Transcriptional Control of Seed Life: New Insights into the Role of the NAC Family.

Transcription factors (TFs) regulate gene expression by binding to specific sequences on DNA through their DNA-binding domain (DBD), a universal process. This update conveys information about the diverse roles of TFs, focusing on the NACs (NAM-ATAF-CUC), in regulating target-gene expression and influencing various aspects of plant biology. NAC TFs appeared before the emergence of land plants. The NAC family constitutes a diverse group of plant-specific TFs found in mosses, conifers, monocots, and eudicots. This update discusses the evolutionary origins of plant NAC genes/proteins from green algae to their crucial roles in plant development and stress response across various plant species. From mosses and lycophytes to various angiosperms, the number of NAC proteins increases significantly, suggesting a gradual evolution from basal streptophytic green algae. NAC TFs play a critical role in enhancing abiotic stress tolerance, with their function conserved in angiosperms. Furthermore, the modular organization of NACs, their dimeric function, and their localization within cellular compartments contribute to their functional versatility and complexity. While most NAC TFs are nuclear-localized and active, a subset is found in other cellular compartments, indicating inactive forms until specific cues trigger their translocation to the nucleus. Additionally, it highlights their involvement in endoplasmic reticulum (ER) stress-induced programmed cell death (PCD) by activating the vacuolar processing enzyme (VPE) gene. Moreover, this update provides a comprehensive overview of the diverse roles of NAC TFs in plants, including their participation in ER stress responses, leaf senescence (LS), and growth and development. Notably, NACs exhibit correlations with various phytohormones (i.e., ABA, GAs, CK, IAA, JA, and SA), and several NAC genes are inducible by them, influencing a broad spectrum of biological processes. The study of the spatiotemporal expression patterns provides insights into when and where specific NAC genes are active, shedding light on their metabolic contributions. Likewise, this review emphasizes the significance of NAC TFs in transcriptional modules, seed reserve accumulation, and regulation of seed dormancy and germination. Overall, it effectively communicates the intricate and essential functions of NAC TFs in plant biology. Finally, from an evolutionary standpoint, a phylogenetic analysis suggests that it is highly probable that the WRKY family is evolutionarily older than the NAC family.

Unified perspective on exponential tilt and bridge algorithms for rare trajectories of discrete Markov processes.

This article analyzes and compares two general techniques of rare event simulation for generating paths of Markov processes over fixed time horizons: exponential tilting and stochastic bridge. These two methods allow us to accurately compute the probability that a Markov process ends within a rare region which is unlikely to be attained. Exponential tilting is a general technique for obtaining an alternative or tilted sampling probability measure, under which the Markov process becomes likely to hit the rare region at terminal time. The stochastic bridge technique involves conditioning paths towards two endpoints: the terminal point and the initial one. The terminal point is generated from some appropriately chosen probability distribution that covers well the rare region. We show that both methods belong to the class of importance sampling procedures by providing a common mathematical framework of these two conceptually different methods of sampling rare trajectories. We also conduct a numerical comparison of these two methods, revealing distinct areas of application for each Monte Carlo method, where they exhibit superior efficiency. Detailed simulation algorithms are provided.

Deletion of Gadd45a Expression in Mice Leads to Cognitive and Synaptic Impairment Associated with Alzheimer's Disease Hallmarks.

Gadd45 genes have been implicated in survival mechanisms, including apoptosis, autophagy, cell cycle arrest, and DNA repair, which are processes related to aging and life span. Here, we analyzed if the deletion of Gadd45a activates pathways involved in neurodegenerative disorders such as Alzheimer's Disease (AD). This study used wild-type (WT) and Gadd45a knockout (Gadd45a-/-) mice to evaluate AD progression. Behavioral tests showed that Gadd45a-/- mice presented lower working and spatial memory, pointing out an apparent cognitive impairment compared with WT animals, accompanied by an increase in Tau hyperphosphorylation and the levels of kinases involved in its phosphorylation in the hippocampus. Moreover, Gadd45a-/- animals significantly increased the brain's pro-inflammatory cytokines and modified autophagy markers. Notably, neurotrophins and the dendritic spine length of the neurons were reduced in Gadd45a-/- mice, which could contribute to the cognitive alterations observed in these animals. Overall, these findings demonstrate that the lack of the Gadd45a gene activates several pathways that exacerbate AD pathology, suggesting that promoting this protein's expression or function might be a promising therapeutic strategy to slow down AD progression.

GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis in the liver by attenuating the TGF-ß1/SMAD3 pathway.

INTRODUCTION: The levels of the cellular energy sensor AMP-activated protein kinase (AMPK) have been reported to be decreased via unknown mechanisms in the liver of mice deficient in growth differentiation factor 15 (GDF15). This stress response cytokine regulates energy metabolism mainly by reducing food intake through its hindbrain receptor GFRAL. OBJECTIVE: To examine how GDF15 regulates AMPK. METHODS: Wild-type and Gdf15-/- mice, mouse primary hepatocytes and the human hepatic cell line Huh-7 were used. RESULTS: Gdf15-/- mice showed glucose intolerance, reduced hepatic phosphorylated AMPK levels, increased levels of phosphorylated mothers against decapentaplegic homolog 3 (SMAD3; a mediator of the fibrotic response), elevated serum levels of transforming growth factor (TGF)-ß1, as well as upregulated gluconeogenesis and fibrosis. In line with these observations, recombinant (r)GDF15 promoted AMPK activation and reduced the levels of phosphorylated SMAD3 and the markers of gluconeogenesis and fibrosis in the liver of mice and in mouse primary hepatocytes, suggesting that these effects may be independent of GFRAL. Pharmacological inhibition of SMAD3 phosphorylation in Gdf15-/- mice prevented glucose intolerance, the deactivation of AMPK and the increase in the levels of proteins involved in gluconeogenesis and fibrosis, suggesting that overactivation of the TGF-ß1/SMAD3 pathway is responsible for the metabolic alterations in Gdf15-/- mice. CONCLUSIONS: Overall, these findings indicate that GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis by lowering the activity of the TGF-ß1/SMAD3 pathway.

CHOP upregulation and dysregulation of the mature form of the SNAT2 amino acid transporter in the placentas from small for gestational age newborns.

BACKGROUND: The placentas from newborns that are small for gestational age (SGA; birth weight < -2 SD for gestational age) may display multiple pathological characteristics. A key determinant of fetal growth and, therefore, birth weight is placental amino acid transport, which is under the control of the serine/threonine kinase mechanistic target of rapamycin (mTOR). The effects of endoplasmic reticulum (ER) stress on the mTOR pathway and the levels of amino acid transporters are not well established. METHODS: Placentas from SGA and appropriate for gestational age (AGA) newborns and the human placental BeWo cell line exposed to the ER stressor tunicamycin were used. RESULTS: We detected a significant increase in the levels of C/EBP homologous protein (CHOP) in the placentas from SGA newborns compared with those from AGA newborns, while the levels of other ER stress markers were barely affected. In addition, placental mTOR Complex 1 (mTORC1) activity and the levels of the mature form of the amino acid transporter sodium-coupled neutral amino acid transporter 2 (SNAT2) were also reduced in the SGA group. Interestingly, CHOP has been reported to upregulate growth arrest and DNA damage-inducible protein 34 (GADD34), which in turn suppresses mTORC1 activity. The GADD34 inhibitor guanabenz attenuated the increase in CHOP protein levels and the reduction in mTORC1 activity caused by the ER stressor tunicamycin in the human placental cell line BeWo, but it did not recover mature SNAT2 protein levels, which might be reduced as a result of defective glycosylation. CONCLUSIONS: Collectively, these data reveal that GADD34A activity and glycosylation are key factors controlling mTORC1 signaling and mature SNAT2 levels in trophoblasts, respectively, and might contribute to the SGA condition. Video Abstract.

The Regulatory Role of MicroRNAs in Obesity and Obesity-Derived Ailments.

Obesity is a condition that is characterized by the presence of excessive adipose tissue in the body. Obesity has become one of the main health concerns worldwide since it can lead to other chronic ailments, such as type 2 diabetes or fatty liver disease, and it could be an aggravating factor in infections. MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression and can play an important role in controlling crucial biological processes involved in the onset of obesity, such as lipogenesis, adipogenesis, lipid metabolism, or the regulation of cytokines and chemokines. Moreover, chemical compounds present in food or food packaging can alter miRNA expression and regulate the aforementioned biological mechanisms related to diabetes onset and progression. Furthermore, therapies, such as bariatric surgery and aerobic exercise training, can also influence the expression profile of miRNAs in obesity. Therefore, the present review provides insight into the current research on the role of miRNAs in obesity and obesity-derived ailments, intending to develop novel therapies to effectively manage these disorders.

Elafibranor upregulates the EMT-inducer S100A4 via PPARß/δ.

Elafibranor is a dual peroxisome proliferator-activated receptor (PPAR)α and ß/δ agonist that has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we examined the effects of elafibranor in mice fed a choline-deficient high-fat diet (CD-HFD), a model of metabolic dysfunction-associated steatohepatitis (MASH) that presents obesity and insulin resistance. Our findings revealed that elafibranor treatment ameliorated steatosis, inflammation, and fibrogenesis in the livers of CD-HFD-fed mice. Unexpectedly, elafibranor also increased the levels of the epithelial-mesenchymal transition (EMT)-promoting protein S100A4 via PPARß/δ activation. The increase in S100A4 protein levels caused by elafibranor was accompanied by changes in the levels of markers associated with the EMT program. The S100A4 induction caused by elafibranor was confirmed in the BRL-3A rat liver cells and a mouse primary hepatocyte culture. Furthermore, elafibranor reduced the levels of ASB2, a protein that promotes S100A4 degradation, while ASB2 overexpression prevented the stimulating effect of elafibranor on S100A4. Collectively, these findings reveal an unexpected hepatic effect of elafibranor on increasing S100A4 and promoting the EMT program.

Soluble epoxide hydrolase-targeting PROTAC activates AMPK and inhibits endoplasmic reticulum stress.

Soluble epoxide hydrolase (sEH) is a drug target with the potential for therapeutic utility in the areas of inflammation, neurodegenerative disease, chronic pain, and diabetes, among others. Proteolysis-targeting chimeras (PROTACs) molecules offer new opportunities for targeting sEH, due to its capacity to induce its degradation. Here, we describe that the new ALT-PG2, a PROTAC that degrades sEH protein in the human hepatic Huh-7 cell line, in isolated mouse primary hepatocytes, and in the liver of mice. Remarkably, sEH degradation caused by ALT-PG2 was accompanied by an increase in the phosphorylated levels of AMP-activated protein kinase (AMPK), while phosphorylated extracellular-signal-regulated kinase 1/2 (ERK1/2) was reduced. Consistent with the key role of these kinases on endoplasmic reticulum (ER) stress, ALT-PG2 attenuated the levels of ER stress and inflammatory markers. Overall, the findings of this study indicate that targeting sEH with degraders is a promising pharmacological strategy to promote AMPK activation and to reduce ER stress and inflammation.

Exploring the Potential Role of Circulating microRNAs as Biomarkers for Predicting Clinical Response to Neoadjuvant Therapy in Breast Cancer.

Breast cancer (BC) is a leading cause of cancer-related deaths among women worldwide. Neoadjuvant therapy (NAT) is increasingly being used to reduce tumor burden prior to surgical resection. However, current techniques for assessing tumor response have significant limitations. Additionally, drug resistance is commonly observed, raising a need to identify biomarkers that can predict treatment sensitivity and survival outcomes. Circulating microRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and have been shown to play a significant role in cancer progression as tumor inducers or suppressors. The expression of circulating miRNAs has been found to be significantly altered in breast cancer patients. Moreover, recent studies have suggested that circulating miRNAs can serve as non-invasive biomarkers for predicting response to NAT. Therefore, this review provides a brief overview of recent studies that have demonstrated the potential of circulating miRNAs as biomarkers for predicting the clinical response to NAT in BC patients. The findings of this review will strengthen future research on developing miRNA-based biomarkers and their translation into medical practice, which could significantly improve the clinical management of BC patients undergoing NAT.

The regulatory role of microRNAs in common eye diseases: A brief review.

MicroRNAs (miRNAs) are highly conserved, small non-coding RNA molecules (∼21 nucleotides) that regulate numerous biological processes, including developmental timing, hematopoiesis, organogenesis, apoptosis, cell differentiation, and proliferation either by mRNA degradation or translation repression. Since eye physiology requires a perfect orchestration of complex regulatory networks, an altered expression of key regulatory molecules such as miRNAs potentially leads to numerous eye disorders. In recent years, comprehensive progress has been made in demonstrating the precise roles of miRNAs, emphasizing their potential use in diagnostic and therapeutic purposes of chronic human diseases. Thus, this review explicitly illustrates the regulatory roles of miRNAs in four common eye disorders, such as cataract, glaucoma, macular degeneration, and uveitis, and their application in disease management.

The distribution of cadmium in soil and cacao beans in Peru.

Peru is the eighth largest producer of cacao beans globally, but high cadmium contents are constraining access to international markets which have set upper thresholds for permitted concentrations in chocolate and derivatives. Preliminary data have suggested that high cadmium concentrations in cacao beans are restricted to specific regions in the country, but to date no reliable maps exist of expected cadmium concentrations in soils and cacao beans. Drawing on >2000 representative samples of cacao beans and soils we developed multiple national and regional random forest models to develop predictive maps of cadmium in soil and cacao beans across the area suitable for cacao cultivation. Our model projections show that elevated concentrations of cadmium in cacao soils and beans are largely restricted to the northern parts of the country in the departments of Tumbes, Piura, Amazonas and Loreto, as well as some very localized pockets in the central departments of Huánuco and San Martin. Unsurprisingly, soil cadmium was the by far most important predictor of bean cadmium. Aside from the south-eastern to north-western spatial trend of increasing cadmium values in soils and beans, the most important predictors of both variables in nation-wide models were geology, rainfall seasonality, soil pH and rainfall. At regional level, alluvial deposits and mining operations were also associated with higher cadmium levels in cacao beans. Based on our predictive map of cadmium in cacao beans we estimate that while at a national level <20 % of cacao farming households might be impacted by the cadmium regulations, in the most affected department of Piura this could be as high as 89 %.

Cuprous oxide nanoparticles incorporated into a polymeric matrix embedded in fabrics to prevent spread of SARS-CoV-2.

This paper describes the development of a coating for cotton and polypropylene (PP) fabrics based on a polymeric matrix embedded with cuprous oxide nanoparticles (Cu2O@SDS NPs) in order to inactivate SARS-CoV-2 and manufactured by a simple process using a dip-assisted layer-by-layer technology, at low curing temperature and without the need for expensive equipment, capable of achieving disinfection rates of up to 99%. The polymeric bilayer coating makes the surface of the fabrics hydrophilic, enabling the transportation of the virus-infected droplets to achieve the rapid inactivation of SARS-CoV-2 by contact with the Cu2O@SDS NPs incorporated in the coated fabrics.

Receptor-binding domain-based SARS-CoV-2 vaccine adjuvanted with cyclic di-adenosine monophosphate enhances humoral and cellular immunity in mice.

Novel adjuvants are highly desired to improve immune responses of SARS-CoV-2 vaccines. This work reports the potential of the stimulator of interferon genes (STING) agonist adjuvant, the cyclic di-adenosine monophosphate (c-di-AMP), in a SARS-CoV-2 vaccine based on the receptor binding domain (RBD). Here, mice immunized with two doses of monomeric RBD adjuvanted with c-di-AMP intramuscularly were found to exhibit stronger immune responses compared to mice vaccinated with RBD adjuvanted with aluminum hydroxide (Al(OH)3 ) or without adjuvant. After two immunizations, consistent enhancements in the magnitude of RBD-specific immunoglobulin G (IgG) antibody response were observed by RBD + c-di-AMP (mean: 15360) compared to RBD + Al(OH)3 (mean: 3280) and RBD alone (n.d.). Analysis of IgG subtypes indicated a predominantly Th1-biased immune response (IgG2c, mean: 14480; IgG2b, mean: 1040, IgG1, mean: 470) in mice vaccinated with RBD + c-di-AMP compared to a Th2-biased response in those vaccinated with RBD + Al(OH)3 (IgG2c, mean: 60; IgG2b: n.d.; IgG1, mean: 16660). In addition, the RBD + c-di-AMP group showed better neutralizing antibody responses as determined by pseudovirus neutralization assay and by plaque reduction neutralization assay with SARS-CoV-2 wild type. Moreover, the RBD + c-di-AMP vaccine promoted interferon-γ secretion of spleen cell cultures after RBD stimulation. Furthermore, evaluation of IgG-antibody titers in aged mice showed that di-AMP was able to improve RBD-immunogenicity at old age after 3 doses (mean: 4000). These data suggest that c-di-AMP improves immune responses of a SARS-CoV-2 vaccine based on RBD, and would be considered a promising option for future COVID-19 vaccines.

Lipotoxicity, glucotoxicity and some strategies to protect vascular smooth muscle cell against proliferative phenotype in metabolic syndrome.

Metabolic syndrome (MetS) is a risk factor for the development of cardiovascular disease (CVD) and atherosclerosis through a mechanism that involves vascular smooth muscle cell (VSMC) proliferation, lipotoxicity and glucotoxicity. Several molecules found to be increased in MetS, including free fatty acids, fatty acid binding protein 4, leptin, resistin, oxidized lipoprotein particles, and advanced glycation end products, influence VSMC proliferation. Most of these molecules act through their receptors on VSMCs by activating several signaling pathways associated with ROS generation in various cellular compartments. ROS from NADPH-oxidase and mitochondria have been found to promote VSMC proliferation and cell cycle progression. In addition, most of the natural or synthetic substances described in this review, including pharmaceuticals with hypoglycemic and hypolipidemic properties, attenuate VSMC proliferation by their simultaneous modulation of cell signaling and their scavenging property due to the presence of a phenolic ring in their structure. This review discusses recent data in the literature on the role that several MetS-related molecules and ROS play in the change from contractile to proliferative phenotype of VSMCs. Hence the importance of proposing an appropriate strategy to prevent uncontrolled VSMC proliferation using antioxidants, hypoglycemic and hypolipidemic agents.

Sampling rare trajectories using stochastic bridges.

The numerical quantification of the statistics of rare events in stochastic processes is a challenging computational problem. We present a sampling method that constructs an ensemble of stochastic trajectories that are constrained to have fixed start and end points (so-called stochastic bridges). We then show that by carefully choosing a set of such bridges and assigning an appropriate statistical weight to each bridge, one can focus more processing power on the rare events of a target stochastic process while faithfully preserving the statistics of these rare trajectories. Further, we also compare the stochastic bridges we produce to the Wentzel-Kramers-Brillouin (WKB) optimal paths of the target process, derived in the limit of low noise. We see that the generated paths, encoding the full statistics of the process, collapse onto the WKB optimal path as the level of noise is reduced. We propose that the method can also be used to judge the accuracy of the WKB approximation at finite levels of noise.

Impact of urban structure on infectious disease spreading.

The ongoing SARS-CoV-2 pandemic has been holding the world hostage for several years now. Mobility is key to viral spreading and its restriction is the main non-pharmaceutical interventions to fight the virus expansion. Previous works have shown a connection between the structural organization of cities and the movement patterns of their residents. This puts urban centers in the focus of epidemic surveillance and interventions. Here we show that the organization of urban flows has a tremendous impact on disease spreading and on the amenability of different mitigation strategies. By studying anonymous and aggregated intra-urban flows in a variety of cities in the United States and other countries, and a combination of empirical analysis and analytical methods, we demonstrate that the response of cities to epidemic spreading can be roughly classified in two major types according to the overall organization of those flows. Hierarchical cities, where flows are concentrated primarily between mobility hotspots, are particularly vulnerable to the rapid spread of epidemics. Nevertheless, mobility restrictions in such types of cities are very effective in mitigating the spread of a virus. Conversely, in sprawled cities which present many centers of activity, the spread of an epidemic is much slower, but the response to mobility restrictions is much weaker and less effective. Investing resources on early monitoring and prompt ad-hoc interventions in more vulnerable cities may prove helpful in containing and reducing the impact of future pandemics.

Phytochemicals mediated modulation of microRNAs and long non-coding RNAs in cancer prevention and therapy.

MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are two main categories of noncoding RNAs (ncRNAs) that can influence essential biological functions in various ways, as well as their expression and function are tightly regulated in physiological homeostasis. Additionally, the dysregulation of these ncRNAs seems to be crucial to the pathogenesis of human diseases. The latest findings indicate that ncRNAs execute vital roles in cancer initiation and progression, and the cancer phenotype can be reversed by modulating their expression. Available scientific discoveries suggest that phytochemicals such as polyphenols, alkaloids, terpenoids, and organosulfur compounds can significantly modulate multiple cancer-associated miRNAs and lncRNAs, thereby inhibiting cancer initiation and development. However, despite promising outcomes of experimental research, only a few clinical trials are currently being conducted to evaluate the therapeutic effectiveness of these compounds. Nevertheless, understanding phytochemical-mediated ncRNA regulation in cancer and the underlying molecular mechanisms on tumor pathophysiology can aid in the development of novel therapeutic strategies to combat this deadly disease.

Full-bandwidth electrophysiology of seizures and epileptiform activity enabled by flexible graphene microtransistor depth neural probes.

Mapping the entire frequency bandwidth of brain electrophysiological signals is of paramount importance for understanding physiological and pathological states. The ability to record simultaneously DC-shifts, infraslow oscillations (<0.1 Hz), typical local field potentials (0.1-80 Hz) and higher frequencies (80-600 Hz) using the same recording site would particularly benefit preclinical epilepsy research and could provide clinical biomarkers for improved seizure onset zone delineation. However, commonly used metal microelectrode technology suffers from instabilities that hamper the high fidelity of DC-coupled recordings, which are needed to access signals of very low frequency. In this study we used flexible graphene depth neural probes (gDNPs), consisting of a linear array of graphene microtransistors, to concurrently record DC-shifts and high-frequency neuronal activity in awake rodents. We show here that gDNPs can reliably record and map with high spatial resolution seizures, pre-ictal DC-shifts and seizure-associated spreading depolarizations together with higher frequencies through the cortical laminae to the hippocampus in a mouse model of chemically induced seizures. Moreover, we demonstrate the functionality of chronically implanted devices over 10 weeks by recording with high fidelity spontaneous spike-wave discharges and associated infraslow oscillations in a rat model of absence epilepsy. Altogether, our work highlights the suitability of this technology for in vivo electrophysiology research, and in particular epilepsy research, by allowing stable and chronic DC-coupled recordings.

Raw data of silver extraction from sodium-silver jarosite using three different lixiviants in alkaline medium.

This article presents the raw data of silver concentration ([Ag]) obtained as a function of time (t) from silver leaching experiments, which were conducted using a synthetic sodium-silver jarosite and different complexing agents: thiosulfate, thiocyanate, and cyanide. Leaching experiments were performed under different conditions of temperature, pH and lixiviant concentration. The data refer to the article "Silver leaching from jarosite-type compounds using cyanide and non-cyanide lixiviants: a kinetic approach" (Islas et al., 2021), in which they were used to determine the leaching kinetics of jarosite-type compounds. The datasets were obtained experimentally from batch experiments. Concentration of silver, [Ag], was determined in each experiment as a function of time by atomic absorption spectroscopy. The information presented in this article can be useful for engineering students interested in mineral processing; particularly, for the calculation of kinetic parameters of silver leaching process. The data could also help in the formulation, implementation, or optimization of strategies for extraction of valuable metals from residues generated by the hydrometallurgical industry.

A 1024-Channel 10-Bit 36- µW/ch CMOS ROIC for Multiplexed GFET-Only Sensor Arrays in Brain Mapping.

This paper presents a 1024-channel neural read-out integrated circuit (ROIC) for solution-gated GFET sensing probes in massive µECoG brain mapping. The proposed time-domain multiplexing of GFET-only arrays enables low-cost and scalable hybrid headstages. Low-power CMOS circuits are presented for the GFET analog frontend, including a CDS mechanism to improve preamplifier noise figures and 10-bit 10-kS/s A/D conversion. The 1024-channel ROIC has been fabricated in a standard 1.8-V 0.18- µm CMOS technology with 0.012 mm 2 and 36 µ W per channel. An automated methodology for the in-situ calibration of each GFET sensor is also proposed. Experimental ROIC tests are reported using a custom FPGA-based µECoG headstage with 16×32 and 32×32 GFET probes in saline solution and agar substrate. Compared to state-of-art neural ROICs, this work achieves the largest scalability in hybrid platforms and it allows the recording of infra-slow neural signals.