Representations and generalization in artificial and brain neural networks.

Humans and animals excel at generalizing from limited data, a capability yet to be fully replicated in artificial intelligence. This perspective investigates generalization in biological and artificial deep neural networks (DNNs), in both in-distribution and out-of-distribution contexts. We introduce two hypotheses: First, the geometric properties of the neural manifolds associated with discrete cognitive entities, such as objects, words, and concepts, are powerful order parameters. They link the neural substrate to the generalization capabilities and provide a unified methodology bridging gaps between neuroscience, machine learning, and cognitive science. We overview recent progress in studying the geometry of neural manifolds, particularly in visual object recognition, and discuss theories connecting manifold dimension and radius to generalization capacity. Second, we suggest that the theory of learning in wide DNNs, especially in the thermodynamic limit, provides mechanistic insights into the learning processes generating desired neural representational geometries and generalization. This includes the role of weight norm regularization, network architecture, and hyper-parameters. We will explore recent advances in this theory and ongoing challenges. We also discuss the dynamics of learning and its relevance to the issue of representational drift in the brain.

Practice efficiency and total cost of care with bispecifics and CAR-T in relapsed/refractory diffuse large B-cell lymphoma: an institutional perspective1.

Aim: Novel treatment options for relapsed/refractory diffuse large B-cell lymphoma include T-cell targeting therapies. Practice efficiency and cost are important for informed treatment decisions. Materials/methods: An institutional decision-maker cost model was developed for 6-month, 1-year and median cycles of treatment time horizons comparing practice efficiency and costs of epcoritamab vs glofitamab and axicabtagene ciloleucel (axi-cel). Results: Overall, epcoritamab required the shortest personnel and chair time, except over 1 year (second shortest chair time). Across all time horizons, epcoritamab was cost-saving vs axi-cel and had similar costs to glofitamab on a per-month basis. Conclusion: Epcoritamab reduced personnel and chair time. Additionally, epcoritamab was cost-saving vs axi-cel and had similar costs to glofitamab on a per-month basis.

There are new ways to treat diffuse large B-cell lymphoma, which is a type of cancer called lymphoma. When new treatments are available it is important to see if they take more or less time to give to patients and how much they cost versus other treatments. This study looked at three drugs used to treat diffuse large B-cell lymphoma, including epcoritamab, axi-cel and glofitamab. It estimated the time and cost with those treatments in patients who get them for 6 months, 1 year or for the most common length of time in the clinical trials. In most of the scenarios, epcoritamab had the least time needed for nurses or doctors and the least time needed for a patient to be in a chair in a clinic. When thinking about the cost per month, epcoritamab saved money versus axi-cel and was similar to glofitamab.

Olea europaea leaf exosome-like nanovesicles encapsulated in a hyaluronic acid / tannic acid hydrogel dressing with dual "defense-repair" effects for treating skin photoaging.

Photoaging, primarily caused by ultraviolet (UV) light, is the major factor in extrinsic skin aging. Existing anti-photoaging strategies mainly focus on early sun protection or repairing damaged skin, lacking a comprehensive treatment strategy. Therefore, this study developed a dressing that actively shields against UV radiation and repairs photoaged skin, offering double protection. This study utilized exosome-like nanovesicles derived from Olea europaea leaves (OLELNVs), enhancing them into a potent core biomaterial with high-dose effects and skin-friendly, non-cytotoxic inhibition of cell aging. These nanovesicles were incorporated into a cross-linked hyaluronic acid (HA) and tannic acid (TA) hydrogel with strong UV-absorbing properties, creating the OLELNVs@HA/TA hydrogel system. In vitro and in vivo experiments demonstrated that OLELNVs@HA/TA hydrogel can effectively reduce UV-induced skin damage and promote skin repair and regeneration. Additionally, RNA-seq and clustering analysis of miR168a-5p predicted targets revealed significant down-regulation of the NF-κB signaling pathway, mediating inflammatory aging responses. Overall, the OLELNVs@HA/TA hydrogel represents a novel dual-strategy approach for clinical application in combating photoaging.

Reliable biological and multi-omics research through biometrology.

Metrology is the science of measurement and its applications, whereas biometrology is the science of biological measurement and its applications. Biometrology aims to achieve accuracy and consistency of biological measurements by focusing on the development of metrological traceability, biological reference measurement procedures, and reference materials. Irreproducibility of biological and multi-omics research results from different laboratories, platforms, and analysis methods is hampering the translation of research into clinical uses and can often be attributed to the lack of biologists' attention to the general principles of metrology. In this paper, the progresses of biometrology including metrology on nucleic acid, protein, and cell measurements and its impacts on the improvement of reliability and comparability in biological research are reviewed. Challenges in obtaining more reliable biological and multi-omics measurements due to the lack of primary reference measurement procedures and new standards for biological reference materials faced by biometrology are discussed. In the future, in addition to establishing reliable reference measurement procedures, developing reference materials from single or multiple parameters to multi-omics scale should be emphasized. Thinking in way of biometrology is warranted for facilitating the translation of high-throughput omics research into clinical practices.

Full-term pregnancy with retroperitoneal giant mucinous cyst: A case report and literature review.

RATIONALE: Retroperitoneal benign cysts during pregnancy are extremely rare and often remain asymptomatic until they attain a very large size. Diagnosis typically relies on a pathological tissue biopsy. The decision to pursue 1-step or 2-step surgical treatment should be tailored to each individual case rather than generalized. PATIENT CONCERNS: This case report presents the unique scenario of a pregnant woman with a confirmed pregnancy complicated by a large retroperitoneal cyst. The patient had a retroperitoneal cyst during her initial pregnancy, which went undetected during the first cesarean section. However, it was identified during her second pregnancy by which time it had grown to 13.0 cm × 15.0 cm × 25.0 cm, and extended from the liver margin to right ovarian pelvic infundibulopelvic ligament. Consequently, it was removed smoothly during her second cesarean section. DIAGNOSES: Postoperative pathology results indicated a massive retroperitoneal mucinous cystadenoma. INTERVENTIONS: The giant retroperitoneal cyst was smoothly excised during the second cesarean delivery for 1-step surgical treatment. OUTCOMES: Under the combined spinal and epidural anesthesia, a live female infant was delivered at 38 3/7 gestational weeks and the neonatal weight was 3200g. Under general anesthesia with endotracheal intubation, the giant retroperitoneal cyst was excised smoothly without complications. LESSONS: The findings of this case report contribute to the understanding of the diagnostic modalities, surgical approaches and postoperative considerations of giant retroperitoneal cysts associated with pregnancy.

Investigation of the correlation between the change in the projected lung area and forced vital capacity using biphasic chest dynamic digital radiography: a cross-sectional study.

Background: Chest dynamic digital radiography (DDR) is used as a supplementary tool for the routine pulmonary function test (PFT); however, its potential as a novel standard PFT method has yet to be explored. Therefore, the present study aimed to investigate the correlation between the change in the projected lung area (ΔPLA) and forced vital capacity (FVC) using chest DDR, and to establish a DDR-FVC estimation model and a predictive value model for the ΔPLA. Methods: In total, 139 participants who underwent chest DDR and the PFT in the same period at The First Affiliated Hospital of Guangzhou Medical University from April 2022 to February 2023 were prospectively included in the study. The patients' age, gender, height, and weight measurements were recorded. Additionally, the ΔPLA was measured, and the IWS workstation software was used for automated outlining and calculation. Subsequently, a correlation analysis and regression analysis models were employed to examine the relationship between the ΔPLA, FVC, and individual physiological characteristics. Additionally, an independent sample t-test was used to determine whether there were any significant differences between the normal and abnormal FVC groups. Results: The 139 participants were grouped according to the results of the ratio of measured/predicted FVC values (FVC%pred); those with an FVC%pred ≥80%, were allocated to the normal FVC group, and those with an FVC%pred <80% were allocated to the abnormal FVC group. The correlation coefficient was >0.8 in the full sample; the ΔPLA showed a significant linear correlation with the measured FVC value [r=0.81, 95% confidence interval (CI): 0.75-0.86, P<0.001]. There was a significant difference in the ΔPLA between the normal and abnormal FVC groups. With the ΔPLA, age, gender, height, and weight as predictor variables, the following DDR-FVC estimation model was established: DDR-FVC estimation model = -0.997 + 1.35×10-4 × ΔPLA + 0.017 × height - 0.014 × age + 0.249 × gender (1 for male and 0 for female) [adjusted R2 (adj. R2)=0.731, F=94.615, P<0.001]. The following formula was used to determine the predictive value of the ΔPLA: Predictive value of ΔPLA = -12,504.287 + 173.185 × height + 62.971 × weight - 84.933 × age (adj. R2=0.393, F=20.453, P<0.001). Conclusions: There was a linear correlation between the ΔPLA measured by biphasic chest DDR and the FVC. A model for estimating the FVC was established based on the ΔPLA, which allows the FVC to be assessed by the ΔPLA measured by biphasic chest DDR. A predictive value model for the ΔPLA was also established to provide ΔPLA reference values for assessment and comparison.

Liraglutide does not increase heart rate of diabetic patients during acute myocardial infarction.

BACKGROUND: Glucagon-like peptide 1 receptor agonists have been shown to reduce all-cause and cardiovascular mortality in patients with Type 2 diabetes mellitus (T2DM). The probable increase in heart rate hinders its early usage in acute myocardial infarction patients. In our study, we aimed to find out whether the use of liraglutide in patients with acute myocardial infarction as early as at the time of hospitalization would increase the heart rate. METHODS: This was an observational retrospective study. From December 2020 to August 2021, 200 patients with acute myocardial infarction were included in our study and divided into three groups: T2DM + liraglutide group (n = 46), T2DM + non-liraglutide group (n = 42), and non-T2DM group (n = 112). The primary outcomes were the differences in heart rate. Secondary outcomes were differences in systolic and diastolic blood pressure. RESULTS: There were no significant differences in heart rate among the three groups at admission, the day before the first shot of liraglutide, and before discharge. There was also no significant difference in heart rate between diabetic patients with acute myocardial infarction and those on liraglutide during the hospital stay. And there were no differences of beta-blocker dosages among the three groups. Liraglutide did not affect the blood pressure during acute myocardial infarction. CONCLUSIONS: Liraglutide did not increase the heart rate in diabetic patients during acute myocardial infarction and did not lead to an increase in the dose of beta-blockers in the patients. It also had no effect on blood pressure and showed better efficacy in lowering glucose levels without additional hypoglycemic events.

A single dose of ketamine relieves fentanyl-induced-hyperalgesia by reducing inflammation initiated by the TLR4/NF-κB pathway in rat spinal cord neurons.

A large amount of clinical evidence has revealed that ketamine can relieve fentanyl-induced hyperalgesia. However, the underlying mechanism is still unclear. In the current study, a single dose of ketamine (5 mg/kg or 10 mg/kg), TAK-242 (3 mg/kg), or saline was intraperitoneally injected into rats 15 min before four subcutaneous injections of fentanyl. Results revealed that pre-administration of ketamine alleviated fentanyl-induced hyperalgesia according to hind paw-pressure and paw-withdrawal tests. High-dose ketamine can reverse the expression of toll-like receptor-dimer (d-TLR4), phospho- nuclear factor kappa-B (p-NF-κB, p-p65), cyclooxygenase-2 (COX-2), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) 1 d after fentanyl injection in the spinal cord. Moreover, fentany-linduced-hyperalgesia and changes in the expression of the aforementioned proteins can be attenuated by TAK-242, an inhibitor of TLR4, as well as ketamine. Importantly, TLR4, p-p65, COX-2, and IL-1ß were expressed in neurons but not in glial cells in the spinal cord 1 d after fentanyl injection. In conclusion, results suggested that a single dose of ketamine can relieve fentanyl-induced-hyperalgesia via the TLR4/NF-κB pathway in spinal cord neurons.

Microstructural Characterization and Prior Particle Boundary (PPB) of PM Nickel-Based Superalloys by Spark Plasma Sintering (SPS).

This research investigates the microstructure and defects of powder metallurgy (PM) nickel-based superalloys prepared by spark plasma sintering (SPS). The densification, microstructural evolution, and precipitate phase evolution processes of FGH96 superalloy after powder heat treatment (PHT) and sintering via SPS are specifically analyzed. Experimental results demonstrate that SPS technology, when applied to sinter at the sub-solidus temperature of the γ' phase, effectively mitigates the formation of a prior particle boundary (PPB). Based on experimental and computational findings, it has been determined that the presence of elemental segregation and Al2O3 oxides on the surface of pre-alloyed powders leads to the preferential precipitation of MC-type carbides and Al2O3 and ZrO2 oxides in the sintering necks during the hot consolidation process, resulting in the formation of PPB. This study contributes to the understanding of microstructural modifications achieved through SPS technology, providing crucial information for optimizing sintering conditions and reducing the widespread occurrence of PPB, ultimately enhancing the material performance of PM nickel-based superalloys.

Curve fitting and jump detection on nonparametric regression with missing data.

In this paper, by virtual of the inverse probability weighted technique, we considered the jump-preserving estimation on the nonparametric regression models with missing data on response variable. First, we used local piecewise-linear expansion respectively with left and right kernel to approximate the unknown regression function. Second, we obtained the left- and right-limit estimation of regression function at each observed points and then determinated the final estimators by residual sums of squares. Third, we presented the convergence rate of estimators and the residual sums of squares. Finally, we illustrated the performance of our proposed method through some simulation studies and a conjunctivitis example from The Affiliated Hospital of Hangzhou Normal University.

Differential regulation of H3K9/H3K14 acetylation by small molecules drives neuron-fate-induction of glioma cell.

Differentiation therapy using small molecules is a promising strategy for improving the prognosis of glioblastoma (GBM). Histone acetylation plays an important role in cell fate determination. Nevertheless, whether histone acetylation in specific sites determines GBM cells fate remains to be explored. Through screening from a 349 small molecule-library, we identified that histone deacetylase inhibitor (HDACi) MS-275 synergized with 8-CPT-cAMP was able to transdifferentiate U87MG GBM cells into neuron-like cells, which were characterized by cell cycle arrest, rich neuron biomarkers, and typical neuron electrophysiology. Intriguingly, acetylation tags of histone 3 at lysine 9 (H3K9ac) were decreased in the promoter of multiple oncogenes and cell cycle genes, while ones of H3K9ac and histone 3 at lysine 14 (H3K14ac) were increased in the promoter of neuron-specific genes. We then compiled a list of genes controlled by H3K9ac and H3K14ac, and proved that it is a good predictive power for pathologic grading and survival prediction. Moreover, cAMP agonist combined with HDACi also induced glioma stem cells (GSCs) to differentiate into neuron-like cells through the regulation of H3K9ac/K14ac, indicating that combined induction has the potential for recurrence-preventive application. Furthermore, the combination of cAMP activator plus HDACi significantly repressed the tumor growth in a subcutaneous GSC-derived tumor model, and temozolomide cooperated with the differentiation-inducing combination to prolong the survival in an orthotopic GSC-derived tumor model. These findings highlight epigenetic reprogramming through H3K9ac and H3K14ac as a novel approach for driving neuron-fate-induction of GBM cells.

Evaluation of the Shear Performance of Douglas-Fir Wood at Elevated Temperatures.

Shear fracture frequently occurs in timber beams and panels subjected to transverse loads. At elevated temperatures, wood will undergo complex physical and chemical processes which significantly affect the shear properties. In this paper, the v-notched Douglas-fir specimens with three different shear planes: (a) Radial-Tangential (RT); (b) Radial-Longitudinal (RL), and (c) Longitudinal-Radial (LR), were fabricated and tested under the elevated temperatures from 20 °C to 180 °C. The digital image correlation (DIC) technique was used to measure the shear strain. It was found that the shear plane had a significant effect on the failure modes, shear strength, and shear modulus. The shear strength and shear modulus generally decreased with the increase of temperature. However, the shear strength was significantly improved when the hardening of the dry lignin occurred between 100 °C and 140 °C. Moreover, the design curve for the shear strength in Eurocode 5 is conservative for all the specimens with different shear planes.

Modelling of Web-Crippling Behavior of Pultruded GFRP I Sections at Elevated Temperatures.

The concentrated transverse load may lead to the web crippling of pultruded GFRP sections due to the lower transverse mechanical properties. Several investigations have been conducted on the web-crippling behavior of the GFRP sections under room temperature. However, the web-crippling behavior is not yet understood when subjected to elevated temperatures. To address this issue, a finite element model considering the temperature-dependent material properties, Hashin failure criterion and the damage evolution law are successfully developed to simulate the web-crippling behavior of the GFRP I sections under elevated temperatures. The numerical model was validated by the web-crippling experiments at room temperature with the end-two-flange (ETF) and end bearing with ground support (EG) loading configurations. The developed model can accurately predict the ultimate loads and failure modes. Moreover, it was found that the initial damage was triggered by exceeding the shear strength at the web-flange junction near the corner of the bearing plate and independent of the elevated temperatures and loading configurations. The ultimate load and stiffness decreased obviously with the increasing temperature. At 220 °C, the ultimate load of specimens under ETF and EG loading configurations significantly decreased by 57% and 62%, respectively, whereas the elastic stiffness obviously reduced by 87% and 88%, respectively.

Experimental Study on the Bending and Shear Behaviors of Chinese Paulownia Wood at Elevated Temperatures.

Chinese Paulownia wood has been extensively used in the construction of timber buildings and lightweight sandwich structures. However, the bending and shear behaviors at elevated temperatures were not well understood. A total of 162 specimens were tested to investigate the bending, tangential shear, and radial shear performances of Chinese Paulownia wood under temperatures from 20 to 220 °C. It was found that the bending specimens exhibited ductile failure due to the progressive damage after reaching the peak load, while the tangential and radial shear specimens exhibited brittle shear failure along the shear plane. The elevated temperatures had limited effects on the failure modes. Under the same temperature, the retention rate of the modulus of elasticity is significantly higher than that of the modulus of rupture. Moreover, the bending strength, tangential shear strength, and radial shear strength generally and nonlinearly decreased with the increasing temperature. The EN 1995-1-2 design curve for the shear strength of wood at elevated temperatures is conservative for both the tangential and radial shear specimens. However, the design curve may not be adopted to estimate the tangential shear strength at temperatures higher than 220 °C.

"Seminal testosterone", rising viewpoint of local spermatogenesis in nonobstructive azoospermia: One center long-term bidirectional cohort study.

Objective: Reproductive hormones are a traditional good method to evaluate spermatogenesis but might not accurately represent local spermatogenesis. To find a more accurate method, seminal reproductive hormones were studied. Methods: A bidirectional cohort study was performed. A total of 126 infertile men from 2018 to 2019 were retrospectively analyzed. They were divided into nonobstructive azoospermia (NOA), oligozoospermia (OLZ) and normal (NOR) groups. A prospective study was conducted on patients in the NOA and OLZ groups for 2 years. Microscopic testicular sperm extraction was performed for NOA patients, who were divided into a focal spermatogenesis group (FS) and an idiopathic azoospermia group (IA). Drug treatment was for OLZ patients, who were divided into a valid group (VA) and an invalid group (IN). The differences in sperm parameters and reproductive hormones were compared. ANOSIM analysis was used between and within groups. Pearson correlation analysis, CO inertia analysis and Proctor's analysis were for relationships. ROC curve for the specificity and sensitivity. Time series analysis was for the trends between hormones and time. Results: The b-FSH, b-LH, s-T and ΔT in the NOA group were significantly higher than those in the OLZ and NOR groups. However, the s-FSH, s-E2, s-P, ΔFSH, ΔLH, ΔP and ΔE2 were lower. Thirty-one NOA patients underwent MTSE, of whom 12 had sperm (FS) and 19 had no sperm (IA). The s-FSH and s-E2 of the FS group were higher than those of the IA group. Twenty-six OLZ patients completed 30 days of treatment, of which 11 had an improved sperm count (VA) and 15 had no (IN). The ΔT of the VA group was higher than that of the IN group. After follow-up for 2 years, 18 patients' results showed that b-FSH, b-LH and s-T were different over time, with delays of 19, 3 and -19 days. SC is closely related to pH, s-FSH, s-LH, s-E2, s-P, s-T, b-FSH, b-LH, ΔFSH, ΔLH, ΔP, ΔE2 and ΔT. There were complex common trends and relationships between different kinds of hormones. s-FSH, s-LH, s-E2, s-P, s-T, b-FSH and b-LH were useful to judge spermatogenesis, of which s-T, b-FSH and b-LH were more sensitive. If s-T, b-FSH and b-LH reached 64.4, 9.4 and 4.7, respectively, their prediction performance was the strongest. Conclusion: Seminal testosterone is sensitive for judging local spermatogenesis in nonobstructive azoospermia patients, which may be the direction of local spermatogenesis in nonobstructive azoospermia. Clinical trial registration: http://www.chictr.org.cn/index.aspx, identifier ChiCTR2200060463.

Effects of varicocele and microsurgical varicocelectomy on the metabolites in semen.

The influence of varicocele and microsurgical varicocelectomy on semen quality remains unclear. Few studies have investigated the relationship between semen metabolism and the abnormalities in reproductive function caused by varicocele, however, there is no study on the changes of semen metabolism after microsurgical varicocelectomy. Here, we used the non-targeted and targeted metabolic analysis to investigate the different metabolites in seminal plasma within normal, varicocele, and varicocelectomy groups. We clearly showed that varicocele significantly affects semen metabolism, and microsurgical varicocelectomy can reverse this metabolic abnormality. Moreover, we characterized the landscape of three dipeptides in the seminal plasma of patients with varicocele that have not been identified previously in human tissues or biofluids. Interestingly, the levels of these three dipeptides decreased after microsurgical varicocelectomy coincident with an improvement in semen quality. Western blotting confirmed the downregulation of DPEP3 (dipeptidase 3) in the varicocele group and the upregulation of DPEP3 in the varicocelectomy group. Furthermore, we found that eight metabolites may be helpful to distinguish varicocele patients from normal subjects. Our results may be applied to earlier diagnosis or to predict the outcome of microsurgery for varicocele.

"Dancing Coins?" Unexpected Finding During microsurgery and Potential Risk of Sperm Damage: Intrascrotal Calculi: A Retrospective Analysis.

Objective: Microsurgery of andrology always brings unexpected findings. Scrotal calculi are rare and unique, which are easily confused with tumor. To understand its etiology and harm, our study retrospectively analyzed the clinical characteristics of men with scrotal calculi to provide a reference for clinical practice. Methods: The clinical data of patients who underwent microscopic testicular sperm extraction (MTESE) and microscopic epididymal sperm aspiration (MESA) from January 1, 2018 to December 31, 2021 were retrospectively analyzed. Data screening was performed on cases in which calculi were found or not, and the relationship between calculi and spermatogenesis was analyzed. Results: A total of 405 patients were recruited. After screening, 218 nonobstructive azoospermia (NOA), 83 obstructive azoospermia (OA), and 13 cryptozoospermia (CZ) patients were included in the study. Calculi were found in 3 patients [incidence was 0.74% (3/405)], in which 2 patients had obstructive azoospermia (1 was epididymal calculi, 1 was intrascrotal calculi) and 1 patient had cryptozoospermia (intrascrotal calculi). Pathological results showed that chronic granuloma with abscess infiltration appeared in epididymal tissue, basement membrane thickening and fibrosis appeared in seminiferous tubules, and fibrous hyperplasia with calcium deposition was found in scrotal calculus. White blood cells, lymphocytes, red blood cells, abstinence time and urethritis were closely related to the occurrence of calculi. While abstinence time might be a potential predictor, which increased the risk by approximately 1.2 times. Conclusion: Disturbance of the testicular microenvironment caused by lymphocyte infiltration may be the main reason for scrotal calculi and ultimately cause spermatogenesis disorders. Prolonged sexual abstinence was a potential risk.

Short-Term Plasticity Regulates Both Divisive Normalization and Adaptive Responses in Drosophila Olfactory System.

In Drosophila, olfactory information received by olfactory receptor neurons (ORNs) is first processed by an incoherent feed forward neural circuit in the antennal lobe (AL) that consists of ORNs (input), inhibitory local neurons (LNs), and projection neurons (PNs). This "early" olfactory information processing has two important characteristics. First, response of a PN to its cognate ORN is normalized by the overall activity of other ORNs, a phenomenon termed "divisive normalization." Second, PNs respond strongly to the onset of ORN activities, but they adapt to prolonged or continuously varying inputs. Despite the importance of these characteristics for learning and memory, their underlying mechanisms are not fully understood. Here, we develop a circuit model for describing the ORN-LN-PN dynamics by including key neuron-neuron interactions such as short-term plasticity (STP) and presynaptic inhibition (PI). By fitting our model to experimental data quantitatively, we show that a strong STP balanced between short-term facilitation (STF) and short-term depression (STD) is responsible for the observed nonlinear divisive normalization in Drosophila. Our circuit model suggests that either STP or PI alone can lead to adaptive response. However, by comparing our model results with experimental data, we find that both STP and PI work together to achieve a strong and robust adaptive response. Our model not only helps reveal the mechanisms underlying two main characteristics of the early olfactory process, it can also be used to predict PN responses to arbitrary time-dependent signals and to infer microscopic properties of the circuit (such as the strengths of STF and STD) from the measured input-output relation. Our circuit model may be useful for understanding the role of STP in other sensory systems.

Mechanism study of improving anaerobic co-digestion performance of waste activated sludge and food waste by Fe3O4.

A large amount of waste activated sludge (WAS) and food waste (FW) are produced every year in China. Anaerobic co-digestion is considered to be an effective way to solve this problem. This study applied FW/WAS mixture as co-substrate to create different digestive environment, aiming to understand the mechanism of Fe3O4 particles in promoting AD performance. The results showed that the addition of Fe3O4 presented various performances when facing different digestive acidification stress brought by different mixing ratios of WAS and FW. Methanogenic pathways and microbial communities varied with substrates' properties. For group A (WAS mono-digestion), the acetoclastic methanogens dominated, 20 mg/g VS (according to the iron element) Fe3O4 could promote methane production, while 200 mg/g VS Fe3O4 would inhibit microbial activity. The promoted methane production by Fe3O4 was attributable to the promotion of sludge hydrolysis. For group B (WAS: FW = 1:0.5, based on VS addition, similarly hereinafter), Fe3O4 triggered direct interspecific electron transfer (DIET) between bacteria and methanogens. For group C (WAS: FW = 1:1), the hydrogenotrophic methanogens dominated, bacteria excreted more non-conductive polysaccharides in EPS to resist unfavorable environment, thereby it prevented their contact with Fe3O4 particles. So, it was difficult for Fe3O4 to trigger DIET and promote the digestive performance of batch experiments in such condition.

Cost-effectiveness of intensification with SGLT2 inhibitors for type 2 diabetes.

OBJECTIVES: Using a US payer perspective, this study aimed to compare the lifetime cost-effectiveness of adding sodium-glucose cotransporter 2 (SGLT2) inhibitors vs switching to glucagon-like peptide 1 receptor agonists (GLP-1 RAs) among patients with type 2 diabetes who were not at glycated hemoglobin A1c target after dual therapy with metformin and dipeptidyl peptidase-4 (DPP-4) inhibitors. STUDY DESIGN: The cost-effectiveness analysis was performed with the validated IQVIA Core Diabetes Model. Treatment effects were obtained from randomized clinical trials with economic data based on published literature. METHODS: Risk of treatment-emergent adverse events and complications were simulated using submodels informed by published risk equations adjusted for patient characteristics, physiological parameters, and history of complications. Outcomes included cumulative incidence of micro- and macrovascular complications, life-years (LYs), quality-adjusted life-years (QALYs), and total costs. Scenario analyses were performed to assess robustness of results to variations in clinical and cost inputs and assumptions. RESULTS: Over a lifetime time horizon, adding an SGLT2 inhibitor dominated the strategy of switching to a GLP-1 RA, improving survival by 0.049 LYs and 0.026 QALYs, and was associated with cost savings of $9511. The majority of the scenario analyses confirmed dominance of the DPP-4 inhibitor + SGLT2 inhibitor pathway vs the GLP-1 RA pathway. The probabilistic sensitivity analysis reinforced the base-case finding of cost savings while gaining QALYs. CONCLUSIONS: Intensification with an SGLT2 inhibitor on top of a DPP-4 inhibitor demonstrated slightly better efficacy and cost savings compared with switching to a GLP-1 RA in patients not at glycemic goal with metformin and a DPP-4 inhibitor.