Comparative analysis of dynamic transcriptomes reveals specific COVID-19 features and pathogenesis of immunocompromised populations.

A dysfunction of human host genes and proteins in coronavirus infectious disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a key factor impacting clinical symptoms and outcomes. Yet, a detailed understanding of human host immune responses is still incomplete. Here, we applied RNA sequencing to 94 samples of COVID-19 patients with and without hematological tumors as well as COVID-19 uninfected non-tumor individuals to obtain a comprehensive transcriptome landscape of both hematological tumor patients and non-tumor individuals. In our analysis, we further accounted for the human-SARS-CoV-2 protein interactome, human protein interactome, and human protein complex subnetworks to understand the mechanisms of SARS-CoV-2 infection and host immune responses. Our data sets enabled us to identify important SARS-CoV-2 (non-)targeted differentially expressed genes and complexes post-SARS-CoV-2 infection in both hematological tumor and non-tumor individuals. We found several unique differentially expressed genes, complexes, and functions/pathways such as blood coagulation (APOE, SERPINE1, SERPINE2, and TFPI), lipoprotein particle remodeling (APOC2, APOE, and CETP), and pro-B cell differentiation (IGHM, VPREB1, and IGLL1) during COVID-19 infection in patients with hematological tumors. In particular, APOE, a gene that is associated with both blood coagulation and lipoprotein particle remodeling, is not only upregulated in hematological tumor patients post-SARS-CoV-2 infection but also significantly expressed in acute dead patients with hematological tumors, providing clues for the design of future therapeutic strategies specifically targeting COVID-19 in patients with hematological tumors. Our data provide a rich resource for understanding the specific pathogenesis of COVID-19 in immunocompromised patients, such as those with hematological malignancies, and developing effective therapeutics for COVID-19. IMPORTANCE: A majority of previous studies focused on the characterization of coronavirus infectious disease 2019 (COVID-19) disease severity in people with normal immunity, while the characterization of COVID-19 in immunocompromised populations is still limited. Our study profiles changes in the transcriptome landscape post-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in hematological tumor patients and non-tumor individuals. Furthermore, our integrative and comparative systems biology analysis of the interactome, complexome, and transcriptome provides new insights into the tumor-specific pathogenesis of COVID-19. Our findings confirm that SARS-CoV-2 potentially tends to target more non-functional host proteins to indirectly affect host immune responses in hematological tumor patients. The identified unique genes, complexes, functions/pathways, and expression patterns post-SARS-CoV-2 infection in patients with hematological tumors increase our understanding of how SARS-CoV-2 manipulates the host molecular mechanism. Our observed differential genes/complexes and clinical indicators of normal/long infection and deceased COVID-19 patients provide clues for understanding the mechanism of COVID-19 progression in hematological tumors. Finally, our study provides an important data resource that supports the increasing value of the application of publicly accessible data sets to public health.

Formation and clinical effects of anti-drug antibodies against biologics in psoriasis treatment: An analysis of current evidence.

BACKGROUND: Formation of anti-drug antibodies (ADAs) against biologics is an important cause of psoriasis treatment failure. OBJECTIVE: This study aimed to summarize the characteristics of ADAs formation under different biological therapies and the influence of ADAs on the clinical effects and safety of biologics in patients with psoriasis. METHODS: PubMed, Embase, and Web of Science databases were searched from their inception to August 2022. Studies on biologics that assessed ADA levels in patients with psoriasis were included. The Cochrane risk-of-bias tool was used to assess the quality of randomized controlled trials (RCTs), the Newcastle-Ottawa Quality Assessment Scale (NOS) for case-control and cohort studies, and the Joanna Briggs Institute (JBI) critical appraisal checklist for single-arm studies. We calculated the pooled incidence with a random-effects model using R software. Subgroup analyses revealed that differences in patient characteristics, disease conditions, study design, and immunoassays may influence ADA generation and detection. RESULTS: The analysis included 86 studies, with a total population of 42,280 individuals. The pooled ADA rates were 0.49%, 2.20%, 2.38%, 4.08%, 7.38%, 7.94%, 14.29%, 21.93%, 29.70%, 31.76%, and 39.58% for secukinumab, etanercept, brodalumab, ustekinumab, tildrakizumab, guselkumab, ixekizumab, risankizumab, infliximab, adalimumab, and bimekizumab, respectively. >70% (95% CI, 0.71-0.81) of ADAs against adalimumab were neutralizing antibodies, and over 70% of ADAs against secukinumab and brodalumab were transient. Concomitant methotrexate therapy with tumor necrosis factor-α (TNF-α) inhibitors decreased ADA levels. Lower infliximab doses and intermittent therapy with interleukin (IL)-23 p19 inhibitors increased ADA formation. Additionally, ADA formation under treatment using TNF-α inhibitors and IL-12/23 p40 inhibitors was associated with lower response rates or serum drug levels, but only high ADA titers reduced the clinical effects of IL-17 inhibitors. The occurrence of IL-23 p19 and TNF-α inhibitors has been linked to injection-site reactions. CONCLUSIONS: Among the 11 biologics, secukinumab, etanercept, and brodalumab resulted in the lowest ADA formation rates. Immunogenicity contributes to lower biological efficacy and a higher likelihood of injection-site reactions. Low doses, intermittent treatment may increase ADA formation. An appropriate biologic should be selected based on the ADA formation rate and course of treatment.

COMP promotes pancreatic fibrosis by activating pancreatic stellate cells through CD36-ERK/AKT signaling pathways.

BACKGROUND: Pancreatic fibrosis is one of the most important pathological features of chronic pancreatitis (CP) and pancreatic stellate cells (PSCs) are the key cells of fibrosis. As an extracellular matrix (ECM) glycoprotein, cartilage oligomeric matrix protein (COMP) is critical for collagen assembly and ECM stability and recent studies showed that COMP exert promoting fibrosis effect in the skin, lungs and liver. However, the role of COMP in activation of PSCs and pancreatic fibrosis remain unclear. We aimed to investigate the role and specific mechanisms of COMP in regulating the profibrotic phenotype of PSCs and pancreatic fibrosis. METHODS: ELISA method was used to determine serum COMP in patients with CP. Mice model of CP was established by repeated intraperitoneal injection of cerulein and pancreatic fibrosis was evaluated by Hematoxylin-Eosin staining (H&E) and Sirius red staining. Immunohistochemical staining was used to detect the expression changes of COMP and fibrosis marker such as α-SMA and Fibronectin in pancreatic tissue of mice. Cell Counting Kit-8, Wound Healing and Transwell assessed the proliferation and migration of human pancreatic stellate cells (HPSCs). Western blotting, qRT-PCR and immunofluorescence staining were performed to detect the expression of fibrosis marker, AKT and MAPK family proteins in HPSCs. RNA-seq omics analysis as well as small interfering RNA of COMP, recombinant human COMP (rCOMP), MEK inhibitors and PI3K inhibitors were used to study the effect and mechanism of COMP on activation of HPSCs. RESULTS: ELISA showed that the expression of COMP significantly increased in the serum of CP patients. H&E and Sirius red staining analysis showed that there was a large amount of collagen deposition in the mice in the CP model group and high expression of COMP, α-SMA, Fibronectin and Vimentin were observed in fibrotic tissues. TGF-ß1 stimulates the activation of HPSCs and increases the expression of COMP. Knockdown of COMP inhibited proliferation and migration of HPSCs. Further, RNA-seq omics analysis and validation experiments in vitro showed that rCOMP could significantly promote the proliferation and activation of HPSCs, which may be due to promoting the phosphorylation of ERK and AKT through membrane protein receptor CD36. rCOMP simultaneously increased the expression of α-SMA, Fibronectin and Collagen I in HPSCs. CONCLUSION: In conclusion, this study showed that COMP was up-regulated in CP fibrotic tissues and COMP induced the activation, proliferation and migration of PSCs through the CD36-ERK/AKT signaling pathway. COMP may be a potential therapeutic candidate for the treatment of CP. Interfering with the expression of COMP or the communication between COMP and CD36 on PSCs may be the next direction for therapeutic research.

Application of fecal collection device in Intensive Care Unit Patients with fecal incontinence Receiving Extracorporeal Membrane Oxygenation: A Comparison Cohort Study.

Objective: The objective of this study was to assess the effectiveness of fecal collection devices in preventing incontinence-associated dermatitis (IAD) and reducing skin care time in ICU patients with fecal incontinence undergoing Extracorporeal Membrane Oxygenation (ECMO). Methods: A nonrandomized comparison cohort (quasi-experimental) study with pre-post comparison was carried out in a general intensive care unit. 85 bedridden patients receiving ECMO with fecal incontinence (FI) in a general intensive care unit between June 2017 and May 2022 participated in the study and separated into two groups according to the fecal collection device they received. 40 were assigned to the Control group (structured IAD preventive care protocol alone) and 45 to the Intervention group (structured IAD preventive care protocol plus application of fecal collection device). The status of IAD was assessed using the Incontinence Associated Dermatitis Intervention Tool (IAD-IT). Fecal consistency was evaluated via the Bristol Stool Scale. Outcome measures included the nursing time for skin care and the incidence of IAD, and bleeding complications between the two groups during the period. Results: Participants in the Intervention group had fewer IAD occurrences than participants in the Control group (13.33% vs. 52.50%, P < .05). The patients in the Intervention group significantly reduced skincare time (63.30±14.09 min in the Control group versus 28.44±2.04 min in the Intervention group, P < .01). There was 3 turning complications for bleeding in the Intervention group and 11 in the Control group and had a significant reduction in urning complications(3 vs.11, P = .022). Conclusions: Applying a fecal collection device may reduce skincare time and reduce occurrences of IAD and bleeding related to turning position for skin care in ICU patients with FI associated with diarrhea receiving ECMO Support.This study offers a more efficient way to use the fecal collection device in ECMO patients.Future research needs to focus on the perianal skin in ECMO patients regarding fecal collection devices connected to continuous low-negative-pressure suction devices.

The seizure classification of focal epilepsy based on the network motif analysis.

Due to the complexity of focal epilepsy and its risk for transiting to the generalized epilepsy, the development of reliable classification methods to accurately predict and classify focal and generalized seizures is critical for the clinical management of patients with epilepsy. In order to holistically understand the seizure propagation behavior of focal epilepsy, we propose a three-node motif reduced network by respectively simplifying the focal region, surrounding healthy region and their critical regions as the single node. Because three-node motif can richly characterize information evolutions, the motif analysis method could comprehensively investigate the seizure behavior of focal epilepsy. Firstly, we define a new seizure propagation marker value to capture the seizure onsets and intensity. Based on the three-node motif analysis, it is shown that the focal seizure and spreading can be categorized as inhibitory seizure, focal seizure, focal-critical seizure and generalized seizures, respectively. The four types of seizures correspond to specific modal types respectively, reflecting the strong correlation between seizure behavior and information flow evolution. In addition, it is found that the intensity difference of outflow and inflow information from the critical node (connection heterogeneity) and the excitability of the critical node significantly affected the distribution and transition of the four seizure types. In particular, the method of local linear stability analysis also verifies the effectiveness of four types of seizures classification. In sum, this paper computationally confirms the complex dynamic behavior of focal seizures, and the study of criticality is helpful to propose novel seizure control strategies.

Retrospective cohort evaluation of non-HIV Castleman disease from a single academic center in Beijing, China.

The purpose is to ascertain the clinical impact of Castleman disease (CD) by reassessment of the real-world data from Peking University First Hospital (PKUFH). The results will contribute to the standardization of diagnosis and treatment on CDs. Based on the last 15-year retrospective real-world data from Peking University First Hospital (PKUFH), we reclassified and re-evaluated the clinical and pathological information of patients with pathologically suspected diagnosis of CD. A total of 203 patients were included in our study, in which the diagnosis of CD was confirmed in 189 cases, including 118 patients with unicentric CD (UCD, n = 118, 62.4%) and 71 patients with multicentric CD (MCD, n = 71, 37.6%). A total of 44.1% (n = 52) of UCDs in our cohort were complicated with paraneoplastic pemphigus (PNP). The treatment of UCD is primarily surgical, with a 5-year overall survival (OS) of 88.1%. Patients with PNP had a poorer prognosis than those without PNP (82.9% (95% CI 123-178) vs 92.8% (95% CI 168-196), log-rank p = 0.041). The rate of concurrent systemic symptoms was 74.6% (n = 53), and renal involvement occurred in 49.3% (n = 35) MCD patients. The MCD treatments were mainly chemotherapy regimens, with a 5-year OS of 77.6% (95% CI, 143-213). Patients with UCD demonstrate a better overall prognosis than patients with MCD. But the prognosis of those complicated with PNP was poor. The differential diagnosis of MCD is extensive. MCD treatment in China is heterogeneous. The inaccessibility of anti-IL-6-targeted drugs in China may contribute to the poor prognosis for patients with MCD.A preprint has previously been published (Guo et al. 34).

Correlation between Flow Temperature and Average Molar Ionic Potential of Ash during Gasification of Coal and Phosphorus-Rich Biomass.

The co-gasification of biomass and coal is helpful for achieving the clean and efficient utilization of phosphorus-rich biomass. A large number of alkali and alkaline earth metals (AAEMs) present in the ash system of coal (or biomass) cause varying degrees of ash, slagging, and corrosion problems in the entrained flow gasifier. Meanwhile, phosphorus is present in the slag in the form of PO43-, which has a strong affinity for AAEMs (especially for Ca2+) to produce minerals dominated by calcium phosphates or alkaline Ca-phosphate, effectively mitigating the aforementioned problems. To investigate the changing behavior of the slag flow temperature (FT) under different CaO/P2O5 ratios, 72 synthetic ashes with varying CaO/P2O5 ratios at different Si/Al contents and compositions were prepared, and their ash fusion temperatures were tested. The effects of different CaO/P2O5 ratios on the FT were analyzed using FactSage thermodynamic simulation. A model for predicting slag FT at different CaO/P2O5 ratios was constructed on the basis of the average molar ionic potential (Ia) method and used to predict data reported from 19 mixed ashes in the literature. The results showed that Ia and FT gradually increased with a decreasing CaO/P2O5 ratio, and the main mineral types shifted from anorthite → mullite → berlinite, which reasonably explained the decrease in ash fusion temperatures in the mixed ash. The established model showed good adaptability to the prediction of 19 actual coal ash FTs in the literature; the deviation of the prediction was in the range of 40 °C. The model proposed between FT and Ia based on the different CaO/P2O5 ratios can be used to predict the low-rank coal and phosphorus-rich biomass and their mixed ashes.

Low-dose decitabine-intensified modified conditioning regimen alleviates aGVHD in AML/MDS patients treated with allogeneic hematopoietic stem cell transplantation.

Background: The widespread adoption of Allogeneic Hematopoietic Stem Cell Transplantation (Allo-HSCT) has significantly improved the survival rates of patients with hematological malignancies. However, Graft-Versus-Host Disease (GVHD) remains a formidable complication, threatening patient prognosis. Recent research has indicated that decitabine (DAC), known for its hypomethylating properties may also exhibit immune-regulatory capabilities and a potential for reducing GVHD incidence and enhancing survival. Methods: We retrospectively reviewed data from AML/MDS patients who underwent Allo-HSCT at our center from January 2010 to January 2023. From a total of 251 patients with complete data, we employed propensity score matching (PSM) to create 100 matched pairs (200 patients) for comprehensive trial analysis. Patients receiving low-dose DAC-containing regimen were matched with those who did not receive DAC. Results: Patients in the DAC group exhibited a significantly lower incidence of grade II-IV acute GVHD (aGVHD) compared to non-DAC group (21% vs. 38%, P=0.013). Univariable and multivariable logistic regression analysis demonstrated DAC intervention as a protective factor against grade II-IV aGVHD (P=0.017, OR=0.47, 95% CI 0.23-0.81; P=0.018, OR=0.46, 95% CI 0.24-0.87). Multivariate competing risk regression further supported administration of decitabine as a protective factor against grade II-IV aGVHD (P=0.038, SHR=0.53, 95%CI 0.29-0.97). There was no significant difference between both groups concerning chronic GVHD, infection, disease relapse, overall survival, disease-free survival and GVHD free, relapse free survival. In MRD negative or intermediate risk subgroup, the grade II-IV aGVHD ameliorating effect of DAC was confirmed as well. Conclusion: Low-dose DAC-intensified modified conditioning regimen could improve prognosis in AML/MDS Patients treated with allogeneic hematopoietic stem cell transplantation.

Task-relevant brain dynamics among cognitive subsystems induced by regional stimulation in a whole-brain computational model.

Cognition involves the global integration of distributed brain regions that are known to work cohesively as cognitive subsystems during brain functioning. Empirical evidence has suggested that spatiotemporal phase relationships between brain regions, measured as synchronization and metastability, may encode important task-relevant information. However, it remains largely unknown how phase relationships aggregate at the level of cognitive subsystems under different cognitive processing. Here, we probe this question by simulating task-relevant brain dynamics through regional stimulation of a whole-brain dynamical network model operating in the resting-state dynamical regime. The model is constructed with structurally embedded Stuart-Laudon oscillators and then fitted with human resting-state functional magnetic resonance imaging data. Based on this framework, we first demonstrate the plausibility of introducing the cognitive system partition into the modeling analysis framework by showing that the clustering of regions across functional networks is better circumscribed by the predefined partition. At the cognitive subsystem level, we focus on how task-relevant phase dynamics are organized in terms of synchronization and metastability. We found that patterns of cognitive synchronization are more task specific, whereas patterns of cognitive metastability are more consistent across different states, suggesting it may encode a more task-general property during cognitive processing, an inherent property conferred by brain organization. This consistent network architecture in cognitive metastability may be related to the distinct functional responses of realistic cognitive systems. We also provide empirical evidence to partially support our computational results. Our paper may provide insights for the mechanisms underlying task-relevant brain dynamics, and establish a model-based link between brain structure, dynamics, and cognition, a fundamental step for computationally aided brain interventions.

A computational network dynamical modeling for abnormal oscillation and deep brain stimulation control of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is associated with multi-nodal abnormalities in brain networks, characterized by recurrent intrusive thoughts (obsessions) and repetitive behaviours or mental acts (compulsions), which might manifest as pathological low-frequency oscillations in the frontal EEG and low-frequency bursting firing patterns in the subthalamus nucleus (STN). Abnormalities in the cortical-striatal-thalamic-cortical (CSTC) loop, including dysregulation of serotonin, dopamine, and glutamate systems, are considered to contribute to certain types of OCD. Here, we extend a biophysical computational model to investigate the effect of orbitofronto-subcortical loop abnormalities on network oscillations. Particularly, the OCD lesion process is simulated by the loss of connectivity from striatal parvalbumin interneurons (PV) to medium spiny neurons (MSNs), excessive activation to the hyperdirect pathway, and high dopamine concentrations. By calculating low-frequency oscillation power in the STN, STN burst index, and average firing rates levels of the cortex and thalamus, we demonstrate that the model can explain the pathology of glutamatergic and dopamine system dysregulation, the effects of pathway imbalance, and neuropsychiatric treatment in OCD. In addition, results indicate the abnormal brain rhythms caused by the dysregulation of orbitofronto-subcortical loop may serve as a biomarker of OCD. Our studies can help to understand the cause of OCD, thereby facilitating the diagnosis of OCD and the development of new therapeutics.

[An MRI study of lateral vascular safety zones in oblique lumbar interbody fusion surgery].

Objective: To study the anatomical characteristics of blood vessels in the lateral segment of the vertebral body through the surgical approach of oblique lumbar interbody fusion (OLIF) using MRI imaging, and evaluate its potential vascular safety zone. Methods: The lumbar MRI data of 107 patients with low back and leg pain who met the selection criteria between October 2019 and November 2022 were retrospectively analyzed. The vascular emanation angles, vascular travel angles, and the length of vessels in the lateral segments of the left vertebral body of L 1-L 5, as well as the distance between the segmental vessels in different Moro junctions of the vertebral body and their distances from the edges of the vertebrae in the same sequence (bottom marked as I, top as S) were measured. The gap between the large abdominal vessels and the lateral vessels of the vertebral body was set as the lateral vascular safe zones of the lumbar spine, and the extent of the safe zones (namely the area between the vessels) was measured. The anterior 1/3 of the lumbar intervertebral disc was taken as the simulated puncture center, and the area with a diameter of 22 mm around it as the simulated channel area. The proportion of vessels in the channel was further counted. In addition, the proportions of segmental vessels at L 5 without a clear travel and with an emanation angel less than 90° were calculated. Results: Except for the differences in the vascular emanation angles between L 4 and L 5, the vascular travel angles between L 1, L 2 and L 4, L 5, and the length of vessels in the lateral segments of the vertebral body among L 1-L 4 were not significant ( P>0.05), the differences in the vascular emanation angles, vascular travel angles, and the length of vessels between the rest segments were all significant ( P<0.05). There was no significant difference in the distance between vessels of L 1, L 2 and L 2, L 3 at Moro Ⅰ-Ⅳ junctions ( P>0.05), in L 3, L 4 and L 4, L 5 at Ⅱ and Ⅲ junction ( P>0.05). There was no significant difference in the vascular distance of L 2, L 3 between Ⅱ, Ⅲ junction and Ⅲ, Ⅳ junction, and the vascular distance of L 3, L 4 between Ⅰ, Ⅱ junction and Ⅲ, Ⅳ junction ( P>0.05). The vascular distance of the other adjacent vertebral bodies was significant different between different Moro junctions ( P<0.05). Except that there was no significant difference in the distance between L 2I and L 3S at Ⅰ, Ⅱ junction, L 3I and L 4S at Ⅱ, Ⅲ junction, and L 2I and L 3S at Ⅲ, Ⅳ junction ( P>0.05), there was significant difference of the vascular distance between the bottom of one segment and the top of the next in the other segments ( P<0.05). Comparison between junctions: Except for the L 3S between Ⅰ, Ⅱ junction and Ⅱ, Ⅲ junction, and L 5S between Ⅰ, Ⅱ junction and Ⅱ, Ⅲ and Ⅲ, Ⅳ junctions had no significant difference ( P>0.05), there were significant differences in the distance between the other segmental vessels and the vertebral edge of the same sequence in different Moro junctions ( P<0.05). The overall proportion of vessels in the simulated channels was 40.19% (43/107), and the proportion of vessels in L 1 (41.12%, 44/107) and L 5 (18.69%, 20/107) was higher than that in the other segments. The proportion of vessels in the channel of Moro zone Ⅰ (46.73%, 50/107) and zone Ⅱ (32.71%, 35/107) was higher than that in the zone Ⅲ, while no segmental vessels in L 1 and L 2 were found in the channel of zone Ⅲ ( χ 2=74.950, P<0.001). Moreover, 26.17% (28/107) of the segmental vessels of lateral L 5 showed no movement, and 27.10% (29/107) vascular emanation angles of lateral L 5 were less than 90°. Conclusion: L 1 and L 5 segmental vessels are most likely to be injured in Moro zones Ⅰ and Ⅱ, and the placement of OLIF channels in L 4, 5 at Ⅲ, Ⅳ junction should be avoided. It is usually safe to place fixation pins at the vertebral body edge on the cephalic side of the intervertebral space, but it is safer to place them on the caudal side in L 1, 2 (Ⅰ, Ⅱ junction), L 3, 4 (Ⅲ, Ⅳ junction), and L 4, 5 (Ⅱ, Ⅲ, Ⅳ junctions).

Real-world outcomes and prognostic factors among patients with acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation.

Acute myeloid leukemia (AML) is a malignant lymphohematopoietic tumor that ranks among the most frequent indications for allogeneic hematopoietic stem cell transplantation (allo-HSCT). This article aims to provide a comprehensive analysis of the application of allo-HSCT for AML and identify prognostic factors to enhance future treatment effect. This retrospective study collected data from 323 patients diagnosed with AML at Peking University First Hospital who underwent allo-HSCT between September 2003 and July 2022. The annual number of transplantations has steadily increased. Our center has observed a rise in the proportion of cytogenetic high-risk and measurable residual disease (MRD) positive patients since 2013, as well as an increase in the number of haploidentical transplantations. The overall leukocyte engraftment time has decreased over the past 20 years. Furthermore, both overall survival (OS) and disease-free survival (DFS) have significantly improved, while non-relapse mortality (NRM) has significantly decreased since 2013. Multivariate analysis identified transplantation before 2013, patients in complete remission (CR) 2 or non-CR, and recipients older than 50 years as risk factors for NRM, while patients in non-CR and patients with positive MRD are risk factors for recurrence. These findings offer insights into AML treatment outcomes in China, highlighting changes in transplantation practices and the need to reduce post-transplant relapse. Effective interventions, such as MRD monitoring and risk stratification schemes, are crucial for further enhancing transplant outcomes.

NHC-catalyzed enantioselective access to ß-cyano carboxylic esters via in situ substrate alternation and release.

A carbene-catalyzed asymmetric access to chiral ß-cyano carboxylic esters is disclosed. The reaction proceeds between ß,ß-disubstituted enals and aromatic thiols involving enantioselective protonation of enal ß-carbon. Two main factors contribute to the success of this reaction. One involves in situ ultrafast addition of the aromatic thiol substrates to the carbon-carbon double bond of the enal substrate. This reaction converts almost all enal substrate to a Thiol-click Intermediate, significantly reducing aromatic thiol substrates concentration and suppressing the homo-coupling reaction of enals. Another factor is an in situ release of enal substrate from the Thiol-click Intermediate for the desired reaction to proceed effectively. The optically enriched ß-cyano carboxylic esters from our method can be readily transformed to medicines that include γ-aminobutyric acids derivatives such as Rolipram. In addition to synthetic utilities, our control of reaction outcomes via in situ substrate modulation and release can likely inspire future reaction development.

Regulating epileptiform discharges by heterogeneous interneurons in thalamocortical model.

Inhibitory interneurons in the cortex are abundant and have diverse roles, classified as parvalbumin (PV), somatostatin (SOM), and vasoactive intestinal polypeptide (VIP) according to chemically defined categories. Currently, their involvement with seizures has been partially uncovered in physiological terms. Here, we propose a corticothalamic model containing heterogeneous interneurons to study the effects of various interneurons on absence seizure dynamics by means of optogenetic stimulation. First, the important role of feedforward inhibition caused by SRN→PV→PN projections on seizures is verified. Then, we demonstrate that light activation targeting either PV or SOM INs can control seizures. Finally, with different inhibition contributions from PV INs and SOM INs, the possible disinhibitory effect of blue light acting on VIP INs is mainly discussed. The results suggest that depending on the inhibition degree of both types, the disinhibition brought about by the VIP INs will trigger seizures, will control seizures, and will not work or cause the PNs to tend toward a high saturation state with high excitability. The circuit mechanism and the related bifurcation characteristics in various cases are emphatically revealed. In the model presented, in addition to Hopf and saddle-node bifurcations, the system may also undergo period-doubling and torus bifurcations under stimulus action, with more complex dynamics. Our work may provide a theoretical basis for understanding and further exploring the role of heterogeneous interneurons, in particular, the VIP INs, a novel target, in absence seizures.

Preassigned-time projective synchronization of delayed fully quaternion-valued discontinuous neural networks with parameter uncertainties.

This paper concerns with the preassigned-time projective synchronization issue for delayed fully quaternion-valued discontinuous neural networks involving parameter uncertainties through the non-separation method. Above all, based on the existing works, a new preassigned-time stability theorem is established. Subsequently, to realize the control goals, two types of novel and simple chattering-free quaternion controllers are designed, one without the power-law term and the other with a hyperbolic-tangent function. They are different from the existing common power-law controller and exponential controller. Thirdly, under the Filippov discontinuity theories and with the aid of quaternion inequality techniques, some novel succinct sufficient criteria are obtained to ensure the addressed systems to achieve the preassigned-time synchronization by using the preassigned-time stability theory. The preassigned settling time is free from any parameter and any initial value of the system, and can be preset according to the actual task demands. Particularly, unlike the existing results, the proposed control methods can effectively avoid the chattering phenomenon, and the time delay part is removed for simplicity. Additionally, the projection coefficient is generic quaternion-valued instead of real-valued or complex-valued, and some of the previous relevant results are extended. Lastly, numerical simulations are reported to substantiate the effectiveness of the control strategies, the merits of preassigned settling time, and the correctness of the acquired results.

Carbene-catalyzed chemoselective reaction of unsymmetric enedials for access to Furo[2,3-b]pyrroles.

A carbene-catalyzed chemoselective reaction of unsymmetric enedials is disclosed. The reaction provides a concise access to bicyclic furo[2,3-b]pyrroles derivatives in excellent selectivity. A main challenge in this reaction is chemoselective reaction of the two aldehyde moieties in the enedial substrates. Mechanistic studies via experiments suggest that our chemoselectivity controls are mostly achieved on the reducing properties of different sited Breslow intermediates. Several side reactions processes and the corresponding side adducts are also studied by high resolution mass spectroscopy analysis. Our method allows for efficient assembly of the furo[2,3-b]pyrrole structural moieties and their analogues widely found in natural products and pharmaceuticals.

Epileptic seizures detection and the analysis of optimal seizure prediction horizon based on frequency and phase analysis.

Changes in the frequency composition of the human electroencephalogram are associated with the transitions to epileptic seizures. Cross-frequency coupling (CFC) is a measure of neural oscillations in different frequency bands and brain areas, and specifically phase-amplitude coupling (PAC), a form of CFC, can be used to characterize these dynamic transitions. In this study, we propose a method for seizure detection and prediction based on frequency domain analysis and PAC combined with machine learning. We analyzed two databases, the Siena Scalp EEG database and the CHB-MIT database, and used the frequency features and modulation index (MI) for time-dependent quantification. The extracted features were fed to a random forest classifier for classification and prediction. The seizure prediction horizon (SPH) was also analyzed based on the highest-performing band to maximize the time for intervention and treatment while ensuring the accuracy of the prediction. Under comprehensive consideration, the results demonstrate that better performance could be achieved at an interval length of 5 min with an average accuracy of 85.71% and 95.87% for the Siena Scalp EEG database and the CHB-MIT database, respectively. As for the adult database, the combination of PAC analysis and classification can be of significant help for seizure detection and prediction. It suggests that the rarely used SPH also has a major impact on seizure detection and prediction and further explorations for the application of PAC are needed.

Carbene-Catalyzed Access to Thiochromene Derivatives: Control of Reaction Pathways via Slow Release of Thiols from Disulfides.

Substrates containing disulfide bonds, which are more stable and less smelling, could be used as thiophenol precursors in organic synthesis. Herein, an N-heterocyclic carbene (NHC)-catalyzed reaction between α-bromoenals and 2,2'-dithiodibenzaldehydes was developed. Through the sustained release strategy, the side reaction can be effectively inhibited, and the chiral thiochromene derivatives can be obtained with good yields and high optical purities. Application studies showed encouraging results when the desired products were explored for antimicrobial utilities in pesticide development.