Recent Progress in Generation of Inner Ear Organoid.

Inner ear organoids play a crucial role in hearing research. In comparison to other animal models and 2D cell culture systems, inner ear organoids offer significant advantages for studying the mechanisms of inner ear development and exploring novel approaches to disease treatment. Inner ear organoids derived from human cells are more closely resemble normal human organs in development and function. The 3D culture system of the inner ear organoid enhances cell-cell interactions and mimics the internal environment. In this review, the progress and limitations of organoid culture methods derived from tissue-specific progenitors and pluripotent stem cells (PSCs) are summarized, which may offer new insights into generating organoids that closely resemble the inner ear in terms of morphology and function.

Novel compound heterozygous variants in MARVELD2 causing autosomal recessive hearing loss in two Chinese families.

BACKGROUND: Hereditary hearing loss is an important component of congenital hearing loss. MARVELD2 (OMIM ID:610572), located in the DFNB49 locus, which encodes a tight junction protein tricellulin playing an important role in the sensory epithelial barrier of the inner ear, may contribute to nonsyndromic autosomal recessive hereditary hearing loss. METHODS: Two Han Chinese pedigrees with hearing loss underwent clinical and genetic analyses. Variants were detected by targeted next-generation sequencing and sequencing data were compared with the Human Genome Reference (GRCh 37/hg 19) to identify mutant genes and loci. Furthermore, online tools such as RDDC, SpliceAI, and REVEL were used to predict risks from different variants. RESULTS: Both two probands failed neonatal hearing screening and were diagnosed with sensorineural hearing loss. A total of 3 mutations were detected in the two families, c.1331+1G>A, c.1325A>G, and c.782G>A. According to ACMG/AMP guidelines, they were judged to be pathogenic, uncertain significance, and uncertain significance, respectively. CONCLUSIONS: These findings contribute to a better understanding of the relationship between different variants of MARVELD2 and hearing. This could further expand the spectrum of deafness gene mutations and contribute to deafness patient management and genetic counseling.

Investigation of silicon doped carbon dots/Carboxymethyl cellulose gel platform with tunable afterglow and dynamic multistage anticounterfeiting.

The remarkable optical properties of carbon dots, particularly their tunable room-temperature phosphorescence, have garnered significant interest. However, challenges such as aggregation propensity and complex phosphorescence control via energy level manipulation during synthesis persist. Addressing these issues, we present a facile gel platform for tunable afterglow materials. This involves chemically cross-linking biomass-derived silicon-doped carbon dots with carboxymethylcellulose and incorporating non-precious metal salts (BaCl2, CaCl2, MgCl2, ZnCl2, ZnBr2, ZnSO4) to enhance phosphorescence. Metal salts boost intersystem crossing via spin-orbit coupling, elevating triplet state transitions and activating phosphorescence. Chemical bonding and salt-induced coordination/electrostatic interactions establish confinement effects, suppressing non-radiative transitions. Diverse salt-gel interactions yield gels with tunable phosphorescence lifetimes (9.48 ms to 32.13-492.39 ms), corresponding to afterglow durations ranging from 3.20 to 11.86 s. With its broad tunability and high recognition, this gel material exhibits promising potential for dynamic multilevel anti-counterfeiting applications.

Silicon-Doped Carbon Dots Crosslinked Carboxymethyl Cellulose Gel: Detection and Adsorption of Fe3.

The excessive emission of iron will pollute the environment and harm human health, so the fluorescence detection and adsorption of Fe3+ are of great significance. In the field of water treatment, cellulose-based gels have attracted wide attention due to their excellent properties and environmental friendliness. If carbon dots are used as a crosslinking agent to form a gel with cellulose, it can not only improve mechanical properties but also show good biocompatibility, reactivity, and fluorescence properties. In this study, silicon-doped carbon dots/carboxymethyl cellulose gel (DCG) was successfully prepared by chemically crosslinking biomass-derived silicon-doped carbon dots with carboxymethyl cellulose. The abundant crosslinking points endow the gel with excellent mechanical properties, with a compressive strength reaching 294 kPa. In the experiment on adsorbing Fe3+, the theoretical adsorption capacity reached 125.30 mg/g. The introduction of silicon-doped carbon dots confers the gel with excellent fluorescence properties and a good selective response to Fe3+. It exhibits a good linear relationship within the concentration range of 0-100 mg/L, with a detection limit of 0.6595 mg/L. DCG appears to be a good application prospect in the adsorption and detection of Fe3+.

Polyhedral Oligomeric Sesquioxane Cross-Linked Chitosan-Based Multi-Effective Aerogel Preparation and Its Water-Driven Recovery Mechanism.

The use of environmentally friendly and non-toxic biomass-based interfacial solar water evaporators has been widely reported as a method for water purification in recent years. However, the poor stability of the water transport layer made from biomass materials and its susceptibility to deformation when exposed to harsh environments limit its practical application. To address this issue, water-driven recovery aerogel (PCS) was prepared by cross-linking epoxy-based polyhedral oligomeric silsesquioxane (EP-POSS) epoxy groups with chitosan (CS) amino groups. The results demonstrate that PCS exhibits excellent water-driven recovery performance, regaining its original volume within a very short time (1.9 s) after strong compression (ε > 80%). Moreover, PCS has a water absorption rate of 2.67 mm s-1 and exhibits an excellent water absorption capacity of 22.09 g g-1 even after ten cycles of absorption-removal. Furthermore, a photothermal evaporator (PCH) was prepared by loading the top layer with hydrothermally reacted tannins (HAs) and Zn2+ complexes. The results indicate that PCH achieves an impressive evaporation rate of 1.89 kg m-2 h-1 under one sun illumination. Additionally, due to the antimicrobial properties of Zn2+, PCH shows inhibitory effects against Staphylococcus aureus and Escherichia coli, thereby extending the application of solar water evaporators to include antimicrobial purification in natural waters.

ROS Balance Autoregulating Core-Shell CeO2@ZIF-8/Au Nanoplatform for Wound Repair.

Reactive oxygen species (ROS) plays important roles in living organisms. While ROS is a double-edged sword, which can eliminate drug-resistant bacteria, but excessive levels can cause oxidative damage to cells. A core-shell nanozyme, CeO2@ZIF-8/Au, has been crafted, spontaneously activating both ROS generating and scavenging functions, achieving the multi-faceted functions of eliminating bacteria, reducing inflammation, and promoting wound healing. The Au Nanoparticles (NPs) on the shell exhibit high-efficiency peroxidase-like activity, producing ROS to kill bacteria. Meanwhile, the encapsulation of CeO2 core within ZIF-8 provides a seal for temporarily limiting the superoxide dismutase and catalase-like activities of CeO2 nanoparticles. Subsequently, as the ZIF-8 structure decomposes in the acidic microenvironment, the CeO2 core is gradually released, exerting its ROS scavenging activity to eliminate excess ROS produced by the Au NPs. These two functions automatically and continuously regulate the balance of ROS levels, ultimately achieving the function of killing bacteria, reducing inflammation, and promoting wound healing. Such innovative ROS spontaneous regulators hold immense potential for revolutionizing the field of antibacterial agents and therapies.

A molecularly defined NAcSh D1 subtype controls feeding and energy homeostasis.

Orchestrating complex behavioral states, such as approach and consumption of food, is critical for survival. In addition to hypothalamus neuronal circuits, the nucleus accumbens (NAc) also plays an important role in controlling appetite and satiety in responses to changing external stimuli. However, the specific neuronal subtypes of NAc involved as well as how the humoral and neuronal signals coordinate to regulate feeding remain incompletely understood. Here, we deciphered the spatial diversity of neuron subtypes of the NAc shell (NAcSh) and defined a dopamine receptor D1(Drd1)- and Serpinb2-expressing subtype located in NAcSh encoding food consumption. Chemogenetics- and optogenetics-mediated regulation of Serpinb2 + neurons bidirectionally regulates food seeking and consumption specifically. Circuitry stimulation revealed the NAcSh Serpinb2 →LH LepR projection controls refeeding and can overcome leptin-mediated feeding suppression. Furthermore, NAcSh Serpinb2 + neuron ablation reduces food intake and upregulates energy expenditure resulting in body weight loss. Together, our study reveals a neural circuit consisted of molecularly distinct neuronal subtype that bidirectionally regulates energy homeostasis, which can serve as a potential therapeutic target for eating disorders.

A parabrachial-hypothalamic parallel circuit governs cold defense in mice.

Thermal homeostasis is vital for mammals and is controlled by brain neurocircuits. Yet, the neural pathways responsible for cold defense regulation are still unclear. Here, we found that a pathway from the lateral parabrachial nucleus (LPB) to the dorsomedial hypothalamus (DMH), which runs parallel to the canonical LPB to preoptic area (POA) pathway, is also crucial for cold defense. Together, these pathways make an equivalent and cumulative contribution, forming a parallel circuit. Specifically, activation of the LPB → DMH pathway induced strong cold-defense responses, including increases in thermogenesis of brown adipose tissue (BAT), muscle shivering, heart rate, and locomotion. Further, we identified somatostatin neurons in the LPB that target DMH to promote BAT thermogenesis. Therefore, we reveal a parallel circuit governing cold defense in mice, which enables resilience to hypothermia and provides a scalable and robust network in heat production, reshaping our understanding of neural circuit regulation of homeostatic behaviors.

Neurocircuitry of Predatory Hunting.

Predatory hunting is an important type of innate behavior evolutionarily conserved across the animal kingdom. It is typically composed of a set of sequential actions, including prey search, pursuit, attack, and consumption. This behavior is subject to control by the nervous system. Early studies used toads as a model to probe the neuroethology of hunting, which led to the proposal of a sensory-triggered release mechanism for hunting actions. More recent studies have used genetically-trackable zebrafish and rodents and have made breakthrough discoveries in the neuroethology and neurocircuits underlying this behavior. Here, we review the sophisticated neurocircuitry involved in hunting and summarize the detailed mechanism for the circuitry to encode various aspects of hunting neuroethology, including sensory processing, sensorimotor transformation, motivation, and sequential encoding of hunting actions. We also discuss the overlapping brain circuits for hunting and feeding and point out the limitations of current studies. We propose that hunting is an ideal behavioral paradigm in which to study the neuroethology of motivated behaviors, which may shed new light on epidemic disorders, including binge-eating, obesity, and obsessive-compulsive disorders.

Cellular Processes Induced by HSV-1 Infections in Vestibular Neuritis.

Herpesvirus is a prevalent pathogen that primarily infects human epithelial cells and has the ability to reside in neurons. In the field of otolaryngology, herpesvirus infection primarily leads to hearing loss and vestibular neuritis and is considered the primary hypothesis regarding the pathogenesis of vestibular neuritis. In this review, we provide a summary of the effects of the herpes virus on cellular processes in both host cells and immune cells, with a focus on HSV-1 as illustrative examples.

A molecularly defined D1 medium spiny neuron subtype negatively regulates cocaine addiction.

The striatum plays a critical role in regulating addiction-related behaviors. The conventional dichotomy model suggests that striatal D1/D2 medium spiny neurons (MSNs) positively/negatively regulate addiction-related behaviors. However, this model does not account for the neuronal heterogeneity and functional diversity of the striatum, and whether MSN subtypes beyond the pan-D1/D2 populations play distinct roles in drug addiction remains unknown. We characterized the role of a tachykinin 2-expressing D1 MSN subtype (Tac2+), present in both rodent and primate striatum, using cocaine addiction mouse models. We found that acute cocaine administration reduces Tac2 neuronal activity, and cocaine conditioning alters neuronal response related to cocaine reward contextual associations. In addition, activation/inhibition of Tac2+ neurons attenuates/promotes cocaine-induced conditioned place preference and cocaine intravenous self-administration. Furthermore, stimulation of the NAc-to-lateral hypothalamic projection of Tac2+ neurons suppresses cocaine reward behavior. Our study reveals an unconventional negative regulatory function of D1 MSNs in drug addiction that operates in a subtype- and projection-specific manner.

Bioinformatics analysis reveals the clinical significance of GIPC2/GPD1L for colorectal cancer using TCGA database.

Background: Colorectal cancer (CRC) causes 700,000 deaths annually and is the fourth deadliest cancer in the world after lung, liver, and stomach cancer. Since CRC is difficult to detect early and has a poor prognosis, it is critical to develop novel biomarkers for its diagnosis, prognosis, and treatment. Methods: The GIPC2 expression in colorectal cancer was examined by the TCGA database analysis, IHC from the human protein atlas and qRT-PCR tests. GO and KEGG enrichment analyses were performed for genes that were both correlated with the expression of GIPC2 and GPD1L. The receiver operating characteristic curve (ROC) analysis and Kaplan-Meier (KM) survival analysis were applied to analyze the prognostic value of GIPC2 and GPD1L for overall survival (OS) and progress free interval (PFI) of CRC patients. Results: We found that GIPC2 was low expressed in colorectal cancer and highly related with the CRC clinical-stage grade and TNM stage. Furthermore, GPD1L is correlated with GIPC2 via the correlation analysis in CRC and they were associated with several important cancer-related pathways. GIPC2 and GPD1L exhibited good diagnostic and prognostic predictive ability for patients with CRC. Conclusions: These results revealed new biomarkers in CRC, we proposed that the GIPC2/GPDL1 might be potential diagnostic and prognostic indicators for CRC, which provides a theoretical basis for our subsequent cellular and animal experiments, so as to reveal the occurrence and development mechanism of CRC more comprehensively.

Comparative study on the in vitro digestibility of chicken protein after different modifications.

The effects of tea polyphenols (TPPs) and ultrasound treatment (UDT) on the digestibility of chicken myofibrillar protein (MPN) in anenhanced oxidation system were investigated. As observed, the original aggregates of MPN were much lower in the UDT-assisted group than in the control protein group, and the difference widened after the incorporation of TPPs. The covalent structures of the UDT-assisted oxidation groups were verified via mass spectrometry and amino acid (AAD) measurements. The peptide abundance increased after the UDT-assisted covalent reaction and most of these peptides were derived from the structural proteins of MPNs according to the results of nano-LC-ESI-MS/MS. Digestion kinetic analysis showed that the digestion level of the EGCG-treated group was better than that of the other treated groups, regardless of the UDT-assisted covalent reaction. Overall, the combination of EGCG oxidation and UDT may be an efficient way to promote the nutritional value of the final MPN products.

Neural circuit control of innate behaviors.

All animals possess a plethora of innate behaviors that do not require extensive learning and are fundamental for their survival and propagation. With the advent of newly-developed techniques such as viral tracing and optogenetic and chemogenetic tools, recent studies are gradually unraveling neural circuits underlying different innate behaviors. Here, we summarize current development in our understanding of the neural circuits controlling predation, feeding, male-typical mating, and urination, highlighting the role of genetically defined neurons and their connections in sensory triggering, sensory to motor/motivation transformation, motor/motivation encoding during these different behaviors. Along the way, we discuss possible mechanisms underlying binge-eating disorder and the pro-social effects of the neuropeptide oxytocin, elucidating the clinical relevance of studying neural circuits underlying essential innate functions. Finally, we discuss some exciting brain structures recurrently appearing in the regulation of different behaviors, which suggests both divergence and convergence in the neural encoding of specific innate behaviors. Going forward, we emphasize the importance of multi-angle and cross-species dissections in delineating neural circuits that control innate behaviors.

Periaqueductal gray neurons encode the sequential motor program in hunting behavior of mice.

Sequential encoding of motor programs is essential for behavior generation. However, whether it is critical for instinctive behavior is still largely unknown. Mouse hunting behavior typically contains a sequential motor program, including the prey search, chase, attack, and consumption. Here, we reveal that the neuronal activity in the lateral periaqueductal gray (LPAG) follows a sequential pattern and is time-locked to different hunting actions. Optrode recordings and photoinhibition demonstrate that LPAGVgat neurons are required for the prey detection, chase and attack, while LPAGVglut2 neurons are selectively required for the attack. Ablation of inputs that could trigger hunting, including the central amygdala, the lateral hypothalamus, and the zona incerta, interrupts the activity sequence pattern and substantially impairs hunting actions. Therefore, our findings reveal that periaqueductal gray neuronal ensembles encode the sequential hunting motor program, which might provide a framework for decoding complex instinctive behaviors.

Pentraxin-3 inhibits milky spots metastasis of gastric cancer by inhibiting M2 macrophage polarization.

Purpose: Recent studies have indicated that Pentraxin-3 (PTX3) is related to invasion, migration and metastasis of gastric cancer cells (GCCs). However, the function of PTX3 in stemness and tumor-associated macrophages (TAMs) polarization in GC has not yet been revealed. Here, we investigated the role of PTX3 in TAMs polarization and stemness in gastric cancer (GC), and further explored the effect of PTX3 on milky spot metastasis of gastric cancer. Methods: PTX3 expression in human gastric cancer tissues was examined with immunohistochemistry (IHC). The influence on stemness of gastric cancer cells was examined by sphere formation assay and western blot. qRT-PCR, IHC and flow cytometry were used to evaluate M1/M2 macrophage signatures. The effects of PTX3 on TAM polarization and milky spots were investigated in vitro and in vivo. The possible mechanism of PTX3 on targeted cytokines and pathway were analyzed by qRT-PCR and western blot. Results: We found that PTX3 was low expressed in gastric carcinoma tissues and associated with stemness and polarization of macrophages. The upregulation of PTX3 inhibited the stemness of GCCs. Furthermore, PTX3 suppressed the polarization of M2 macrophages in the milky spots in vivo and in vitro and inhibited the metastasis of GC into milky spots. PTX3 restrained the expression of interleukin-4 (IL-4) and IL-10 via the inhibition of phosphorylation of the c-Jun N-terminal protein kinase 1/2 (JNK1/2) in GCCs. Conclusion: These results revealed a novel mechanism of PTX3 in GC, which may participate in the development and metastasis of GC by affecting stemness and macrophage polarization. PTX3 should be considered as a crucial biomarker and may be potentially used in targeted therapy in GC progression.

Anchimerically Assisted Selective Cleavage of Acid-Labile Aryl Alkyl Ethers by Aluminum Triiodide and N,N-Dimethylformamide Dimethyl Acetal.

Aluminum triiodide is harnessed by N,N-dimethylformamide dimethyl acetal (DMF-DMA) for the selective cleavage of ethers via neighboring group participation. Various acid-labile functional groups, including carboxylate, allyl, tert-butyldimethylsilyl (TBS), and tert-butoxycarbonyl (Boc), suffer the conditions intact. The method offers an efficient approach to cleaving catechol monoalkyl ethers and to uncovering phenols from acetal-type protecting groups such as methoxymethyl (MOM), methoxyethoxymethyl (MEM), and tetrahydropyranyl (THP) chemoselectively.

One-Step Synthesis of Eu3+-Modified Cellulose Acetate Film and Light Conversion Mechanism.

A CA-Eu(III) complex was synthesized by the coordination reaction of cellulose acetate (CA) and Eu3+ to obtain a CA-Eu light conversion film. This product was then doped with Tb(III) to sensitize the luminescence of Eu3+, which could functionalize the CA film. FTIR and XPS showed that the oxygen atoms in C=O, C-O (O=C-O), and O-H were involved in the complexation with Eu3+ and formed a Eu-O bond. SEM revealed that Eu3+ filled in the pores of the CA film. By changing the experimental conditions, the best fluorescence performance was obtained at the CA: Eu3+ ratio of 3:1 with a reaction time of 65 min. The energy transfer between Tb3+-Eu3+ could be realized by doping Tb3+ to enhance the luminescence of Eu3+. The best fluorescence performance of the CA-Eu-Tb light conversion film was at a Eu3+:Tb3+ ratio of 3:1. Compared with the CA film, the light conversion film has high transparency, high tensile strength, and good flexibility. It can convert the ultraviolet light harmful to plants into red light that is beneficial to photosynthesis. This offers high efficiency and environmental protection in the field of agricultural films.

Zona incerta GABAergic neurons integrate prey-related sensory signals and induce an appetitive drive to promote hunting.

The neural substrates for predatory hunting, an evolutionarily conserved appetitive behavior, remain largely undefined. Photoactivation of zona incerta (ZI) GABAergic neurons strongly promotes hunting of both live and artificial prey. Conversely, photoinhibition of these neurons or deletion of their GABA function severely impairs hunting. Here electrophysiological recordings reveal that ZI neurons integrate prey-related multisensory signals and discriminate prey from non-prey targets. Visual or whisker sensory deprivation reduces calcium responses induced by prey introduction and attack and impair hunting. ZI photoactivation largely corrects the hunting impairment caused by sensory deprivations. Motivational and reinforcing assays reveal that ZI photoactivation is associated with a strong appetitive drive, causing repetitive self-stimulatory behaviors. These ZI neurons project to the periaqueductal gray matter to induce hunting and motivation. Thus, we have delineated the function of ZI GABAergic neurons in hunting, which integrates prey-related sensory signals into prey detection and attack and induces a strong appetitive motivational drive.

AGRP Neurons Project to the Medial Preoptic Area and Modulate Maternal Nest-Building.

AGRP (agouti-related neuropeptide) expressing inhibitory neurons sense caloric needs of an animal to coordinate homeostatic feeding. Recent evidence suggests that AGRP neurons also suppress competing actions and motivations to mediate adaptive behavioral selection during starvation. Here, in adult mice of both sexes we show that AGRP neurons form inhibitory synapses onto ∼30% neurons in the medial preoptic area (mPOA), a region critical for maternal care. Remarkably, optogenetically stimulating AGRP neurons decreases maternal nest-building while minimally affecting pup retrieval, partly recapitulating suppression of maternal behaviors during food restriction. In parallel, optogenetically stimulating AGRP projections to the mPOA or to the paraventricular nucleus of hypothalamus but not to the LHA (lateral hypothalamus area) similarly decreases maternal nest-building. Chemogenetic inhibition of mPOA neurons that express Vgat (vesicular GABA transporter), the population targeted by AGRP terminals, also decreases maternal nest-building. In comparison, chemogenetic inhibition of neurons in the LHA that express vesicular glutamate transporter 2, another hypothalamic neuronal population critical for feeding and innate drives, is ineffective. Importantly, nest-building during low temperature thermal challenge is not affected by optogenetic stimulation of AGRP→mPOA projections. Finally, via optogenetic activation and inhibition we show that distinctive subsets of mPOA Vgat+ neurons likely underlie pup retrieval and maternal nest-building. Together, these results show that AGRP neurons can modulate maternal nest-building, in part through direct projections to the mPOA. This study corroborates other recent discoveries and underscores the broad functions that AGRP neurons play in antagonizing rivalry motivations to modulate behavioral outputs during hunger.SIGNIFICANCE STATEMENT In order for animals to initiate ethologically appropriate behaviors, they must typically decide between behavioral repertoires driven by multiple and often conflicting internal states. How neural pathways underlying individual behaviors interact to coherently modulate behavioral outputs, in particular to achieve a proper balance between behaviors that serve immediate individual needs versus those that benefit the propagation of the species, remains poorly understood. Here, by investigating projections from a neuronal population known to drive hunger behaviors to a brain region critical for maternal care, we show that activation of AGRP→mPOA projections in females dramatically inhibits maternal nest-building while leaving mostly intact pup retrieval behavior. Our findings shed new light on neural organization of behaviors and neural mechanisms that coordinate behavioral selection.