 genotypes. The primary outcome was to define the PK of mavacamten in healthy Chinese participants; the secondary outcome was to examine safety and tolerability. After a single oral dose of 15 or 25 mg mavacamten in fasted healthy adult Chinese individuals, Cmax was reached within a median Tmax of 0.6-1.5 h, indicating rapid absorption. Inter-individual variability was moderate, and individuals carrying non-functional CYP2C19 alleles (*2/*2, *3/*3, or *2/*3) exhibited longer half-life and increased total exposure. After stratification of CYP2C19 genotypes, total mavacamten exposures were similar among different ethnic groups when compared with prior PK studies. No significant adverse events were observed in this study. Single oral administration of mavacamten at 15 mg was well tolerated across all CYP2C19 genotypes, and 25 mg dose was well tolerated in healthy participants with CYP2C19 genotypes UM/RM/NM. The PK profile of mavacamten in the healthy Chinese population was consistent with that in other healthy populations.

Integrated metabolomics and serum-feces pharmacochemistry-based network pharmacology to reveal the mechanisms of an herbal prescription against ulcerative colitis.

BACKGROUND: CDD-2103 is an herbal prescription used to treat ulcerative colitis (UC). This study aimed to uncover its mechanism by integrating metabolomics and serum-feces pharmacochemistry-based network pharmacology. METHODS: A DSS-induced chronic colitis mice model was used to evaluate the anti-colitis effect of CDD-2103. Serum and feces metabolomics were conducted to identify differential metabolites and pathways. In the serum-feces pharmacochemistry study, biological samples were collected from rats treated with CDD-2103. Then, network pharmacology was utilized to predict the targets of the identified compounds. Critical genes were extracted through the above-integrated analysis. The interactions between targets, CDD-2103, and its compounds were validated through molecular docking, immunoblotting, and enzyme activity assays. RESULTS: CDD-2103 alleviated ulcerous symptoms and colonic injuries in colitis mice. Metabolomics study identified differential metabolites associated with tryptophan, glycerophospholipid, and linoleic acid metabolisms. The serum-feces pharmacochemistry study revealed twenty-three compounds, which were subjected to network pharmacology analysis. Integration of these results identified three key targets (AHR, PLA2, and PTGS2). Molecular docking showed strong affinities between the compounds and targets. PTGS2 was identified as a hub gene targeted by most CDD-2103 compounds. Immunoblotting and enzyme activity assays provided further evidence that CDD-2103 alleviates UC, potentially through its inhibitory effect on cyclooxygenase-2 (COX-2, encoded by PTGS2), with alkaloids and curcuminoids speculated as crucial anti-inflammatory compounds. CONCLUSION: This integrated strategy reveals the mechanism of CDD-2103 and provides insights for developing herbal medicine-based therapies for UC.

A new framework for exploratory network mediator analysis in omics data.

Omics methods are widely used in basic biology and translational medicine research. More and more omics data are collected to explain the impact of certain risk factors on clinical outcomes. To explain the mechanism of the risk factors, a core question is how to find the genes/proteins/metabolites that mediate their effects on the clinical outcome. Mediation analysis is a modeling framework to study the relationship between risk factors and pathological outcomes, via mediator variables. However, high-dimensional omics data are far more challenging than traditional data: (1) From tens of thousands of genes, can we overcome the curse of dimensionality to reliably select a set of mediators? (2) How do we ensure that the selected mediators are functionally consistent? (3) Many biological mechanisms contain nonlinear effects. How do we include nonlinear effects in the high-dimensional mediation analysis? (4) How do we consider multiple risk factors at the same time? To meet these challenges, we propose a new exploratory mediation analysis framework, medNet, which focuses on finding mediators through predictive modeling. We propose new definitions for predictive exposure, predictive mediator, and predictive network mediator, using a statistical hypothesis testing framework to identify predictive exposures and mediators. Additionally, two heuristic search algorithms are proposed to identify network mediators, essentially subnetworks in the genome-scale biological network that mediate the effects of single or multiple exposures. We applied medNet on a breast cancer data set and a metabolomics data set combined with food intake questionnaire data. It identified functionally consistent network mediators for the exposures' impact on the outcome, facilitating data interpretation.

Modified Zhenwu Decoction suppresses chronic colitis via targeting macrophage CCR2/Fyn/p38 MAPK signaling axis.

BACKGROUND: Ulcerative colitis (UC) is associated with intestinal macrophage infiltration due to disruption of the mucosal barrier and bacterial invasion. Therefore, it is crucial to identify therapeutic agents capable of attenuating the macrophage-induced inflammatory response to preserve mucosal homeostasis and immune tolerance. The modified Zhenwu decoction (CDD-2103) is a novel herbal formulation developed based on the principles of Traditional Chinese medicine. To date, there are no clinically approved herbal formulations for UC with a well-known mechanism of action on macrophages. PURPOSE: The objective of this study was to systematically investigate the inhibitory effect of the active fraction of CDD-2103 in a mouse model of chronic colitis and delineate the mechanisms underlying its inhibitory action. METHODS: CDD-2103 was extracted into four fractions using organic solvents with increasing polarity. A chronic 49-day dextran sulfate sodium (DSS)-induced colitis mice model, closely resembling human clinical conditions, was used to examine the effect of CDD-2103 on chronic colitis. To confirm the effect of CDD-2103 on macrophages in this chronic colitis model, adoptive macrophage transfer and CCL2 supplementation were conducted. The mechanisms of action of CDD-2103 were further elucidated utilizing bone marrow-derived macrophages (BMDMs). Transcriptome analysis was conducted to gain insights into the underlying mechanism of action of CDD-2103 in BMDMs. RESULTS: Our in vitro and in vivo findings demonstrated that the ethanol-enriched fraction of CDD-2103 exhibited significant anti-inflammatory effects, leading to the suppression of colitis severity. This effect was associated with diminished accumulation of colonic macrophages in the lamina propria of CDD-2103-intervened colitis mice. Specifically, CDD-2103 inhibited CCR2/L2-mediated proinflammatory macrophage infiltration into the colon without affecting macrophage proliferation. Mechanistically, CDD-2103 inhibited Fyn expression-mediated p38 MAPK activation and subsequently suppressed CCR2 expression in BMDMs. CONCLUSIONS: Collectively, our study supports the potential use of CDD-2103 to limit macrophage infiltration, thereby reducing inflammation during UC treatment. CDD-2103 and the components in the ethanolic fraction are promising candidates for the development of novel drugs for UC management. Additionally, our study underscores Fyn-mediated CCR2 expression as a potential therapeutic target for the management of UC.

Tolerogenic dendritic cell-mediated regulatory T cell differentiation by Chinese herbal formulation attenuates colitis progression.

INTRODUCTION: Ulcerative colitis (UC) is a chronic inflammatory disease characterized by loss of immune tolerance to luminal antigens and progressive intestinal tissue injury. Thus, the re-establishment of immune tolerance is crucial for suppressing aberrant immune responses and UC progression. OBJECTIVES: This study aimed to investigate the mechanisms underlying the action of CDD-2103 and its bioactive compounds in mediating immune regulation in mouse models of colitis. METHODS: Two experimental colitis models, chronic 2,4,6-trinitrobenzene sulfonic acid (TNBS)- and T-cell transfer-induced Rag1-/- mice, were used to determine the effects of CDD-2103 on colitis progression. Single-cell transcriptome analysis was used to profile the immune landscape and its interactions after CDD-2103 treatment. Liquid chromatography-mass spectrometry (LC-MS) was used to analyze the major components interacting with lymphoid cells. A primary cell co-culture system was used to confirm the effects of bioactive component. RESULTS: CDD-2103 dose-dependently suppresses the progression of colitis induced by chemicals or T cell transplantation in Rag1-/- mice. The effect of CDD-2103 is primarily attributable to an increase in the de novo generation of regulatory T cells (Tregs) in the lamina propria (LP). Single-cell transcriptomic analysis revealed that CDD-2103 treatment increased the number of tolerogenic dendritic cells (DCs). Mechanistically, CDD-2103 promoted tolerogenic DCs accumulation and function by upregulating several genes in the electron transport chain related to oxidative phosphorylation, leading to increased differentiation of Tregs. Further LC-MS analysis identified several compounds in CDD-2103, particularly those distributed within the mesenteric lymph nodes of mice. Subsequent studies revealed that palmatine and berberine promoted tolerogenic bone marrow-derived dendritic cells (BMDC)-mediated Treg differentiation. CONCLUSION: Overall, our study demonstrated that the clinically beneficial effect of CDD-2103 in the treatment of UC is based on the induction of immune tolerance. In addition, this study supports berberine and palmatine as potential chemical entities in CDD-2103 that modulate immune tolerance.

Challenges and progress in oxygen evolution reaction catalyst development for seawater electrolysis for hydrogen production.

Production of green hydrogen on a large scale can negatively impact freshwater resources. Therefore, using seawater as an electrolyte in electrolysis is a desirable alternative to reduce costs and freshwater reliance. However, there are limitations to this approach, primarily due to the catalyst involved in the oxygen evolution reaction (OER). In seawater, the OER features sluggish kinetics and complicated chemical reactions that compete. This review first introduces the benefits and challenges of direct seawater electrolysis and then summarises recent research into cost-effective and durable OER electrocatalysts. Different modification methods for nickel-based electrocatalysts are thoroughly reviewed, and promising electrocatalysts that the authors believe deserve further exploration have been highlighted.

NLRP3 activation in macrophages promotes acute intestinal injury in neonatal necrotizing enterocolitis.

BACKGROUND: Macrophages are involved in various immune inflammatory disease conditions. This study aimed to investigate the role and mechanism of macrophages in regulating acute intestinal injury in neonatal necrotizing enterocolitis (NEC). METHODS: CD68, nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3), cysteine aspartate-specific protease-1 (caspase-1), and interleukin-1ß (IL-1ß) in paraffin sections of intestinal tissues from NEC and control patients were detected with immunohistochemistry, immunofluorescence, and western blot. Hypertonic pet milk, hypoxia and cold stimulation were used to establish a mouse (wild type and Nlrp3-/-) model of NEC. The mouse macrophage (RAW 264.7) and rat intestinal epithelial cell-6 lines were also cultured followed by various treatments. Macrophages, intestinal epithelial cell injuries, and IL-1ß release were determined. RESULTS: Compared to the gut "healthy" patients, the intestinal lamina propria of NEC patients had high macrophage infiltration and high NLRP3, caspase-1, and IL-1ß levels. Furthermore, in vivo, the survival rate of Nlrp3-/- NEC mice was dramatically improved, the proportion of intestinal macrophages was reduced, and intestinal injury was decreased compared to those of wild-type NEC mice. NLRP3, caspase-1, and IL-1ß derived from macrophages or supernatant from cocultures of macrophages and intestinal epithelial cells also caused intestinal epithelial cell injuries. CONCLUSIONS: Macrophage activation may be essential for NEC development. NLRP3/caspase-1/IL-1ß cellular signals derived from macrophages may be the underlying mechanism of NEC development, and all these may be therapeutic targets for developing treatments for NEC.

Effect of Mavacamten on Chinese Patients With Symptomatic Obstructive Hypertrophic Cardiomyopathy: The EXPLORER-CN Randomized Clinical Trial.

Importance: Mavacamten has shown clinical benefits in global studies for patients with obstructive hypertrophic cardiomyopathy (oHCM), but evidence in the Asian population is lacking. Objective: To evaluate the safety and efficacy of mavacamten compared with placebo for Chinese patients with symptomatic oHCM. Design, Setting, and Participants: This phase 3, randomized, double-blind, placebo-controlled clinical trial was conducted at 12 hospitals in China. Between January 4 and August 5, 2022, patients with oHCM and a left ventricular outflow tract (LVOT) gradient of 50 mm Hg or more and New York Heart Association (NYHA) class II or III symptoms were enrolled and received treatment for 30 weeks. Interventions: Patients were randomized 2:1 to receive mavacamten (starting at 2.5 mg once daily) or placebo for 30 weeks. Main Outcomes and Measures: The primary end point was change in Valsalva LVOT peak gradient from baseline to week 30. Left ventricular outflow tract gradients and left ventricular ejection fraction (LVEF) were assessed by echocardiography, while left ventricular mass index (LVMI) was determined by cardiac magnetic resonance imaging. Analysis was performed on an intention-to-treat basis. Results: A total of 81 patients (mean [SD] age, 51.9 [11.9] years; 58 men [71.6%]) were randomized. Mavacamten demonstrated a significant improvement in the primary end point compared with placebo (least-squares mean [LSM] difference, -70.3 mm Hg; 95% CI, -89.6 to -50.9 mm Hg; 1-sided P < .001). Similar trends were demonstrated for resting LVOT peak gradient (LSM difference, -55.0 mm Hg; 95% CI, -69.1 to -40.9 mm Hg). At week 30, more patients receiving mavacamten than placebo achieved a Valsalva LVOT peak gradient less than 30 mm Hg (48.1% [26 of 54] vs 3.7% [1 of 27]), less than 50 mm Hg (59.3% [32 of 54] vs 7.4% [2 of 27]), and NYHA class improvement (59.3% [32 of 54] vs 14.8% [4 of 27]). Greater improvements were also observed with mavacamten regarding the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (LSM difference, 10.2; 95% CI, 4.4-16.1), N-terminal pro-B-type natriuretic peptide level (proportion of geometric mean ratio, 0.18; 95% CI, 0.13-0.24), high-sensitivity cardiac troponin I level (proportion of geometric mean ratio, 0.34; 95% CI, 0.27-0.42), and LVMI (mean difference, -30.8 g/m2; 95% CI, -41.6 to -20.1 g/m2). Safety and tolerability were similar between mavacamten and placebo. No patients experienced LVEF less than 50%. Conclusions: Mavacamten significantly improved Valsalva LVOT gradient vs placebo for Chinese patients. All secondary efficacy end points were also improved. Mavacamten was well tolerated with no new safety signals. This study supports the efficacy and safety of mavacamten in diverse populations, including Chinese patients. Trial Registration: ClinicalTrials.gov Identifier: NCT05174416.

Cell mediated ECM-degradation as an emerging tool for anti-fibrotic strategy.

Investigation into the role of cells with respect to extracellular matrix (ECM) remodeling is still in its infancy. Particularly, ECM degradation is an indispensable process during the recovery from fibrosis. Cells with ECM degradation ability due to the secretion of various matrix metalloproteinases (MMPs) have emerged as novel contributors to the treatment of fibrotic diseases. In this review, we focus on the ECM degradation ability of cells associated with the repertoire of MMPs that facilitate the attenuation of fibrosis through the inhibition of ECM deposition. Besides, innovative approaches to engineering and characterizing cells with degradation ability, as well as elucidating the mechanism of the ECM degradation, are also illustrated. Studies conducted to date on the use of cell-based degradation for therapeutic purposes to combat fibrosis are summarized. Finally, we discuss the therapeutic potential of cells with high degradation ability, hoping to bridge the gap between benchside research and bedside applications in treating fibrotic diseases.

Suppression of the human malic enzyme 2 modifies energy metabolism and inhibits cellular respiration.

Human mitochondrial NAD(P)+-dependent malic enzyme (ME2) is well-known for its role in cell metabolism, which may be involved in cancer or epilepsy. We present potent ME2 inhibitors based on cyro-EM structures that target ME2 enzyme activity. Two structures of ME2-inhibitor complexes demonstrate that 5,5'-Methylenedisalicylic acid (MDSA) and embonic acid (EA) bind allosterically to ME2's fumarate-binding site. Mutagenesis studies demonstrate that Asn35 and the Gln64-Tyr562 network are required for both inhibitors' binding. ME2 overexpression increases pyruvate and NADH production while decreasing the cell's NAD+/NADH ratio; however, ME2 knockdown has the opposite effect. MDSA and EA inhibit pyruvate synthesis and thus increase the NAD+/NADH ratio, implying that these two inhibitors interfere with metabolic changes by inhibiting cellular ME2 activity. ME2 silence or inhibiting ME2 activity with MDSA or EA decreases cellular respiration and ATP synthesis. Our findings suggest that ME2 is crucial for mitochondrial pyruvate and energy metabolism, as well as cellular respiration, and that ME2 inhibitors could be useful in the treatment of cancer or other diseases that involve these processes.

Advanced glycation end-products as mediators of the aberrant crosslinking of extracellular matrix in scarred liver tissue.

The extracellular matrix of cirrhotic liver tissue is highly crosslinked. Here we show that advanced glycation end-products (AGEs) mediate crosslinking in liver extracellular matrix and that high levels of crosslinking are a hallmark of cirrhosis. We used liquid chromatography-tandem mass spectrometry to quantify the degree of crosslinking of the matrix of decellularized cirrhotic liver samples from patients and from two mouse models of liver fibrosis and show that the structure, biomechanics and degree of AGE-mediated crosslinking of the matrices can be recapitulated in collagen matrix crosslinked by AGEs in vitro. Analyses via cryo-electron microscopy and optical tweezers revealed that crosslinked collagen fibrils form thick bundles with reduced stress relaxation rates; moreover, they resist remodelling by macrophages, leading to reductions in their levels of adhesion-associated proteins, altering HDAC3 expression and the organization of their cytoskeleton, and promoting a type II immune response of macrophages. We also show that rosmarinic acid inhibited AGE-mediated crosslinking and alleviated the progression of fibrosis in mice. Our findings support the development of therapeutics targeting crosslinked extracellular matrix in scarred liver tissue.

A p-orbital honeycomb-Kagome lattice realized in a two-dimensional metal-organic framework.

The experimental realization of p-orbital systems is desirable because p-orbital lattices have been proposed theoretically to host strongly correlated electrons that exhibit exotic quantum phases. Here, we synthesize a two-dimensional Fe-coordinated bimolecular metal-organic framework which constitutes a honeycomb lattice of 1,4,5,8,9,12-hexaazatriphenylene molecules and a Kagome lattice of 5,15-di(4-pyridyl)-10,20-diphenylporphyrin molecules on a Au(111) substrate. Density-functional theory calculations show that the framework features multiple well-separated spin-polarized Kagome bands, namely Dirac cone bands and Chern flat bands, near the Fermi level. Using tight-binding modelling, we reveal that these bands are originated from two effects: the low-lying molecular orbitals that exhibit p-orbital characteristics and the honeycomb-Kagome lattice. This study demonstrates that p-orbital Kagome bands can be realized in metal-organic frameworks by using molecules with molecular orbitals of p-orbital like symmetry.

Differential Evolution Optimization of Microwave Focused Hyperthermia Phased Array Excitation for Targeted Breast Cancer Heating.

Microwave hyperthermia using the phased array applicator is a non-invasive treatment modality for breast cancer. Hyperthermia treatment planning (HTP) is critical to accurately treating breast cancer and avoiding damage to the patient's healthy tissue. A global optimization algorithm, differential evolution (DE) algorithm, has been applied to optimize HTP for breast cancer and its ability to improve the treatment effect was proved by electromagnetic (EM) and thermal simulation results. DE algorithm is compared to time reversal (TR) technology, particle swarm optimization (PSO) algorithm, and genetic algorithm (GA) in HTP for breast cancer in terms of convergence rate and treatment results, such as treatment indicators and temperature parameters. The current approaches in breast cancer microwave hyperthermia still have the problem of hotspots in healthy tissue. DE enhances focused microwave energy absorption into the tumor and reduces the relative energy of healthy tissue during hyperthermia treatment. By comparing the treatment results of each objective function used in DE, the DE algorithm with hotspot to target quotient (HTQ) as the objective function has outstanding performance in HTP for breast cancer, which can increase the focused microwave energy of the tumor and decrease the damage to healthy tissue.

Origin of wiring specificity in an olfactory map revealed by neuron type-specific, time-lapse imaging of dendrite targeting.

How does wiring specificity of neural maps emerge during development? Formation of the adult Drosophila olfactory glomerular map begins with the patterning of projection neuron (PN) dendrites at the early pupal stage. To better understand the origin of wiring specificity of this map, we created genetic tools to systematically characterize dendrite patterning across development at PN type-specific resolution. We find that PNs use lineage and birth order combinatorially to build the initial dendritic map. Specifically, birth order directs dendrite targeting in rotating and binary manners for PNs of the anterodorsal and lateral lineages, respectively. Two-photon- and adaptive optical lattice light-sheet microscope-based time-lapse imaging reveals that PN dendrites initiate active targeting with direction-dependent branch stabilization on the timescale of seconds. Moreover, PNs that are used in both the larval and adult olfactory circuits prune their larval-specific dendrites and re-extend new dendrites simultaneously to facilitate timely olfactory map organization. Our work highlights the power and necessity of type-specific neuronal access and time-lapse imaging in identifying wiring mechanisms that underlie complex patterns of functional neural maps.

The brain's ability to sense, act and remember relies on the intricate network of connections between neurons. Organization of these connections into neural maps is critical for processing sensory information. For instance, different odors are represented by specific neurons in a part of the brain known as the olfactory bulb, allowing animals to distinguish between smells. Projection neurons in the olfactory bulb have extensions known as dendrites that receive signals from sensory neurons. Scientists have extensively used the olfactory map in adult fruit flies to study brain wiring because of the specific connections between their sensory and projection neurons. This has led to the discovery of similar wiring strategies in mammals. But how the olfactory map is formed during development is not fully understood. To investigate, Wong et al. built genetic tools to label specific types of olfactory projection neurons during the pupal stage of fruit fly development. This showed that a group of projection neurons directed their dendrites in a clockwise rotation pattern depending on the order in which they were born: the first-born neuron sent dendrites towards the top right of the antennal lobe (the fruit fly equivalent of the olfactory bulb), while the last-born sent dendrites towards the top left. Wong et al. also carried out high-resolution time-lapse imaging of live brains grown in the laboratory to determine how dendrites make wiring decisions. This revealed that projection neurons send dendrites in all directions, but preferentially stabilize those that extend in the direction which the neurons eventually target. Also, live imaging showed neurons could remove old dendrites (used in the larvae) and build new ones (to be used in the adult) simultaneously, allowing them to quickly create new circuits. These experiments demonstrate the value of imaging specific types of neurons to understand the mechanisms that assemble neural maps in the developing brain. Further work could use the genetic tools created by Wong et al. to study how wiring decisions are determined in this and other neural maps by specific genes, potentially yielding insights into neurological disorders associated with wiring defects.

Design of Ultra-Wideband Phased Array Applicator for Breast Cancer Hyperthermia Therapy.

Focused microwave-hyperthermia therapy has recently emerged as a key technology in the treatment of breast cancer due to non-invasive treatment. An applicator of a three-ring phased array consisting of ultra-wideband (UWB) microstrip antennas was designed for breast cancer therapy and operates at 0.915 GHz and 2.45 GHz. The proposed antenna has an ultra-wideband from 0.7 GHz to 5.5 GHz with resonant frequencies of 0.915 GHz and 2.45 GHz and dimensions of 15 × 43.5 × 1.575 mm3. The number of each ring was chosen to be 12 based on the SAR distribution and the performance indicators of tumor off-center focusing results for four different numbers of single-ring arrays. The homogeneous breast model is applied to a three-ring phased array consisting of 36 elements for focused simulation, and 1 cm3 and 2 cm3 tumors are placed in three different locations in the breast. The simulation results show that the proposed phased array has good performance and the capability to raise the temperature of different volumes of breast cancer above 42.5 °C after choosing a suitable operating frequency. The proposed applicator allows for precise treatment of tumors by selecting the appropriate operating frequency based on the size of the malignant tumor.