Determining the kinetically dominant catalyst in a given catalytic system is a forefront topic in catalysis. The RhCp*Cl22 (Cp* = η5-C5(CH3)5) system pioneered by Maitlis and co-workers is a classic ...precatalyst system from which homogeneous mononuclear Rh1, subnanometer Rh4 cluster, and heterogeneous polymetallic Rh(0) n nanoparticle have all arisen as viable candidates for the true hydrogenation catalyst, depending on the precise substrate, H2 pressure, temperature, and catalyst concentration conditions. Addressed herein is the question of whether the prior assignment of homogeneous, mononuclear Rh1Cp*-based catalysis is correct, or are trace Rh4 subnanometer clusters or possibly Rh(0) n nanoparticles the dominant, actual cyclohexene hydrogenation catalyst at 22 °C and 2.7 atm initial H2 pressure? The observation herein of Rh4 species by in operando-X-ray absorption fine structure (XAFS) spectroscopy, at the only slightly more vigorous conditions of 26 °C and 8.3 atm H2 pressure, and the confirmation of Rh4 clusters by ex situ mass spectroscopy raises the question of the dominant, room temperature, and mild pressure cyclohexene hydrogenation catalyst derived from the classic RhCp*Cl22 precatalyst pioneered by Maitlis and co-workers. Ten lines of evidence are provided herein to address the nature of the true room temperature and mild pressure cyclohexene hydrogenation catalyst derived from RhCp*Cl22. Especially significant among those experiments are quantitative catalyst poisoning experiments, in the present case using 1,10-phenanthroline. Those poisoning studies allow one to distinguish mononuclear Rh1, subnanometer Rh4 cluster, and Rh(0) n nanoparticle catalysis hypotheses. The evidence obtained provides a compelling case for a mononuclear, Rh1Cp*-based cyclohexene hydrogenation catalyst at 22 °C and 2.7 atm H2 pressure. The resultant methodology, especially the quantitative catalyst poisoning experiments in combination with in operando spectroscopy, is expected to be more broadly applicable to the study of other systems and the “what is the true catalyst?” question.
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IJS, KILJ, NUK, PNG, UL, UM
Mutations in chromatin regulator ASXL1 are frequently identified in myeloid malignancies, in particular ∼40% of patients with chronic myelomonocytic leukemia (CMML). ASXL1 mutations are associated ...with poor prognosis in CMML and significantly co-occur with NRAS mutations. Here, we show that concurrent ASXL1 and NRAS mutations defined a population of CMML patients who had shorter leukemia-free survival than those with ASXL1 mutation only. Corroborating this human data, Asxl1−/− accelerated CMML progression and promoted CMML transformation to acute myeloid leukemia (AML) in NrasG12D/+ mice. NrasG12D/+;Asxl1−/− (NA) leukemia cells displayed hyperactivation of MEK/ERK signaling, increased global levels of H3K27ac, upregulation of Flt3. Moreover, we find that NA-AML cells overexpressed all the major inhibitory immune checkpoint ligands: programmed death-ligand 1 (PD-L1)/PD-L2, CD155, and CD80/CD86. Among them, overexpression of PD-L1 and CD86 correlated with upregulation of AP-1 transcription factors (TFs) in NA-AML cells. An AP-1 inhibitor or short hairpin RNAs against AP-1 TF Jun decreased PD-L1 and CD86 expression in NA-AML cells. Once NA-AML cells were transplanted into syngeneic recipients, NA-derived T cells were not detectable. Host-derived wild-type T cells overexpressed programmed cell death protein 1 (PD-1) and T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) receptors, leading to a predominant exhausted T-cell phenotype. Combined inhibition of MEK and BET resulted in downregulation of Flt3 and AP-1 expression, partial restoration of the immune microenvironment, enhancement of CD8 T-cell cytotoxicity, and prolonged survival in NA-AML mice. Our study suggests that combined targeted therapy and immunotherapy may be beneficial for treating secondary AML with concurrent ASXL1 and NRAS mutations.
•Asxl1−/− accelerated CMML progression and promoted CMML transformation to AML in NrasG12D/+ mice.•A suppressive immune microenvironment and upregulation of AP-1 TFs promote CMML transformation to AML.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The sequela of COVID-19 include a broad spectrum of symptoms that fall under the umbrella term post-COVID-19 condition or syndrome (PCS). Immune dysregulation, autoimmunity, endothelial dysfunction, ...viral persistence, and viral reactivation have been identified as potential mechanisms. However, there is heterogeneity in expression of biomarkers, and it is unknown yet whether these distinguish different clinical subgroups of PCS. There is an overlap of symptoms and pathomechanisms of PCS with postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). No curative therapies are available for ME/CFS or PCS. The mechanisms identified so far provide targets for therapeutic interventions. To accelerate the development of therapies, we propose evaluating drugs targeting different mechanisms in clinical trial networks using harmonized diagnostic and outcome criteria and subgrouping patients based on a thorough clinical profiling including a comprehensive diagnostic and biomarker phenotyping.
Background
Subjective cognitive decline (SCD) can predict the progression to mild cognitive impairment. Visual memory deficits in mildly impaired patients relate to decreased activity in brain ...regions beyond the medial temporal lobe, such as the parahippocampal place area (PPA). PPA's response to visual scenes is weaker in healthy older than younger adults but equally associated with memory recognition. PPA's response to scenes' perceptual details during encoding might support that association. Whether perceptual detail processing is reduced in SCD can help elucidate the disparity between perceived decline and normal performance. Here we test whether older adults with SCD ('SCD') use perceptual details to a lesser extent than older adults without SCD ('CON') and whether this is observed during the encoding or retrieval of a scene memory task.
Methods
We measured BOLD‐fMRI activity in 37 healthy older adults (SCD: 16) during encoding, and calculated hit rate, false alarm rate, and total recognition accuracy during retrieval. We analyzed BOLD‐fMRI activity during scene encoding in PPA. PPA was defined based on a functional Neurosynth meta‐analysis of studies including the term "place" and further constrained to the lingual and posterior parahippocampal gyri, and posterior‐temporal and temporal‐occipital fusiform cortices. Scenes' perceptual details were quantified as the number of unique objects in it (high‐load: > 4; low‐load: < 4).
Results
During encoding, PPA activity was higher for high‐load than low‐load scenes (P = 2.08e‐06) but did not differ between SCD and CON (P = .763), indicating comparable encoding of perceptual details across groups. Nevertheless, during retrieval, SCD appeared to benefit significantly less from perceptual details than CON (P = .018), as their false alarm rates were similar for high‐ and low‐load scenes (P = .879), whereas CON's were significantly lower for high‐load than low‐load scenes (P = .002).
Conclusions
Although tentative, our results suggest that SCD encode perceptual details similar to CON but use details to a lesser extent than CON when new information must be differentiated from old information during retrieval. Accordingly, memory complaints in SCD may reflect the perception of a 'lower‐resolution' retrieval, especially in the face of new information.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
Background
Subjective cognitive decline (SCD) can predict the progression to mild cognitive impairment. Visual memory deficits in mildly impaired patients relate to decreased activity in ...brain regions beyond the medial temporal lobe, such as the parahippocampal place area (PPA). PPA's response to visual scenes is weaker in healthy older than younger adults but equally associated with memory recognition. PPA's response to scenes' perceptual details during encoding might support that association. Whether perceptual detail processing is reduced in SCD can help elucidate the disparity between perceived decline and normal performance. Here we test whether older adults with SCD ('SCD') use perceptual details to a lesser extent than older adults without SCD ('CON') and whether this is observed during the encoding or retrieval of a scene memory task.
Methods
We measured BOLD‐fMRI activity in 37 healthy older adults (SCD: 16) during encoding, and calculated hit rate, false alarm rate, and total recognition accuracy during retrieval. We analyzed BOLD‐fMRI activity during scene encoding in PPA. PPA was defined based on a functional Neurosynth meta‐analysis of studies including the term "place" and further constrained to the lingual and posterior parahippocampal gyri, and posterior‐temporal and temporal‐occipital fusiform cortices. Scenes' perceptual details were quantified as the number of unique objects in it (high‐load: > 4; low‐load: < 4).
Results
During encoding, PPA activity was higher for high‐load than low‐load scenes (
P
= 2.08e‐06) but did not differ between SCD and CON (
P
= .763), indicating comparable encoding of perceptual details across groups. Nevertheless, during retrieval, SCD appeared to benefit significantly less from perceptual details than CON (
P
= .018), as their false alarm rates were similar for high‐ and low‐load scenes (
P
= .879), whereas CON's were significantly lower for high‐load than low‐load scenes (
P
= .002).
Conclusions
Although tentative, our results suggest that SCD encode perceptual details similar to CON but use details to a lesser extent than CON when new information must be differentiated from old information during retrieval. Accordingly, memory complaints in SCD may reflect the perception of a 'lower‐resolution' retrieval, especially in the face of new information.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background and purpose
Fatigue and low sleep quality in multiple sclerosis (MS) are closely related symptoms. Here, the associations between the brain's functional connectivity (FC) and fatigue and ...low sleep quality were investigated to determine the degree of neural distinctiveness of these symptoms.
Method
A hundred and four patients with relapsing–remitting MS (age 38.9 ± 10.2 years, 66 females) completed the Modified Fatigue Impact Scale and the Pittsburgh Sleep Quality Index and underwent resting‐state functional magnetic resonance imaging. FC was analyzed using independent‐component analysis in sensorimotor, default‐mode, fronto‐parietal and basal‐ganglia networks. Multiple linear regression models allowed us to test the association between FC and fatigue and sleep quality whilst controlling for one another as well as for demographic, disease‐related and imaging variables.
Results
Higher fatigue correlated with lower sleep quality (r = 0.54, p < 0.0001). Higher fatigue was associated with lower FC of the precentral gyrus in the sensorimotor network, the precuneus in the posterior default‐mode network and the superior frontal gyrus in the left fronto‐parietal network, independently of sleep quality. Lower sleep quality was associated with lower FC of the left intraparietal sulcus in the left fronto‐parietal network, independently of fatigue. Specific associations were found between fatigue and the sensorimotor network's global FC and between low sleep quality and the left fronto‐parietal network's global FC.
Conclusion
Despite the high correlation between fatigue and low sleep quality in the clinical picture, our findings clearly indicate that, on the neural level, fatigue and low sleep quality in MS are associated with decreased FC in distinct functional brain networks.
Fatigue and low sleep quality often co‐occur in multiple sclerosis. This study shows that fatigue and low sleep quality are independent at the neural level, involving sensorimotor and fronto‐parietal brain networks, respectively.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The International Prognostic Scoring System has been revised (IPSS-R) to predict prognosis of patients with myelodysplastic syndromes at diagnosis. To validate the use of the IPSS-R assessed before ...transplant rather than at diagnosis we performed a retrospective analysis of the EBMT database. A total of 579 patients had sufficient information available to calculate IPSS-R at transplant. Median overall survival (OS) from transplant was significantly different according to IPSS-R: very low 23.6 months, low 55.0 months, intermediate 19.7 months, high 13.5 months, very high 7.8 months (P<0.001). In a multivariate Cox model the following parameters were significant risk factors for OS: IPSS-R, graft source, age and prior treatment. Median relapse free survival also showed significant differences according to IPSS-R: very low: 23.6 months, low: 24.8 months, intermediate 10.6 months, high 7.9 months, very high 5.5 months (P<0.001). Multivariate risk factors for relapse-free survival (RFS) were: IPSS-R, reduced intensity conditioning, graft source and prior treatment. A trend for an increased relapse incidence was noted for very high risk IPSS-R. We conclude that the IPSS-R at transplant is a useful prognostic score for predicting OS and RFS after transplantation, capturing both disease evolution and response to prior treatment before transplant.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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