bluuebunny/crossref_metadata_2025 huggingface dataset:
Images of the Priesthood: An Analysis of Catholic Sermons from the Late Seventeenth Century
Authors: Dürr Renate
Published: July 2002

“All,therefore, who consider themselves Christians may be absolutely certain that we are all equally priests.”1With this declaration Martin Luther categorically repudiated the Catholic understanding of priesthood as a holy estate with indelible marks bestowed at consecration. According to the reformers all Christians, in principle, have the same authority in word and sacrament, but only those authorized by the respective community of believers may wield it. This assessment not only reflected certain irregularities within the clergy but also signified a completely new definition of the priesthood. It cannot be understood outside the context of existing contemporary criticism—not only from reformatory circles—of the state of numerous parishes who suffered under poorly educated, morally unacceptable (from a contemporary point of view) or indeed absent clergymen. The Catholic Church's answer to this challenge, therefore, had two aims: plans for far-reaching reforms were intended to renew the image of priests and, primarily, to provide effective pastoral care. Polemical theological debates against Protestants and discussions within the Catholic Church were intended not only to strengthen the certainty of the fundamental essence of priestly identity but also to facilitate a differentiation of Catholic from Protestant understanding. The decisions of the Council of Trent also touched both areas. At the 23rdsession both the theological basis of the sacrament of consecration and the plans to reform the rules concerning the bishops' obligatory residence in their parishes were debated.2
Self- diffusion of H2O in stevensite gel: effects of temperature and clay fraction
Authors: Nakashima Y.
Published: July 2002

Self-diffusion coefficients of water molecules (1H2O) in Na-stevensite gel were measured by pulsed-gradient spin-echo (PGSE) proton nuclear magnetic resonance (NMR). The effects of clay fraction (0.00 37.7 wt.%) and temperature (20.0 60.3°C) were studied. The results show: (1) phenomenologically, the H2O self-diffusivity in the clay gel,D, is expressed byD/D0= exp( 0.0198w) whereD0is the H2O self-diffusivity in bulk water of the temperature andwis the clay weight fraction (wt.%). (2) The activation energy of the diffusivity in the stevensite gel is nearly equal to that in bulk water. Thus, the normalized diffusivity,D/D0, obeys a temperature-independent master curve. (3) The exponential dependence ofD/D0onwforw<25 wt.% (≈ 12 vol.%) can be explained by a random walk model, in which unbound H2O molecules diffuse in the geometrically tortuous pore structure of randomly scattered clay mineral grains. (4) The measured diffusivity can also be explained by a model of unbound H2O diffusing in a polymer network with a specific meshsize or characteristic interval of the crosslinkage.
Tungsten-bearing rutile from the Kori Kollo gold mine, Bolivia
Authors: Rice C. M. , Darke K. E. , Still J. W. , Lachowski E. E.
Published: July 2002

W-bearing rutile formed during alteration of jarosite by resurgent hydrothermal fluids in the oxide zone of the Kori Kollo gold deposit. The rutile shows sector zoning in basal sections and well developed multiple growth zones, both defined in backscatter electron images by variations in the W content. The maximum WO3content is 5.3 wt.% and W substitutes for Ti with double substitution of Fe to maintain charge balance. The causes of multiple growth bands are considered to be changes in externally controlled variables occurring in a shallow hydrothermal system. Whereas Ti is probably leached from biotite in dacitic rocks, the W is introduced by hydrothermal fluids.
A soluble form of the murine common γ chain is present at high concentrations in vivo and suppresses cytokine signaling
Authors: Meißner Udo , Blum Horst , Schnare Markus , Röllinghoff Martin , Gessner André
Published: July 2002

The common gamma-chain (γc) is a component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 and is essential for their signal transduction. Western blotting and a newly established enzyme-linked immunosorbent assay detected substantial constitutive levels (50-250 ng/mL) of soluble γc (sγc) in sera of murine inbred strains. It was demonstrated that purified immune cells, such as T, B, and natural killer cells, and macrophages released this protein after activation. Transfection experiments with cDNA encoding the full-length γc showed that shedding of the transmembrane receptor led to the release of sγc. The shedding enzymes, however, appeared to be distinct from those cleaving other cytokine receptors because inhibitors of metalloproteases (eg, TAPI) did not influence sγc release. In vivo, superantigen-induced stimulation of T cells enhanced sγc serum concentrations up to 10-fold within 6 hours. Because these findings demonstrated regulated expression of a yet unknown molecule in the immune response, further experiments were performed to assess the possible function(s) of sγc. A physiological role of sγc was indicated by its capacity to specifically inhibit cell growth induced by γc-dependent cytokines. Mutational analysis revealed that the C-terminus and the WSKWS motif are essential for the cytokine inhibitory effect of the sγc and for binding of the molecule to cytokine receptor-expressing cells. Thus, competitive displacement of the transmembrane γc by excess sγc is the most likely mechanism of cell growth inhibition. It was implied that naturally produced sγc is a negative modulator of γc-dependent cytokines.
The soluble murine type I interferon receptor Ifnar-2 is present in serum, is independently regulated, and has both agonistic and antagonistic properties
Authors: Hardy Matthew P. , Owczarek Catherine M. , Trajanovska Suzana , Liu Xiang , Kola Ismail , Hertzog Paul J.
Published: July 2002

The ability to modify responses to type I interferons (IFNs) could alter processes such as hematopoiesis and immunity, which involve endogenous IFNs and responses to exogenous IFNs. The data presented here support a significant role for a recently identified soluble isoform of the murine type I IFN receptor, muIfnar-2a, as an efficient regulator of IFN responses. The messenger RNA (mRNA) transcript encoding muIfnar-2a is generally more abundant than that encoding the transmembrane isoform, muIfnar-2c. Furthermore, the ratio ofmuIfnar-2a:2c transcripts varied from more than 10:1 in the liver and other organs to less than 1:1 in bone-marrow macrophages, indicating independent regulation of the 2 transcripts encoding receptor isoforms and suggesting that the soluble muIfnar-2a levels are biologically relevant in some organs. Western blot analysis showed that soluble muIfnar-2 was present at high levels in murine serum and other biologic fluids and bound type I IFN. Recombinant muIfnar-2a competitively inhibited the activity of both IFNα and β in reporter assays using the L929 cell line and in antiproliferative and antiviral assays using primary cells. Surprisingly, using primary thymocytes fromIfnar-2−/− mice, recombinant muIfnar-2a formed a complex with IFN α or β and muIfnar-1 at the cell surface and transmitted an antiproliferative signal. These data indicate potential dual actions of soluble muIfnar-2 and imply that a signal can be transduced through the Ifnar-1 chain of the receptor complex in the absence of the cytoplasmic domain of Ifnar-2. Therefore, our results suggest that soluble Ifnar-2 is an important regulator of endogenous and systemically administered type I IFN.
Characterization of novel natural killer (NK)–cell and γδ T-cell lines established from primary lesions of nasal T/NK-cell lymphomas associated with the Epstein-Barr virus
Authors: Nagata Hiroshi , Konno Akiyoshi , Kimura Nobuhiro , Zhang Yu , Kimura Michiko , Demachi Ayako , Sekine Teruaki , Yamamoto Kohtaro , Shimizu Norio
Published: July 2002

Studies on nasal T/natural killer (NK)–cell lymphoma have been hampered by its tendency to cause necrosis. Thus, the establishment of cell lines of this neoplasm would seem to be valuable. This study attempted to establish cell lines from primary lesions of this tumor, and successfully obtained 2 novel Epstein-Barr virus (EBV)–positive cell lines, SNK-6 and SNT-8, by means of high-dose recombinant interleukin 2. Flow cytometry showed that SNK-6 had an NK-cell phenotype, CD3−CD4−CD8−CD19−CD56+T-cell receptor (TCR) α/β− TCR γ/δ−, whereas SNT-8 was CD3+CD4−CD8−CD19−CD56+TCR α/β− TCR γ/δ+. These were consistent with immunophenotypes of their original tumors, and the cell lines had monoclonal EBV clones identical to ones in their original tumors. Thus, the cell lines developed from cells forming the primary lesions. Genotypic analysis showed that SNK-6 had unrearranged TCR and immunoglobulin heavy-chain genes, supporting the conclusion that SNK-6 was of NK-cell lineage. On the other hand, SNT-8 had rearranged TCR β-, γ-, and δ-chain genes, and together with its phenotype, SNT-8 proved to be a γδ T-cell line. This is the first report of the establishment of cell lines from primary lesions of nasal T/NK cell lymphomas, and the results demonstrated that there are at least 2 lineages, NK- and γδ T-cell, in this neoplasm. Moreover, it has been suggested that nasal T/NK cell lymphomas of these lineages may belong to the same clinicopathologic entity because both types of cases shared common clinical and histopathologic features.
Selective down-regulation of high-affinity IgE receptor (FcεRI) α-chain messenger RNA among transcriptome in cord blood–derived versus adult peripheral blood–derived cultured human mast cells
Authors: Iida Makoto , Matsumoto Kenji , Tomita Hisashi , Nakajima Toshiharu , Akasawa Akira , Ohtani Noriko Yuyama , Yoshida Ning Lu , Matsui Keiko , Nakada Akiko , Sugita Yuji , Shimizu Yuji , Wakahara Shunichi , Nakao Toru , Fujii Yasuyuki , Ra Chisei , Saito Hirohisa
Published: July 2002

Substantial numbers of human mast cells (MCs) were generated from umbilical cord blood (CB) and from adult peripheral blood (PB). A single CB progenitor produced 15 436 MCs, whereas a single PB progenitor produced 807 MCs on average. However, PB-derived MCs were far more active than CB-derived MCs in terms of high-affinity IgE receptor (FcεRI)-mediated reactions. One million sensitized PB-derived MCs released 3.6 μg histamine, 215 pg IL-5, and 14 ng granulocyte macrophage–colony-stimulating factor (GM-CSF), whereas 106 sensitized CB-derived MCs released only 0.8 μg histamine, 31 pg IL-5, and 0.58 ng GM-CSF on anti-IgE challenge. However, ionophore A23 187 released similar levels of histamine from the 2 MC types. PB-derived MCs highly expressed surface FcεRI α chain, and CB-derived MCs almost lacked it in the absence of IgE. PB-derived MCs expressed approximately 5 times higher levels of messenger RNA (mRNA) for FcεRI α chain than CB-derived MCs, but mRNAs for β and γ chains of the receptors were equally expressed. Among the approximately 5600 kinds of full-length human genes examined by using the high-density oligonucleotide probe-array system, FcεRIα was ranked the fifth most increased transcript in PB-derived MCs. The 4 other increased transcripts were unrelated to MC function. These results suggest that IgE-mediated reactions may be restricted during early infancy through the selective inhibition of FcεRIα transcription, which is probably committed at progenitor stages and is, at least in part, cytokine-insensitive.
Phorbol ester up-regulates capacities for nuclear translocation and phosphorylation of 5-lipoxygenase in Mono Mac 6 cells and human polymorphonuclear leukocytes
Authors: Werz Oliver , Klemm Jenny , Samuelsson Bengt , Rådmark Olof
Published: July 2002

The leukotrienes are inflammatory mediators derived from arachidonic acid. It was demonstrated that the priming of leukocytes with phorbol-12-myristate-13-acetate (PMA) leads to the increased formation of 5-lipoxygenase (5-LO) products in parallel with the increased association of 5-LO with the nucleus and the activation of kinases that can phosphorylate 5-LO in vitro. Stimulation of the monocytic cell line Mono Mac 6 with calcium ionophore gave low 5-LO product formation and no detectable redistribution of 5-LO. However, after priming of Mono Mac 6 cells with phorbol esters, ionophore led to the association of 45% to 75% of cellular 5-LO with the nuclear membrane, to 5-LO kinase activation, to enhanced release of arachidonate, and to substantial leukotriene synthesis. Similar results were obtained for human polymorphonuclear leukocytes stimulated with low-dose ionophore. In addition, for each cell type, PMA priming up-regulated leukotriene biosynthesis in the presence of exogenous arachidonic acid. A protein kinase inhibitor, calphostin C, reduced the association of 5-LO with the nucleus and 5-LO kinase activity, and the formation of 5-LO products was inhibited. These results suggest that PMA up-regulates leukotriene biosynthesis not only by increasing the release of endogenous arachidonate, but also by increasing the capacity for 5-LO phosphorylation and for the translocation of 5-LO to the nucleus in leukocytes.
Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma
Authors: Shaughnessy John , Gabrea Ana , Qi Ying , Brents Leslie , Zhan Fenghaung , Tian Erming , Sawyer Jeffrey , Barlogie Bart , Bergsagel P. Leif , Kuehl Michael
Published: July 2002

Reciprocal chromosomal translocations, which are mediated by errors in immunoglobulin heavy chain (IgH) switch recombination or somatic hypermutation as plasma cells are generated in germinal centers, are present in most multiple myeloma (MM) tumors. These translocations dysregulate an oncogene that is repositioned in proximity to a strong IgH enhancer. There is a promiscuous array of nonrandom chromosomal partners (and oncogenes), with the 3 most frequent partners (11q13 [cyclin D1]; 4p16 [FGFR3 and MMSET]; 16q23 [c-maf]) involved in nearly half of MM tumors. It is now shown that a novel t(6;14)(p21;q32) translocation is present in 1 of 30 MM cell lines and that this cell line uniquely overexpresses cyclin D3. The cloned breakpoint juxtaposes gamma 4 switch sequences with 6p21 sequences that are located about 65 kb centromeric to the cyclin D3 gene. By metaphase chromosome analysis, the t(6;14) (p21;q32) translocation was identified in 6 of 150 (4%) primary MM tumors. Overexpression of cyclin D3 messenger RNA (mRNA) was identified by microarray RNA expression analysis in 3 of 53 additional primary MM tumors, each of which was found to have a t(6;14) translocation breakpoint by interphase fluorescence in situ hybridization analysis. One tumor has a t(6;22)(p21;q11) translocation, so that cyclin D3 is bracketed by the IgL and IgH breakpoints. These results provide the first clear evidence for primary dysregulation of cyclin D3 during tumorigenesis. It is suggested that the initial oncogenic event for most MM tumors is a primary immunoglobulin translocation that dysregulates cyclin D1, cyclin D3, and other oncogenes to provide a proliferative stimulus to postgerminal center plasma cells.
Lipoprotein (a) binds and inactivates tissue factor pathway inhibitor: a novel link between lipoproteins and thrombosis
Authors: Caplice Noel M. , Panetta Carmelo , Peterson Timothy E. , Kleppe Laurel S. , Mueske Cheryl S. , Kostner Gert M. , Broze George J. , Simari Robert D.
Published: July 2002

Lipoprotein (a) [Lp(a)] has been associated with both anti-fibrinolytic and atherogenic effects. However, no direct link currently exists between this atherogenic lipoprotein and intravascular coagulation. The current study examined the binding and functional effects of Lp(a), its lipoprotein constituents, apoliprotein (a) [apo(a)] and low-density lipoprotein (LDL), and lysine-plasminogen (L-PLG), which shares significant homology with apo(a), on tissue factor pathway inhibitor (TFPI), a major regulator of tissue factor-mediated coagulation. Results indicate that Lp(a), apo(a), and PLG but not LDL bound recombinant TFPI (rTFPI) in vitro and that apo(a) bound to a region spanning the last 37 amino acid residues of the c-terminus of TFPI. The apparent binding affinity for TFPI was much higher for Lp(a) (KD ∼150 nM) compared to PLG (KD ∼800 nM) and nanomolar concentrations of apo(a) (500 nM) inhibited PLG binding to TFPI. Lp(a) also inhibited in a concentration-dependent manner rTFPI activity and endothelial cell surface TFPI activity in vitro, whereas PLG had no such effect. Moreover physiologic concentrations of PLG (2 μM) had no effect on the concentration-dependent inhibition of TFPI activity induced by Lp(a). In human atherosclerotic plaque, apo(a) and TFPI immunostaining were shown to coexist in smooth muscle cell–rich areas of the intima. These data suggest a novel mechanism whereby Lp(a) through its apo(a) moiety may promote thrombosis by binding and inactivating TFPI.
Characterization of the T-cell repertoire in autologous graft-versus-host disease (GVHD): evidence for the involvement of antigen-driven T-cell response in the development of autologous GVHD
Authors: Miura Yuji , Thoburn Christopher J. , Bright Emilie C. , Sommer Matthias , Lefell Susan , Ueda Mikio , Nakao Shinji , Hess Allan D.
Published: July 2002

Administration of cyclosporine A (CsA) after autologous stem cell transplantation elicits an autoimmune syndrome with pathology similar to graft-versus-host disease (GVHD). This syndrome, termed autologous GVHD, is associated with the appearance of autoreactive T cells directed at major histocompatibility class (MHC) class II antigens. In the rat model of autologous GVHD, clonal analysis reveals that the effector T cells are highly conserved and recognize a peptide from the invariant chain peptide presented by MHC class II. Although human autologous GVHD effector T cells share a similar phenotypic specificity, clonality of the response in humans has not been determined. To examine the human effector T-cell response, the T-cell repertoire of peripheral blood lymphocytes was assessed by complementarity-determining region 3 (CDR3) size distribution analysis and T-cell clonotype analysis in 26 patients treated with CsA after transplantation. Autologous GVHD developed in 3 of 4 patients with human leukocyte antigen (HLA)-DRB1*0701, and clonal expansions of β-chain variable region (BV)16+ T cells were shared. Clonal expansions within BV15+ and BV22+ T cells were also detected in 4 of 6 patients with HLA-DRB1*1501 and in 3 of 4 patients with HLA-DRB1*0401, respectively. Sequencing of BV16 cDNA for which the CDR3 size pattern exhibited apparent clone predominance revealed an identical CDR3 peptide sequence in 2 different patients, one with HLA-DRB1*0701 and the other with HLA-DRB1*1502. These findings indicate that the discrete antigen-driven expansion of T cells is involved in autologous GVHD.
A comparison of murine T-cell–depleted adult bone marrow and full-term fetal blood cells in hematopoietic engraftment and immune reconstitution
Authors: Chen Benny J. , Cui Xiuyu , Sempowski Gregory D. , Gooding Maria E. , Liu Congxiao , Haynes Barton F. , Chao Nelson J.
Published: July 2002

Umbilical cord blood has been increasingly used as a source of hematopoietic stem cells. A major area of concern for the use of cord blood transplantation is the delay in myeloid and lymphoid recovery. To directly compare myeloid and lymphoid recovery using an animal model of bone marrow and cord blood as sources of stem cells, hematopoietic engraftment and immune recovery were studied following infusion of T-cell–depleted adult bone marrow or full-term fetal blood cells, as a model of cord blood in a murine allogeneic transplantation model (C57BL/6 [H-2b] → BALB/c [H-2d]). Allogeneic full-term fetal blood has poorer radioprotective capacity but greater long-term engraftment potential on a cell-to-cell basis compared with T-cell–depleted bone marrow. Allogeneic full-term fetal blood recipients had decreased absolute numbers of T, B, and dendritic cells compared with bone marrow recipients. Splenic T cells in allogeneic full-term fetal blood recipients proliferated poorly, were unable to generate cytotoxic effectors against third-party alloantigens in vitro, and failed to generate alloantigen-specific cytotoxic antibodies in vivo. In addition, reconstituting T cells in fetal blood recipients had decreased mouse T-cell receptorδ single-joint excision circles compared with bone marrow recipients. At a per-cell level, B cells from fetal blood recipients did not proliferate as well as those found in bone marrow recipients. These results suggest that full-term fetal blood can engraft allogeneic hosts across the major histocompatibility barrier with slower hematopoietic engraftment and impaired immune reconstitution.
Successful treatment of pure red cell aplasia with rituximab in patients with chronic lymphocytic leukemia
Authors: Ghazal Hassan
Published: July 2002

Pure red cell aplasia (PRCA) is a rare complication in patients with chronic lymphocytic leukemia (CLL). It is characterized by reticulocytopenia and by an absence of red cell precursors in the bone marrow. Unlike autoimmune hemolytic anemia, which is characterized by an increased number of reticulocytes, positive Coombs test findings, and a high serum level of lactate dehydrogenase. Two patients with B-cell CLL are reported to have developed PRCA, one while on chemotherapy with fludarabine and one seeking treatment for de novo PRCA. Both responded dramatically to therapy with monoclonal antibody rituximab (Rituxan) in a short period of time and continued to be transfusion-independent. These are the first 2 reported patients for whom rituximab treatment for PRCA in CLL was successful, and this treatment deserves further investigation.
Different ploidy levels of megakaryocytes generated from peripheral or cord blood CD34+ cells are correlated with different levels of platelet release
Authors: Mattia Gianfranco , Vulcano Francesca , Milazzo Luisa , Barca Alessandra , Macioce Giampiero , Giampaolo Adele , Hassan H. Jane
Published: July 2002

Ploidy could be the key to understanding megakaryocyte (MK) biology and platelet production. Human CD34+ cells purified from umbilical cord blood (CB) and peripheral blood (PB) were investigated on their capability to give rise, in a serum-free medium containing thrombopoietin, to MKs and platelets. CB-MKs showed reduced polyploidization and platelet number compared with PB-MKs, but a similar membrane phenotype. Most CB-MKs showed a 2N content of DNA (∼80%) and only 2.6% had 8N, whereas 40% of the PB cells had 8N or more. Platelets were substantially released in PB culture from day 12; at day 14 the CB-derived MKs were able to release platelets although at a reduced level (∼35%), correlating with their reduced size. A direct correlation was demonstrated by sorting polyploid cells from PB-MKs and evaluating the platelets released in the supernatant. Furthermore, the study analyzed the expression and distribution of cyclin D3 and cyclin B1. Cyclin D3 protein was increased in PB in comparison to CB-MKs; in PB culture most cells rapidly became positive, whereas in CB-derived cells cyclin D3 expression was evident only from day 9 and in a reduced percentage. Cyclin B1 was essentially localized at the nuclear level in the CB and was expressed during the whole culture. In PB-MKs, at day 9, a reduction was observed, correlating with an advanced ploidy state. The data indicate the inability of the CB-MKs to progress in the endomitotic process and a direct correlation between DNA content and platelet production.
Blockade of B7/CD28 in mixed lymphocyte reaction cultures results in the generation of alternatively activated macrophages, which suppress T-cell responses
Authors: Tzachanis Dimitrios , Berezovskaya Alla , Nadler Lee M. , Boussiotis Vassiliki A.
Published: July 2002

Blockade of B7/CD28 costimulation allows human haploidentical bone marrow transplantation without graft-versus-host disease. This study shows that blockade of B7/CD28 in anergizing mixed lymphocyte reaction (MLR) cultures of peripheral blood mononuclear cells results in the generation of alternatively activated macrophages (AAMΦ). In contrast, priming MLR cultures result in generation of classically activated macrophages (CAMΦ). AAMΦ had enhanced expression of CD14, major histocompatibility complex class II, and CD23; produced alternative macrophage activation-associated CC-chemokine 1 (AMAC-1) chemokine; and displayed increased phagocytotic activity but decreased ability for antigen presentation. Suppression subtractive hybridization revealed that although AAMΦ had undergone terminal maturation and differentiation, they entered a distinct gene expression program as compared with CAMΦ and selectively expressed β2-microglobulin, lysozyme, ferritin heavy and light chain, and the scavenger receptors macrophage mannose receptor and sortilin. Anergic T cells isolated from cultures that led to the development of AAMΦ produced low amounts of interleukin-2 (IL-2), IL-4, and interferon-γ, but high amounts of IL-10. Addition of anti–IL-10 neutralizing monoclonal antibody in anergizing cultures reversed the functional characteristics of AAMΦ, indicating that at least one mechanism involved in the generation of AAMΦ was mediated by IL-10. Importantly, when added in MLR cultures, AAMΦ suppressed T-cell responses. Therefore, besides direct inhibition of T-cell costimulation, blockade of B7/CD28 may facilitate induction of T-cell unresponsiveness by generating AAMΦ. Because in healthy individuals, AAMΦ are found in the placenta and lung, where they protect from unwanted immune reactivity, the results suggest that AAMΦ may play a critical role in the induction of transplantation tolerance.
Glycated Hemoglobin A1c Time in Range and Dementia in Older Adults With Diabetes
Authors: Underwood Patricia C. , Zhang Libin , Mohr David C. , Prentice Julia C. , Nelson Richard E. , Budson Andrew E. , Conlin Paul R.
Published: August 2024

Importance

Individuals with diabetes commonly experience Alzheimer disease and related dementias (ADRD). Factors such as hypoglycemia, hyperglycemia, and glycemic variability have been associated with increased risk of ADRD. Traditional glycemic measures, such as mean glycated hemoglobin A1c (HbA1c), may not identify the dynamic and complex pathophysiologic factors in the association between diabetes and ADRD. The HbA1c time in range (TIR) is a previously developed measure of glycemic control that expresses HbA1c stability over time within specific ranges. This measure may inform the current understanding of the association between glucose levels over time and ADRD incidence.

Objective

To examine the association between HbA1c TIR and incidence of ADRD in older veterans with diabetes.

Design, Setting, and Participants

The study sample for this cohort study was obtained from administrative and health care utilization data from the Veterans Health Administration and Medicare from January 1, 2004, to December 31, 2018. Veterans 65 years or older with diabetes were assessed. Participants were required to have at least 4 HbA1c tests during the 3-year baseline period, which could start between January 1, 2005, and December 31, 2014. Data analysis was conducted between July and December 2023.

Main Outcomes and Measures

Hemoglobin A1c TIR was calculated as the percentage of days during baseline in which HbA1c was in individualized target ranges based on clinical characteristics and life expectancy, with higher HbA1c TIR viewed as more favorable. The association between HbA1c TIR and ADRD incidence was estimated. Additional models considered ADRD incidence in participants who were above or below HbA1c target ranges most of the time.

Results

The study included 374 021 veterans with diabetes (mean [SD] age, 73.2 [5.8] years; 369 059 [99%] male). During follow-up of up to 10 years, 41 424 (11%) developed ADRD. Adjusted Cox proportional hazards regression models showed that lower HbA1c TIR was associated with increased risk of incident ADRD (HbA1c TIR of 0 to <20% compared with ≥80%: hazard ratio, 1.19; 95% CI, 1.16-1.23). Furthermore, the direction of out-of-range HbA1c levels was associated with incident ADRD. Having greater time below range (≥60%, compared with ≥60% TIR) was associated with significantly increased risk (hazard ratio, 1.23; 95% CI, 1.19-1.27). Findings remained significant after excluding individuals with baseline use of medications associated with hypoglycemia risk (ie, insulin and sulfonylureas) or with hypoglycemia events.

Conclusions and Relevance

In this study of older adults with diabetes, increased HbA1c stability within patient-specific target ranges was associated with a lower risk of ADRD. Lower HbA1c TIR may identify patients at increased risk of ADRD.
1D Silver Nanowires/2D Graphene Composite Flexible Transparent Electrodes Induced by Superwetting Transfer
Authors: Zhao Xuanting , Zhang Yuqiang , Chen Xingchao , Ma Chuao , Liu Chan , Liu Hongliang , Diao Shen
Published: August 2024

Silver nanowires (AgNWs) are promising materials for the fabrication of high‐performance flexible transparent electrodes (FTEs) due to their excellent optoelectronic properties, mechanical flexibility, and low‐cost solution processability. However, one serious obstacle that hinders the application of AgNWs‐based electrodes is the high contact resistance between AgNWs. Established methods for reducing contact resistance such as light‐induced welding, heat‐induced welding, and chemical welding require complex post‐treatment of the prepared AgNWs electrodes. Herein, a fully solution‐processable strategy is reported based on superwetting‐induced transfer for the preparation of composite FTEs electrodes without additional complex post‐process. The generated composite electrode is composed of 1D AgNWs as the percolation network and 2D graphene nanosheets as the conductivity‐enhanced component, significantly reducing the sheet resistance of the AgNWs film from 80.6 to 27.1 Ω·sq−1 while maintaining optical transmittance as high as 89.0%. The composite electrodes also exhibit superior mechanical bending stability and chemical stability. The composite electrodes are successfully applied to transparent heating devices, which show favorable thermal stability and heating effect. This study provides a new manner for the preparation of high‐performance FTEs, which can be compatible with large‐area and continuous production.
Primate cerebrospinal fluid CHI3L1 reflects brain TREM2 agonism
Authors: Schauer Stephen P. , Cho Chang Hoon , Novikova Gloriia , Roth Gillie A. , Lee Julie , Sharma Anup D. , Foley Alejandro R. , Ng Carl , Shen Philip , Choi Meena , Ma Taylur P. , Phu Lilian , Budayeva Hanna G. , Cheung Tommy K. , Lalehzadeh Guita , Imperio Jose , Ngu Hai , Etxeberria Ainhoa , Liang Yuxin , Rezzonico Mitchell G. , Dourado Michelle , Huang Kevin , Lai Zijuan , Hokom Martha , Pandya Nikhil J. , Newton Dwight , Abdel‐Haleem Alyaa M. , Chan Pamela , Lee Donna , Tassew Nardos G. , Sangaraju Dewakar , O'Connor Deborah , Hötzel Isidro , Stark Kimberly L. , Chou Carolina , Foreman Oded , Easton Amy , Wildsmith Kristin R. , Sperinde Gizette , Rose Christopher M. , Friedman Brad A. , Fuji Reina N. , Weimer Robby M. , Meilandt William J. , Sadekar Shraddha , Nugent Alicia A. , Biever Anne
Published: August 2024

INTRODUCTION

Triggering receptor expressed on myeloid cells 2 (TREM2) agonists are being clinically evaluated as disease‐modifying therapeutics for Alzheimer's disease. Clinically translatable pharmacodynamic (PD) biomarkers are needed to confirm drug activity and select the appropriate therapeutic dose in clinical trials.

METHODS

We conducted multi‐omic analyses on paired non‐human primate brain and cerebrospinal fluid (CSF), and stimulation of human induced pluripotent stem cell–derived microglia cultures after TREM2 agonist treatment, followed by validation of candidate fluid PD biomarkers using immunoassays. We immunostained microglia to characterize proliferation and clustering.

RESULTS

We report CSF soluble TREM2 (sTREM2) and CSF chitinase‐3‐like protein 1 (CHI3L1/YKL‐40) as PD biomarkers for the TREM2 agonist hPara.09. The respective reduction of sTREM2 and elevation of CHI3L1 in brain and CSF after TREM2 agonist treatment correlated with transient microglia proliferation and clustering.

DISCUSSION

CSF CHI3L1 and sTREM2 reflect microglial TREM2 agonism and can be used as clinical PD biomarkers to monitor TREM2 activity in the brain.

Highlights

CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2) reflects brain target engagement for a novel TREM2 agonist, hPara.09.

CSF chitinase‐3‐like protein 1 reflects microglial TREM2 agonism.

Both can be used as clinical fluid biomarkers to monitor TREM2 activity in brain.
Actomyosin forces in cell migration: Moving beyond cell body retraction
Authors: Weißenbruch Kai , Mayor Roberto
Published: August 2024

In textbook illustrations of migrating cells, actomyosin contractility is typically depicted as the contraction force necessary for cell body retraction. This dogma has been transformed by the molecular clutch model, which acknowledges that actomyosin traction forces also generate and transmit biomechanical signals at the leading edge, enabling cells to sense and shape their migratory path in mechanically complex environments. To fulfill these complementary functions, the actomyosin system assembles a gradient of contractile energy along the front‐rear axis of migratory cells. Here, we highlight the hierarchic assembly and self‐regulatory network structure of the actomyosin system and explain how the kinetics of different nonmuscle myosin II (NM II) paralogs synergize during contractile force generation. Our aim is to emphasize how protrusion formation, cell adhesion, contraction, and retraction are spatiotemporally integrated during different modes of migration, including chemotaxis and durotaxis. Finally, we hypothesize how different NM II paralogs might tune aspects of migration in vivo, highlighting future research directions.
Luminous blue carbon quantum dots employing Anisomeles indica (catmint) induce apoptotic signaling pathway in triple negative breast cancer (TNBC) cells
Authors: Kumar Ponnuchamy , Mahalakshmi Marimuthu , Anitha Selvaraj , Durgadevi Sabapathi , Govarthanan Muthusamy
Published: August 2024

Herein, luminous blue carbon quantum dots (CDs) employing Anisomeles indica (Catmint) were reported with imaging, self‐targeting, and therapeutic effects on triple‐negative breast cancer (TNBC, MDA‐MB‐231) cells. The salient features of CDs generated from catmint are as follows: i) optical studies confirm CDs with excitation‐dependent emission; ii) high‐throughput characterization authenticates the formation of CDs with near‐spherical shape with diameter ranging between 5 and 15 nm; iii) CDs induce cytotoxicity (3.22 ± 0.64 μg/ml) in triple‐negative breast cancer (TNBC, MDA‐MB‐231) cells; iv) fluorescence microscopy demonstrates that CDs promote apoptosis by increasing reactive oxygen species (ROS) and decreasing mitochondrial membrane potential; v) CDs significantly up‐regulate pro‐apoptotic gene expression levels such as caspases‐8/9/3. Finally, our work demonstrates that catmint‐derived CDs are prospective nanotheranostics that augment cancer targeting and imaging.
Retinoids Molecular Probes by Late‐stage Azide Insertion – Functional Tools to Decrypt Retinoid Metabolism
Authors: Coulleray Jessica , Kindler Alexia , Rima Mohamad , Cahuzac Héloïse , Rochel Natacha , Chaubet Guilhem , Krezel Wojciech , Wagner Alain
Published: August 2024

Studying the complex and intricate retinoids metabolic pathways by chemical biology approaches requires design and synthesis of biologically functional molecular probes. Only few of such molecular retinoid probes could be found in literature, most of them bearing a molecular structure quite different from natural retinoids. To provide close‐to‐native retinoid probes, we have developed a versatile late‐stage method for the insertion of azide function at the C4 position of several retinoids. This one‐step process opens straightforward access to different retinoid and carotenoid probes from commercially available precursors. We have further demonstrated that the different molecular probes retain ability of the original compound to activate genes’ transcription, despite azide insertion, highlighting biological activities that were further validated in zebrafish in vivo model. The present work paves the way to future studies on vitamin A's metabolism.
Kondensatkühlung verschafft Effizienzplus
Authors: Bälz Uwe , Wäsche Timo
Published: August 2024

Wasserdampf ist als Wärmeträger etabliert und seine optimale Nutzung wird angesichts steigender Energiepreise immer wichtiger. Für die energiesparende Regelung der Dampf‐Wärmeübertragung gibt es die dampfseitige Regelung und die kondensatseitige Anstauregelung. Den effizientesten Prozess erreicht mit einer Kondensatanstauregelung.
A new design of double predictive proportional integral control strategy for first order plus dead time industrial processes
Authors: Hu Chonggao , Hou Yuqiao , Bai Jianjun , Zou Hongbo
Published: August 2024

When the Smith predictive controller controls the first‐order plus dead time process, it is too sensitive to the parameter changes of the system, leading to poor system stability and no practical application value. First, this paper derives and proves the equivalent form of the Smith‐proportional‐integral‐derivative (PID) control strategy as a predictive PI (PPI) control strategy. Second, this paper proposes a new double predictive PI control strategy (DPPI), where the DPPI controller mainly consists of a predictive PI controller and a predictor with an integral link. Again, for the integral predictor in the DPPI control strategy, two new regulation parameters are introduced, which can effectively regulate the control performance and robustness of the control system, improve the degree of freedom of the controller design, and give the principles for the adjustment of the DPPI controller parameters. Finally, it has been verified through simulation experiments that the proposed method can significantly improve response speed and effectively resist external perturbations with good control effect and robust stability.
Clinical best practices in interdisciplinary management of human epidermal growth factor receptor 2 antibody‐drug conjugates–induced interstitial lung disease/pneumonitis: An expert consensus in China
Authors: Xu Chunwei , Chen Zhanhong , Xia Yuanli , Shi Yanxia , Fu Peifen , Chen Yiding , Wang Xian , Zhang Lili , Li Hengyu , Chen Wenyan , Fu Jianfei , Huang Liming , Shu Jingde , Wang Ouchen , Wu Weizhu , Xie Bojian , Wang Ting , Zhang Weiping , Shen Shurong , Li Qun , Luo Ting , Zhang Bin , Xie Yanru , Wang Hongxia , Wang Qian , Wang Wenxian , Li Ziming , Song Zhengbo , Fang Wenfeng , Zhong Wenzhao , Zhang Yongchang , Zhan Ping , Liu Hongbing , Lv Tangfeng , Miao Liyun , Min Lingfeng , Wang Feng , Meng Rui , Zhu Youcai , Wang Lin , Wan Bing , Wang Dong , Hao Yue , Zhou Jianya , Huang Long , Zhang Zhang , Lv Donglai , Fang Meiyu , Lu Yuanzhi , Si Lu , Song Yong , Wang Xiaojia
Published: August 2024

Antibody–drug conjugates (ADCs) have demonstrated effectiveness in treating various cancers, particularly exhibiting specificity in targeting human epidermal growth factor receptor 2 (HER2)‐positive breast cancer. Recent advancements in phase 3 clinical trials have broadened current understanding of ADCs, especially trastuzumab deruxtecan, in treating other HER2‐expressing malignancies. This expansion of knowledge has led to the US Food and Drug Administration's approval of trastuzumab deruxtecan for HER2‐positive and HER2‐low breast cancer, HER2‐positive gastric cancer, and HER2‐mutant nonsmall cell lung cancer. Concurrent with the increasing use of ADCs in oncology, there is growing concern among health care professionals regarding the rise in the incidence of interstitial lung disease or pneumonitis (ILD/p), which is associated with anti‐HER2 ADC therapy. Studies on anti‐HER2 ADCs have reported varying ILD/p mortality rates. Consequently, it is crucial to establish guidelines for the diagnosis and management of ILD/p in patients receiving anti‐HER2 ADC therapy. To this end, a panel of Chinese experts was convened to formulate a strategic approach for the identification and management of ILD/p in patients treated with anti‐HER2 ADC therapy. This report presents the expert panel's opinions and recommendations, which are intended to guide the management of ILD/p induced by anti‐HER2 ADC therapy in clinical practice.
Filamentous Aerogels for Electromagnetic Shielding
Authors: Rezaei Zahra , Prince Elisabeth , Kamkar Milad
Published: August 2024

The unrelenting expansion of electronics and wireless communications has brought an onslaught of electromagnetic interference and environmental radiation as a new form of pollution. Filamentous aerogels offer a viable solution to this growing challenge: with their hierarchical inter‐ and intra‐filament porosities, they have recently shown great promise as EMI shielding materials. The multidirectional EM wave scattering within their hierarchical porous structure enhances attenuation much higher than conventional monolithic aerogels. This concept paper summarizes recent groundbreaking efforts in filamentous aerogel fabrication, with a focus on liquid streaming and 3D printing approaches. Further research and development could see filamentous aerogels emerge as next‐generation materials to combat the intensification of electromagnetic environmental impacts.
Research on linear active disturbance rejection control strategy based on grid‐forming inverters
Authors: Hu Meng Jie , Tang Yu
Published: August 2024

Grid‐forming inverters play a vital role in connecting renewable energy sources to the grid, and maintaining stable output voltage is essential for system operation. However, traditional dual‐PI voltage–current loop control suffers from slow response and weak disturbance rejection, leading to suboptimal control performance of grid‐connected inverter output voltage. Moreover, employing traditional dual‐PI control in grid‐connected inverters results in low output impedance, making them prone to subsynchronous oscillations and instability under strong grid conditions. To address these challenges, this study introduces a novel dual‐loop control strategy based on linear active disturbance rejection control (LADRC), wherein voltage loop is regulated by LADRC while current loop employs PI control. Quantitative analysis and experimental findings demonstrate that compared with traditional dual‐PI voltage–current loop control, the LADRC‐based dual‐loop control strategy offers higher bandwidth and lower steady‐state error, thereby enhancing the tracking speed and precision of grid‐forming inverter output voltage. The LADRC‐based dual‐loop control strategy reduces output impedance in grid‐forming inverter systems, lowering THD of output voltage and improving harmonic suppression under nonlinear loads. Experimental results show its robustness against strong grid conditions compared with traditional dual‐PI control, ensuring stable output voltage.
Genomic analysis of NE Atlantic sardine (Sardina pilchardus) reveals reduced variation in a recently established North Sea population and directs reconsideration of management units
Authors: McKeown Niall J. , Campanella Fabio , Silva Joana F. , Roel Beatriz A. , Healey Amy J. E. , Shaw Paul W. , van der Kooij Jeroen
Published: August 2024

The European sardine (Sardina pilchardus) is under intense fishing pressure and exhibits distributional/abundance shifts linked to environmental change. The current understanding of population demographics needed for sustainable management is uncertain due to concerns that previous genetic studies lacked resolution and limited sampling of sardine north of the Bay of Biscay. To address these issues, we performed mtDNA sequencing and genome wide SNP analysis of samples collected across the Bay of Biscay, Celtic Sea, English Channel and North Sea. The complete SNP data reported a lack of structure throughout the sampled area compatible with high gene flow. A consensus suite of positive outlier SNPs was identified which reported a significant correlation with geographical distance with the largest differentiation between the southern Bay of Biscay and North Sea samples which also reported a significant mtDNA ΦST. While the roles of dispersal limitation and environmental heterogeneity underpinning this require further study, this adds to growing evidence that selection is influencing sardine population structure against a background of high gene flow. The results indicate that while there may be a level of demographic independence between North Sea and South Biscay sardine, the current delimitation of central (Biscay) and northern (Channel and Celtic Sea) operational stocks may misrepresent connectivity between the Biscay and Channel. The North Sea sample exhibited markedly lower mtDNA and nuclear variation than other samples. As sardine have only recently invaded the North Sea such reduced genetic variation is compatible with predictions for peripheral leading‐edge populations but contrasts with patterns for other small pelagic species and emphasises the need to consider species‐specific genetic structure in ecosystem‐based management. Nascent management of the North Sea sardine fishery must ensure that current low levels of genetic diversity are not eroded further as this may decrease the species adaptive potential and inhibit its expansion.
Quenched PVDF/PMMA Porous Matrix for Triboelectric Energy Harvesting and Sensing
Authors: Mubarak Assem , Sarsembayev Bayandy , Serik Yerzhigit , Onabek Abdirakhman , Kappassov Zhanat , Bakenov Zhumabay , Tsuchiya Kazuyoshi , Kalimuldina Gulnur
Published: August 2024

The rapid development of nanotechnology has significantly revolutionized wearable electronics and expanded their functionality. Through introducing innovative solutions for energy harvesting and autonomous sensing, this research presents a cost‐effective strategy to enhance the performance of triboelectric nanogenerators (TENGs). The TENG was fabricated from polyvinylidene fluoride (PVDF) and N, N′‐poly(methyl methacrylate) (PMMA) blend with a porous structure via a novel optimized quenching method. The developed approach results in a high β‐phase content (85.7%) PVDF/3wt.%PMMA porous blend, known for its superior piezoelectric properties. PVDF/3wt.%PMMA modified porous TENG demonstrates remarkable electrical output, with a dielectric constant of 40 and an open‐circuit voltage of approximately 600 V. The porous matrix notably increases durability, enduring over 36 000 operational cycles without performance degradation. Moreover, practical applications were explored in this research, including powering LEDs and pacemakers with a maximum power output of 750 mW m−2. Also, TENG served as a self‐powered tactile sensor for robotic applications in various temperature conditions. The work highlights the potential of the PVDF/PMMA porous blend to utilize the next‐generation self‐powered sensors and power small electronic devices.