Adult microglial TGFß1 is required for microglia homeostasis via an autocrine mechanism to maintain cognitive function in mice.

While TGF-ß signaling is essential for microglial function, the cellular source of TGF-ß1 ligand and its spatial regulation remains unclear in the adult CNS. Our data supports that microglia but not astrocytes or neurons are the primary producers of TGF-ß1 ligands needed for microglial homeostasis. Microglia-Tgfb1 KO leads to the activation of microglia featuring a dyshomeostatic transcriptome that resembles disease-associated, injury-associated, and aged microglia, suggesting microglial self-produced TGF-ß1 ligands are important in the adult CNS. Astrocytes in MG-Tgfb1 inducible (i)KO mice show a transcriptome profile that is closely aligned with an LPS-associated astrocyte profile. Additionally, using sparse mosaic single-cell microglia KO of TGF-ß1 ligand we established an autocrine mechanism for signaling. Here we show that MG-Tgfb1 iKO mice present cognitive deficits, supporting that precise spatial regulation of TGF-ß1 ligand derived from microglia is required for the maintenance of brain homeostasis and normal cognitive function in the adult brain.

Ventral striatum dopamine release encodes unique properties of visual stimuli in mice.

The mesolimbic dopamine system is an evolutionarily conserved set of brain circuits that play a role in attention, appetitive behavior, and reward processing. In this circuitry, ascending dopaminergic projections from the ventral midbrain innervate targets throughout the limbic forebrain, such as the ventral striatum/nucleus accumbens (NAc). Dopaminergic signaling in the NAc has been widely studied for its role in behavioral reinforcement, reward prediction error encoding, and motivational salience. Less well characterized is the role of dopaminergic neurotransmission in the response to surprising or alerting sensory events. To address this, we used the genetically encoded dopamine sensor dLight1 and fiber photometry to explore the ability of striatal dopamine release to encode the properties of salient sensory stimuli in mice, such as threatening looming discs. Here, we report that lateral NAc (LNAc) dopamine release encodes the rate and magnitude of environmental luminance changes rather than the visual stimulus threat level. This encoding is highly sensitive, as LNAc dopamine could be evoked by light intensities that were imperceptible to human experimenters. We also found that light-evoked dopamine responses are wavelength-dependent at low irradiances, independent of the circadian cycle, robust to previous exposure history, and involve multiple phototransduction pathways. Thus, we have further elaborated the mesolimbic dopamine system's ability to encode visual information in mice, which is likely relevant to a wide body of scientists employing light sources or optical methods in behavioral research involving rodents.

Enhanced Intraoperative Communication of Tumor Margins Using 3D Scanning and Mapping: The Computer-Aided Design Margin.

We have implemented a novel intraoperative communication system for head and neck surgical pathology using 3D scanning technology and computer-aided design (CAD) software. Here, we highlight our CAD margin protocol, in which we 3D scan head and neck oncologic surgical specimens and map frozen section results. This enhances the communication of margin status between surgeons and pathologists and delivers visual anatomic guidance for re-resection when needed. Laryngoscope, 133:1914-1918, 2023.

Living bioethics, clinical ethics committees and children's consent to heart surgery.

This discussion paper considers how seldom recognised theories influence clinical ethics committees. A companion paper examined four major theories in social science: positivism, interpretivism, critical theory and functionalism, which can encourage legalistic ethics theories or practical living bioethics, which aims for theory-practice congruence. This paper develops the legalistic or living bioethics themes by relating the four theories to clinical ethics committee members' reported aims and practices and approaches towards efficiency, power, intimidation, justice, equality and children's interests and rights. Different approaches to framing ethical questions are also considered. Being aware of the four theories' influence can help when seeking to understand and possibly change clinical ethics committee routines. The paper is not a research report but is informed by a recent study in two London paediatric cardiac units. Forty-five practitioners and related experts were interviewed, including eight members of ethics committees, about the work of informing, preparing and supporting families during the extended process of consent to children's elective heart surgery. The mosaic of multidisciplinary teamwork is reported in a series of papers about each profession, including this one on bioethics and law and clinical ethics committees' influence on clinical practice. The qualitative social research was funded by the British Heart Foundation, in order that more may be known about the perioperative views and needs of all concerned. Questions included how disputes can be avoided, how high ethical standards and respectful cooperation between staff and families can be encouraged, and how minors' consent or refusal may be respected, with the support of clinical ethics committees.

Good Reporting Practice for Thermophysical and Thermochemical Property Measurements (IUPAC Technical Report).

Scientific projects frequently involve measurements of thermophysical, thermochemical, and other related properties of chemical compounds and materials. These measured property data have significant potential value for the scientific community, but incomplete and inaccurate reporting often hampers their utilization. The present IUPAC Technical Report summarizes the needs of chemical engineers and researchers as consumers of these data and shows how publishing practices can improve information transfer. In the Report, general principles of Good Reporting Practice are developed together with examples illustrating typical cases of reporting issues. Adoption of these principles will improve the quality, reproducibility, and usefulness of experimental data, bring a better level of consistency to results, and increase the efficiency and impact of research. Closely related to Good Reporting Practice, basic elements of Good Research Practice are also introduced with a goal to reduce the number of ambiguities and unresolved problems within the thermophysical property data domain.

Light-guided sectioning for precise in situ localization and tissue interface analysis for brain-implanted optical fibers and GRIN lenses.

Optical implants to control and monitor neuronal activity in vivo have become foundational tools of neuroscience. Standard two-dimensional histology of the implant location, however, often suffers from distortion and loss during tissue processing. To address that, we developed a three-dimensional post hoc histology method called "light-guided sectioning" (LiGS), which preserves the tissue with its optical implant in place and allows staining and clearing of a volume up to 500 µm in depth. We demonstrate the use of LiGS to determine the precise location of an optical fiber relative to a deep brain target and to investigate the implant-tissue interface. We show accurate cell registration of ex vivo histology with single-cell, two-photon calcium imaging, obtained through gradient refractive index (GRIN) lenses, and identify subpopulations based on immunohistochemistry. LiGS provides spatial information in experimental paradigms that use optical fibers and GRIN lenses and could help increase reproducibility through identification of fiber-to-target localization and molecular profiling.

Response to Comments on "Recent global decline of CO2 fertilization effects on vegetation photosynthesis".

Our study suggests that the global CO2 fertilization effect (CFE) on vegetation photosynthesis has declined during the past four decades. The Comments suggest that the temporal inconsistency in AVHRR data and the attribution method undermine the results' robustness. Here, we provide additional evidence that these arguments did not affect our finding and that the global decline in CFE is robust.

Dorsal Raphe Dopamine Neurons Signal Motivational Salience Dependent on Internal State, Expectation, and Behavioral Context.

The ability to recognize motivationally salient events and adaptively respond to them is critical for survival. Here, we tested whether dopamine (DA) neurons in the dorsal raphe nucleus (DRN) contribute to this process in both male and female mice. Population recordings of DRNDA neurons during associative learning tasks showed that their activity dynamically tracks the motivational salience, developing excitation to both reward-paired and shock-paired cues. The DRNDA response to reward-predicting cues was diminished after satiety, suggesting modulation by internal states. DRNDA activity was also greater for unexpected outcomes than for expected outcomes. Two-photon imaging of DRNDA neurons demonstrated that the majority of individual neurons developed activation to reward-predicting cues and reward but not to shock-predicting cues, which was surprising and qualitatively distinct from the population results. Performing the same fear learning procedures in freely-moving and head-fixed groups revealed that head-fixation itself abolished the neural response to aversive cues, indicating its modulation by behavioral context. Overall, these results suggest that DRNDA neurons encode motivational salience, dependent on internal and external factors.SIGNIFICANCE STATEMENT Dopamine (DA) contributes to motivational control, composed of at least two functional cell types, one signaling for motivational value and another for motivational salience. Here, we demonstrate that DA neurons in the dorsal raphe nucleus (DRN) encode the motivational salience in associative learning tasks. Neural responses were dynamic and modulated by the animal's internal state. The majority of single-cells developed responses to reward or paired cues, but not to shock-predicting cues. Additional experiments with freely-moving and head-fixed mice showed that head-fixation abolished the development of cue responses during fear learning. This work provides further characterization on the functional roles of overlooked DRNDA populations and an example that neural responses can be altered by head-fixation, which is commonly used in neuroscience.

Prepronociceptin-Expressing Neurons in the Extended Amygdala Encode and Promote Rapid Arousal Responses to Motivationally Salient Stimuli.

Motivational states consist of cognitive, emotional, and physiological components controlled by multiple brain regions. An integral component of this neural circuitry is the bed nucleus of the stria terminalis (BNST). Here, we identify that neurons within BNST that express the gene prepronociceptin (PnocBNST) modulate rapid changes in physiological arousal that occur upon exposure to motivationally salient stimuli. Using in vivo two-photon calcium imaging, we find that PnocBNST neuronal responses directly correspond with rapid increases in pupillary size when mice are exposed to aversive and rewarding odors. Furthermore, optogenetic activation of these neurons increases pupillary size and anxiety-like behaviors but does not induce approach, avoidance, or locomotion. These findings suggest that excitatory responses in PnocBNST neurons encode rapid arousal responses that modulate anxiety states. Further histological, electrophysiological, and single-cell RNA sequencing data reveal that PnocBNST neurons are composed of genetically and anatomically identifiable subpopulations that may differentially tune rapid arousal responses to motivational stimuli.

Quantifying the Farmland Application of Compost to Help Meet California's Organic Waste Diversion Law.

California's landmark waste diversion law, SB 1383, mandates the diversion of 75% of organic waste entering landfills by 2025. Much of this organic waste will likely be composted and applied to farms. However, compost is expensive and energy intensive to transport, which limits the distance that compost can be shipped. Though the diversion of organic waste from landfills in California has the potential to significantly reduce methane emissions, it is unclear if enough farmland exists in close proximity to each city for the distribution of compost. To address this knowledge gap, we develop the Compost Allocation Network (CAN), a geospatial model that simulates the production and transport of waste for all California cities and farms across a range of scenarios for per capita waste production, compost application rate, and composting conversion rate. We applied this model to answer two questions: how much farmland can be applied with municipal compost and what percentage of the diverted organic waste can be used to supplement local farmland. The results suggest that a composting system that recycles nutrients between cities and local farms has the potential to play a major role in helping California meet SB 1383 while reducing state emissions by -6.3 ± 10.1 MMT CO2e annually.

Fat embolism syndrome: Experience from an Australian trauma centre.

BACKGROUND: Fat Embolism Syndrome (FES) is a rare condition where circulating fat emboli can lead to life threatening multisystem dysfunction. Diagnosis of FES occurs mainly by exclusion. The aim of this study was to describe the injury, event details, and factors associated with the diagnosis of FES following trauma presenting to a Level 1 Trauma Centre in Melbourne, Australia. METHODS: Medical records of all patients with a complication of FES between 2006 and 2018 were retrospectively reviewed. Demographics, injury factors, hospital event details, radiological procedures and length of stay were collected. RESULTS: Thirty six patients, with median age of 26 years (IQR 19, 42) and median Injury Severity Score (ISS) of 18.5 (IQR 10, 27) were diagnosed with FES. Other associated factors included male gender (86%) and having one or more long bone fractures (97%). Of the major FES diagnostic criteria, 94% of patients experienced hypoxia, 36% had mental status changes, whereas only 11% had petechiae. Computed Tomography Pulmonary Angiogram (CTPA) was performed on 19 patients (53%) with all being negative for pulmonary embolus. Most demonstrated ground glass opacity (58%), and FES was reported as the likely cause of patient presentation in 53% of cases. CONCLUSION: FES following trauma was rare, with its diagnosis based on clinical factors including long bone fracture and hypoxia, and the exclusion of other respiratory diagnoses. CTPA was frequently used since 2008 and further research is warranted to determine if this radiological procedure can assist with more definitive diagnosis of FES.

Machine learning-guided channelrhodopsin engineering enables minimally invasive optogenetics.

We engineered light-gated channelrhodopsins (ChRs) whose current strength and light sensitivity enable minimally invasive neuronal circuit interrogation. Current ChR tools applied to the mammalian brain require intracranial surgery for transgene delivery and implantation of fiber-optic cables to produce light-dependent activation of a small volume of tissue. To facilitate expansive optogenetics without the need for invasive implants, our engineering approach leverages the substantial literature of ChR variants to train statistical models for the design of high-performance ChRs. With Gaussian process models trained on a limited experimental set of 102 functionally characterized ChRs, we designed high-photocurrent ChRs with high light sensitivity. Three of these, ChRger1-3, enable optogenetic activation of the nervous system via systemic transgene delivery. ChRger2 enables light-induced neuronal excitation without fiber-optic implantation; that is, this opsin enables transcranial optogenetics.

Optical dopamine monitoring with dLight1 reveals mesolimbic phenotypes in a mouse model of neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder whose neurodevelopmental symptoms include impaired executive function, attention, and spatial learning and could be due to perturbed mesolimbic dopaminergic circuitry. However, these circuits have never been directly assayed in vivo. We employed the genetically encoded optical dopamine sensor dLight1 to monitor dopaminergic neurotransmission in the ventral striatum of NF1 mice during motivated behavior. Additionally, we developed novel systemic AAV vectors to facilitate morphological reconstruction of dopaminergic populations in cleared tissue. We found that NF1 mice exhibit reduced spontaneous dopaminergic neurotransmission that was associated with excitation/inhibition imbalance in the ventral tegmental area and abnormal neuronal morphology. NF1 mice also had more robust dopaminergic and behavioral responses to salient visual stimuli, which were independent of learning, and rescued by optogenetic inhibition of non-dopaminergic neurons in the VTA. Overall, these studies provide a first in vivo characterization of dopaminergic circuit function in the context of NF1 and reveal novel pathophysiological mechanisms.

Electrospinning of Cellulose Nanocrystal-Filled Poly (Vinyl Alcohol) Solutions: Material Property Assessment.

Poly (vinyl alcohol) (PVA) and cellulose nanocrystals (CNC) random composite mats were prepared using the electrospinning method. PVA/CNC mats were reinforced with weight concentrations of 0, 20 and 50% CNC (w/w) relative to PVA. Scanning electron microscopy was used to measure the fiber diameter, which ranged from 377 to 416 nm. Thermogravimetric analysis (TGA) confirmed the presence of CNC fibers in the mat fibers which were not visible by scanning electron microscope (SEM). Mechanical testing was conducted using ASTM D 638 on each sample group at 10 mm min-1. Neat PVA and PVA/CNC mats were heat treated at 170 °C for 2h hours, and the morphological structure was maintained with some fiber diameter reduction. Mechanical property results after heat treatment showed a decrease in tensile strength, an increase in tensile stiffness and a decrease in strain to yield (%). This effect was attributable to enhanced diffusion bonding of the mat fiber intersections. The CNC fibers also increased mat stiffness, and reduced strain to yield in non-treated mats. The use of CNCs show potential for compounding into bulk polymer composites as a reinforcement filler, and also show promise for chemical crosslinking attributable to the -OH groups on both the PVA, in addition to esterification of the vinyl group, and CNC.

Large Pockels effect in micro- and nanostructured barium titanate integrated on silicon.

The electro-optical Pockels effect is an essential nonlinear effect used in many applications. The ultrafast modulation of the refractive index is, for example, crucial to optical modulators in photonic circuits. Silicon has emerged as a platform for integrating such compact circuits, but a strong Pockels effect is not available on silicon platforms. Here, we demonstrate a large electro-optical response in silicon photonic devices using barium titanate. We verify the Pockels effect to be the physical origin of the response, with r42 = 923 pm V-1, by confirming key signatures of the Pockels effect in ferroelectrics: the electro-optic response exhibits a crystalline anisotropy, remains strong at high frequencies, and shows hysteresis on changing the electric field. We prove that the Pockels effect remains strong even in nanoscale devices, and show as a practical example data modulation up to 50 Gbit s-1. We foresee that our work will enable novel device concepts with an application area largely extending beyond communication technologies.

Surface chemistry of the frog sticky-tongue mechanism.

Frogs capture their prey with a highly specialized tongue. Recent studies indicate this tongue is covered with fibril-forming mucus that acts as a pressure sensitive adhesive. However, no analysis of the interfacial chemistry of frog tongue mucus has been performed. The goal of this study is to examine the chemical structure of the surface of mucus after a tongue strike. Previous studies of mucus from other animals suggest that mucus from a frog's tongue consists of mucins-serine-, threonine-, and proline-rich glycoproteins. Therefore, the authors expect to observe chemical bonds associated with glycoproteins, as well as fibrils formed at the mucus-tongue interface. To test this hypothesis, they collected both near-edge x-ray absorption fine structure (NEXAFS) microscopy images and sum frequency generation (SFG) vibrational spectra from layers of mucus left after frog tongue strikes on cleaned glass slides. NEXAFS imaging demonstrates a uniform distribution of amide, hydroxyl, and carbon-carbon bonds across the mucus surface. Difference spectra of individual N1s and C1s K-edge spectra pulled from these images indicate a structure consistent with fibril formation as well as disorder of oligosaccharide groups near the mucus surface. C-H region SFG spectra reveal surface active modes which likely stem from serine and threonine within the mucin protein. Combined, this work suggests that glycoproteins are well-ordered at the mucus-tongue interface.

Quantum Confinement in Oxide Heterostructures: Room-Temperature Intersubband Absorption in SrTiO3/LaAlO3 Multiple Quantum Wells.

The Si-compatibility of perovskite heterostructures offers the intriguing possibility of producing oxide-based quantum well (QW) optoelectronic devices for use in Si photonics. While the SrTiO3/LaAlO3 (STO/LAO) system has been studied extensively in the hopes of using the interfacial two-dimensional electron gas in Si-integrated electronics, the potential to exploit its giant 2.4 eV conduction band offset in oxide-based QW optoelectronic devices has so far been largely ignored. Here, we demonstrate room-temperature intersubband absorption in STO/LAO QW heterostructures at energies on the order of hundreds of meV, including at energies approaching the critically important telecom wavelength of 1.55 µm. We demonstrate the ability to control the absorption energy by changing the width of the STO well layers by a single unit cell and present theory showing good agreement with experiment. A detailed structural and chemical analysis of the samples via scanning transmission electron microscopy and electron energy loss spectroscopy is presented. This work represents an important proof-of-concept for the use of transition metal oxide QWs in Si-compatible optoelectronic devices.

Dopaminergic dysfunction in neurodevelopmental disorders: recent advances and synergistic technologies to aid basic research.

Neurodevelopmental disorders (NDDs) represent a diverse group of syndromes characterized by abnormal development of the central nervous system and whose symptomatology includes cognitive, emotional, sensory, and motor impairments. The identification of causative genetic defects has allowed for creation of transgenic NDD mouse models that have revealed pathophysiological mechanisms of disease phenotypes in a neural circuit- and cell type-specific manner. Mouse models of several syndromes, including Rett syndrome, Fragile X syndrome, Angelman syndrome, Neurofibromatosis type 1, etc., exhibit abnormalities in the structure and function of dopaminergic circuitry, which regulates motivation, motor behavior, sociability, attention, and executive function. Recent advances in technologies for functional circuit mapping, including tissue clearing, viral vector-based tracing methods, and optical readouts of neural activity, have refined our knowledge of dopaminergic circuits in unperturbed states, yet these tools have not been widely applied to NDD research. Here, we will review recent findings exploring dopaminergic function in NDD models and discuss the promise of new tools to probe NDD pathophysiology in these circuits.

A 3D-printed modular device for imaging the brain of small birds.

BACKGROUND: One potential barrier to using in vivo imaging in any new animal species is solving the basic problem of how to hold animals safely and securely during scans. NEW METHOD: In this paper, we describe the design, fabrication, use, and positional reproducibility of a 3D-printed plastic device (the Avian Imaging Device, or AID) for imaging the brain of 1 or 2 small songbirds. We designed two different types of head cones to use with this device: one that was not contoured and designed for anesthesia induction, and one contoured to the shape of a house sparrow head, designed to be used with a pre-anesthetized animal. RESULTS: Compared to no holder, using the AID with both contoured and non-contoured head cones significantly reduced the amount of translation necessary to align the head in pairs of CT scans (by 78% and 90%, respectively); using the contoured head cone also significantly reduced the amount of rotation necessary for head alignment in registering pairs of scans (by 90%). COMPARISON WITH EXISTING METHOD(S): Using an animal holder that can not only securely hold animals but which has high positional reproducibility is essential to take advantage of the maximum resolution possible with small animal imaging. 3D-printed materials are also compatible with PET and CT, environmentally stable, and fast and inexpensive to make. CONCLUSIONS: Researchers can learn from the design of the AID and use our CAD models as a starting point for fabricating devices for multiple small-animal imaging needs.