Miracle-dz/UniFAR-FTUs huggingface dataset:
ACKR3–arrestin2/3 complexes reveal molecular consequences of GRK-dependent barcoding

Atypical chemokine receptor 3 (ACKR3, also known as CXCR7) is a scavenger receptor that regulates extracellular levels of the chemokine CXCL12 to maintain responsiveness of its partner, the G protein-coupled receptor (GPCR), CXCR4. ACKR3 is notable because it does not couple to G proteins and instead is completely biased towards arrestins. Our previous studies revealed that GRK2 and GRK5 install distinct distributions of phosphates (or “barcodes”) on the ACKR3 carboxy terminal tail, but how these unique barcodes drive different cellular outcomes is not understood. It is also not known if arrestin2 (Arr2) and 3 (Arr3) bind to these barcodes in distinct ways. Here we report cryo-electron microscopy structures of Arr2 and Arr3 in complex with ACKR3 phosphorylated by either GRK2 or GRK5. Unexpectedly, the finger loops of Arr2 and 3 directly insert into the detergent/membrane instead of the transmembrane core of ACKR3, in contrast to previously reported “core” GPCR–arrestin complexes. The distance between the phosphorylation barcode and the receptor transmembrane core regulates the interaction mode of arrestin, alternating between a tighter complex for GRK5 sites and heterogenous primarily “tail only” complexes for GRK2 sites. Arr2 and 3 bind at different angles relative to the core of ACKR3, likely due to differences in membrane/micelle anchoring at their C-edge loops. Our structural investigations were facilitated by Fab7, a novel Fab that binds both Arr2 and 3 in their activated states irrespective of receptor or phosphorylation status, rendering it a potentially useful tool to aid structure determination of any native GPCR–arrestin complex. The structures provide unprecedented insight into how different phosphorylation barcodes and arrestin isoforms can globally affect the configuration of receptor–arrestin complexes. These differences may promote unique downstream intracellular interactions and cellular responses. Our structures also suggest that the 100% bias of ACKR3 for arrestins is driven by the ability of arrestins, but not G proteins, to bind GRK-phosphorylated ACKR3 even when excluded from the receptor cytoplasmic binding pocket.
Neural networks with optimized single-neuron adaptation uncover biologically plausible regularization

Neurons in the brain have rich and adaptive input-output properties. Features such as heterogeneous f-I curves and spike frequency adaptation are known to place single neurons in optimal coding regimes when facing changing stimuli. Yet, it is still unclear how brain circuits exploit single-neuron flexibility, and how network-level requirements may have shaped such cellular function. To answer this question, a multi-scaled approach is needed where the computations of single neurons and neural circuits must be considered as a complete system. In this work, we use artificial neural networks to systematically investigate single-neuron input-output adaptive mechanisms, optimized in an end-to-end fashion. Throughout the optimization process, each neuron has the liberty to modify its nonlinear activation function, parametrized to mimic f-I curves of biological neurons, and to learn adaptation strategies to modify activation functions in real-time during a task. We find that such networks show much-improved robustness to noise and changes in input statistics. Importantly, we find that this procedure recovers precise coding strategies found in biological neurons, such as gain scaling and fractional order differentiation/integration. Using tools from dynamical systems theory, we analyze the role of these emergent single-neuron properties and argue that neural diversity and adaptation play an active regularization role, enabling neural circuits to optimally propagate information across time.
Single cell RNA analysis uncovers the cell differentiation trajectories and functionalization for air breathing of frog lung

The evolution and development of vertebrate lungs have received extensive concerns for the significance in terrestrial adaptation. Amphibians possess the most primitive lungs among tetrapods, underscoring the evolutionary importance of lungs in bridging the transition from aquatic to terrestrial life. However, the intricate process of cell differentiation during amphibian lung development is still lacking. Using single cell RNA-seq, we identified 21 cell types in the developing lung of a land-dwelling frog (Microhyla fissipes). We elucidated that single type of alveolar epithelial cells (AECs) existed in amphibian and the diversity of AECs may correspond to the capacity for terrestrial adaptation in tetrapods. Based on pseudotime trajectories analysis, we revealed previously unrecognized developmental-specific transition cell states of epithelial and endothelial cells supporting the rapid morphogenesis of lung during metamorphic climax. We illustrated the cellular and molecular processes during lung functionalization. These findings uncover the cell differentiation trajectories and functionalization for air breathing of frog lungs and highlight the evolutionary peculiarity of the primitive lungs. Graphical abstract
Taxonomy of Pseudomonas spp determines interactions with Bacillus subtilis

Bacilli and pseudomonads are among the most well-studied microorganisms commonly found in soil, and frequently co-isolated. Despite this, no systematic approach has been employed to assess the pairwise compatibility of members from these genera. Here, we screened 720 fluorescent soil isolates for their effects on Bacillus subtilis pellicle formation in two types of media and found a predictor for interaction outcome in Pseudomonas taxonomy. Interactions were context-dependent and both medium composition and culture conditions strongly influenced interactions. Negative interactions were associated with Pseudomonas capeferrum, Pseudomonas entomophila and Pseudomonas protegens, and 2,4-diacetylphloroglucinol was confirmed as a strong (but not exclusive) inhibitor of B. subtilis. Non-inhibiting strains were closely related to Pseudomonas trivialis and Pseudomonas lini, but in this case, cocultures with increased B. subtilis pellicle formation were spatially segregated. Our study is the first to propose an overall negative outcome from pairwise interactions between B. subtilis and fluorescent pseudomonads, hence cocultures comprising members from these groups are likely to require additional microorganisms for coexistence.
Model connectivity: leveraging the power of encoding models to overcome the limitations of functional connectivity

Functional connectivity (FC) is the most popular method for recovering functional networks of brain areas with fMRI. However, because FC is defined as temporal correlations in brain activity, FC networks are confounded by noise and lack a precise functional role. To overcome these limitations, we developed model connectivity (MC). MC is defined as similarities in encoding model weights, which quantify reliable functional activity in terms of interpretable stimulus- or task-related features. To compare FC and MC, both methods were applied to a naturalistic story listening dataset. FC recovered spatially broad networks that are confounded by noise, and that lack a clear role during natural language comprehension. By contrast, MC recovered spatially localized networks that are robust to noise, and that represent distinct categories of semantic concepts. Thus, MC is a powerful data-driven approach for recovering and interpreting the functional networks that support complex cognitive processes.
Drosophila axis extension is robust to an orthogonal pull by invaginating mesoderm

As tissues grow and change shape during animal development, they physically pull and push on each other and these mechanical interactions can be important for morphogenesis. During Drosophila gastrulation, mesoderm invagination temporally overlaps with the extension of the ectodermal germband; the latter is caused primarily by Myosin II-driven polarised cell intercalation. Here we investigate the impact of mesoderm invagination on ectoderm extension, examining possible mechanical and mechanotransductive effects on Myosin II recruitment and polarised cell intercalation. We find that the germband ectoderm is deformed by the mesoderm pulling in the orthogonal direction, showing mechanical coupling between these tissues. However, we do not find a significant change in Myosin II planar polarisation in response to mesoderm invagination, nor an effect on the rate of junction shrinkage leading to cell intercalation events. We find some impact on the orientation of neighbour exchange events, and an increased rate of growth of new cell junctions, but this makes little difference to the rate of cell intercalation. We conclude that the cellular mechanisms of axis extension are robust to the mechanical pull of mesoderm invagination.
Beyond Traditional Methods: Innovative Integration of LISS IV and Sentinel 2A Imagery for Unparalleled Insight into Himalayan Ibex Habitat Suitability

Despite advancements in remote sensing, satellite imagery is underutilized in conservation research. Multispectral data from various sensors have great potential for mapping landscapes, but distinct spectral and spatial resolution capabilities are crucial for accurately classifying wildlife habitats. Our study aimed to develop a technique for precisely discerning habitat categories for the Himalayan Ibex (Capra sibirica) using different satellite imagery. To address both spectral and spatial challenges, we utilized LISS IV and Sentinel 2A data and integrated the LISS IV data with Sentinel 2A data along with their corresponding geometric information. Employing multiple supervised classification algorithms, we found the Random Forest (RF) algorithm to outperform others. The integrated (LISS IV-Sentinel 2A) classified image achieved the highest accuracy, with an overall accuracy of 86.17% and a Kappa coefficient of 0.84. To map the suitable habitat of the Ibex, we conducted ensemble modeling using the Land Cover Land Use (LCLU) of all three image types (LISS IV, Sentinel 2A, Integrated) and other predictors such as topographical, soil type, vegetation, and water radiometric indices. The integrated model provided the most accurate prediction of suitable habitat for the Ibex, surpassing the other two LCLU classes derived from individual images. The Soil Adjusted Vegetation Index (SAVI) and elevation were identified as crucial factors in identifying suitable habitats These findings hold valuable implications for the development of effective conservation strategies, as accurate classification schemes enable the identification of vital landscape elements. By precisely classifying LULC satellite images and identifying crucial habitats for the Ibex, this pilot study provides a new and valuable strategy for conservation planning. It enhances our ability to preserve and protect the habitat of wildlife species in the mountain ecosystem of the Himalayas.
Theta cycle dynamics of spatial representations in the lateral septum

An internal representation of the environment – or map – allows animals to evaluate multiple routes and adapt their navigation strategy to current needs and future goals. The hippocampal formation plays a crucial role in learning a spatial map and using the map for goal-directed navigation. The lateral septum forms a major node for connections between the hippocampus and subcortical brain regions that could link the spatial map to motivation and reward processing centers such as the ventral tegmental area and hypothalamus. It is not known, however, how the lateral septum contributes to the processing of spatial information and route planning. In this study, we investigated the temporal dynamics of spatial representations in the lateral septum. Neuropixels probes were used to record cellular activity along the dorsal-ventral extent of the lateral septum while rats performed one of two spatial navigation tasks in a Y-maze. The activity of a large fraction of cells was theta rhythmic and a subset of cells showed evidence of being active on alternate theta cycles (theta cycle skipping). Both theta rhythmicity and cycle skipping were strongest in the dorsal lateral septum. Similarly, spatially selective firing was most prominent in the dorsal lateral septum. Using neural decoding, we show that the lateral septum cell population encodes both the current location and alternatingly the possible future paths within single theta cycles when rats approach the choice point in the maze. Our data further shows that the alternating expression of spatial representations in the lateral septum is task-dependent, such that it is strongest when the task also requires the animals to alternate between rewarded goal arms. These data suggest that task demands and experience shape which representations are activated near a choice point. The lateral septum receives strong input from hippocampal place cells, and while there may be integration and transformation of incoming spatial signals, our findings support the idea that hippocampal spatial representations and their temporal dynamics are conveyed to subcortical projection areas through the lateral septum.
Development of potent dual BET/HDAC inhibitors via pharmacophore merging and structure-guided optimization

Bromodomain and extra-terminal motif (BET) proteins and histone deacetylases (HDACs) are prime targets in cancer therapy. Recent research has particularly focused on the development of dual BET/HDAC inhibitors for hard-to-treat tumors such as pancreatic cancer. Here, we have developed a new series of potent dual BET/HDAC inhibitors by choosing starting scaffolds that enabled us to optimally merge the two functionalities into a single compound. Systematic structure-guided modification of both warheads then led to optimized binders that were superior in potency to both parent compounds, with the best molecules of this series binding to both BRD4 bromodomains as well as HDAC1/2 with EC50 values in the 100-nanomolar range in cellular NanoBRET target engagement assays. Importantly, this on-target activity also translated into promising efficacy in pancreatic cancer and NUT midline carcinoma cells. Our lead molecules effectively blocked histone H3 deacetylation in pancreatic cancer cells and upregulated the tumor suppressor HEXIM1 and proapoptotic p57, both markers of BET inhibition. In addition, they have the potential to downregulate oncogenic drivers of NUT midline carcinoma, as demonstrated for MYC and TP63 mRNA levels. Overall, this study expands the portfolio of available dual BET/class I HDAC inhibitors for future translational studies in different cancer models.
Internal waves in fluid flows. Possible coexistence with turbulence

Waves in fluid flows represents the underlying theme of this research work. Wave interactions in fluid flows are part of multidisciplinary physics. It is known that many ideas and phenomena recur in such apparently diverse fields, as solar physics, meteorology, oceanography, aeronautical and hydraulic engineering, optics, and population dynamics. In extreme synthesis, waves in fluids include, on the one hand, surface and internal waves, their evolution, interaction and associated wave-driven mean flows; on the other hand, phenomena related to nonlinear hydrodynamic stability and, in particular, those leading to the onset of turbulence. Close similarities and key differences exist between these two classes of phenomena. In the hope to get hints on aspects of a potential overall vision, this study considers two different systems located at the opposite limits of the range of existing physical fluid flow situations: first, sheared parallel continuum flows - perfect incompressibility and charge neutrality - second, the solar wind - extreme rarefaction and electrical conductivity. Therefore, the activity carried out during the doctoral period consists of two parts. The first is focused on the propagation properties of small internal waves in parallel flows. This work was partly carried out in the framework of a MISTI-Seeds MITOR project proposed by Prof. D. Tordella (PoliTo) and Prof. G. Staffilani (MIT) on the long term interaction in fluid flows. The second part regards the analysis of solar-wind fluctuations from in situ measurements by the Voyagers spacecrafts at the edge of the heliosphere. This work was supported by a second MISTI-Seeds MITOR project, proposed by D. Tordella (PoliTo), J. D. Richardson (MIT, Kavli Institute), with the collaboration of M. Opher (BU).
Challenges in active particles methods: Theory and applications

This paper is a brief introduction to the mathematical tools employed in the modeling and simulation of the interactions of a large number of living entities, and provides a presentation of the papers published in a special issue devoted to this topic. In addition, we bring to the reader’s attention some perspective ideas on possible objectives of future researches.
Very-Low-Birthweight Neonates: Do Outcomes Differ in Multiple Compared with Singleton Gestations?

The purpose of this study is to determine if outcomes for very-low-birthweight (VLBW) neonates differ in multiple versus singleton gestations. This is a retrospective cohort study of neonates weighing less than 1500 g admitted to a neonatal intensive care unit from 1993 to 2004. Outcome variables were necrotizing enterocolitis, death, and/or severe intraventricular hemorrhage (IVH). Statistical analysis included univariate and multivariate analysis. During the study period, 1769 VLBW infants including 465 multiples and 1304 singletons were identiﬁed. Gestational age and birthweight were similar; conversely white race (68% multiples versus 43% singletons), maternal age (28.7 (cid:1) 5.7 versus 26.1 (cid:1) 6.5 years), born at facility (95% versus 86%), antenatal steroids (74% versus 58%), preeclampsia (14% versus 24%), and preterm labor (74% versus 62%) were signiﬁcantly different. Correcting for these, VLBW multiples had a higher odds ratio (OR) of death and/or severe IVH, OR 1.4 (1.03–1.95). In our population, VLBW multiple gestations were at elevated odds for death and/or severe IVH compared with VLBW singletons.
Optimal Brownian Stopping between radially symmetric marginals in general dimensions

Given an initial (resp., terminal) probability measure $\mu$ (resp., $\nu$) on $\mathbb{R}^d$, we characterize those optimal stopping times $\tau$ that maximize or minimize the functional $\mathbb{E} |B_0 - B_\tau|^{\alpha}$, $\alpha > 0$, where $(B_t)_t$ is Brownian motion with initial law $B_0\sim \mu$ and with final distribution --once stopped at $\tau$-- equal to $B_\tau\sim \nu$. The existence of such stopping times is guaranteed by Skorohod-type embeddings of probability measures in "subharmoic order" into Brownian motion. This problem is equivalent to an optimal mass transport problem with certain constraints, namely the optimal subharmonic martingale transport. Under the assumption of radial symmetry on $\mu$ and $\nu$, we show that the optimal stopping time is a hitting time of a suitable barrier, hence is non-randomized and is unique.
The 30-Minute Decision-to-Incision Interval for Emergency Cesarean Delivery: Fact or Fiction?

The objective of this study was to evaluate the effect of the current guideline of 30-minute decision-to-incision interval (D-I) in emergent cesarean delivery (ECD) on neonatal and maternal outcomes. A retrospective chart review was conducted of pregnant women who underwent ECDs between January 1999 and December 2001. The overall median D-I was 20 minutes (range, 5 to 57 minutes). In 83 women (group I), D-I was 4 30 minutes, and in 28 women (group II), it exceeded 30 minutes. Group I had more neonates with cord pH < 7.00, seizures, encephalopathy, and lower Apgar scores at 1 and 5 minutes than group II, but were not statistically signiﬁcant. There was no signiﬁcant difference in neonatal admission to the neonatal intensive care unit or length of stay between the two groups. Maternal complications were higher in group I, but not statistically signiﬁcant. Although it was achieved in most of the ECDs, the guideline of 30-minute D-I does not seem to improve neonatal nor worsen maternal outcomes.
Oxytocin Receptor Blockade: A New Principle in the Treatment of Preterm Labor?

The concentration of myometrial and decidual oxytocin receptors increases dramatically in normal women in late pregnancy, causing enhanced uterine sensitivity to physiologic levels of oxytocin. Similar increase in myometrial oxytocin receptors has been found in women in preterm labor, indicating a role for oxytocin also in idiopathic preterm labor. A newly synthesized oxytocin analogue, 1-deamino-2-D-Tyr-(OEt)-4-Thr- 8-Orn-oxytocin, has been found to be a competitive inhibitor of oxytocin. The present study was conducted to test its efficacy in suppressing uterine contractions during preterm labor in women. Twelve patients with established, uncomplicated preterm labor between 27 and 33 weeks of gestational age were given intravenous infusions of the analogue for 1.5 to 13 hours during continuous external cardiotocographic monitoring. In nine patients inhibition of uterine contractions was achieved and further progression in cervical scores was arrested. In three patients, all at 27 weeks of gestational age, no significant tocolytic effect was observed during a 1.5-hour infusion of the analogue and the patients were then given ritodrine intravenously. No side effects were observed in any of the patients. These preliminary findings support the concept that an increased concentration of uterine oxytocin receptors is an important etiologic factor in uncomplicated preterm labor and therefore oxytocin receptor blockade may be a therapeutic alternative for this condition.
Rapid Mechanical Ventilation Effects on Tracheal Airway Pressure, Lung Volume, and Blood Gases of Rabbits

The purpose of this study was to demonstrate that ventilation of rabbit lungs (whose mechanics are similar to those of human infants) at rapid rates will lead to large alterations in tracheal airway pressures, tidal volume, and functional residual capacity (FRC) with only minor changes in arterial blood gases. Thirteen rabbits were ventilated at rates of 30, 60, 90, and 120 breaths per minutes (BPM) with pressures of 17/2 cm H 2 O. Tracheal peak inspiratory pressure (PIP) was always lower than ventilator PIP and decreased to 11 ± 1 cm H 2 O at 120 BPM. Positive end-expiratory pressure (PEEP) in the trachea was always greater than 2 cm H 2 O and increased with rate (3.5 cm H 2 O at 120 BPM). Tidal volume decreased as rates were increased such that rates above 60 BPM resulted in insignificant changes in minute ventilation and arterial blood gases. However, the FRC increased from 16 (30 BPM) to 25 ml/kg (120 BPM), a 56% increase, suggesting large increases in end-expiratory alveolar pressure. We conclude that rapid-rate ventilation (> 60 BPM) of healthy rabbits results in significant increases in both tracheal PEEP and FRC without significantly affecting arterial blood gases. The increased tracheal PEEP and FRC are manifestations of inadvertent PEEP. The increased FRC without concomitant increase in PaO 2 implicates alveolar overdistention. We speculate that rapid-rate ventilation of human infants having lung mechanics similar to rabbits, will also result in inadvertent PEEP and alveolar overdistention.