COVID-19 is associated with a wide range of clinical manifestations, including autoimmune features and autoantibody production. Here we develop three protein arrays to measure IgG autoantibodies associated with connective tissue diseases, anti-cytokine antibodies, and anti-viral antibody responses in serum from 147 hospitalized COVID-19 patients. Autoantibodies are identified in approximately 50% of patients but in less than 15% of healthy controls. When present, autoantibodies largely target autoantigens associated with rare disorders such as myositis, systemic sclerosis and overlap syndromes. A subset of autoantibodies targeting traditional autoantigens or cytokines develop de novo following SARS-CoV-2 infection. Autoantibodies track with longitudinal development of IgG antibodies recognizing SARS-CoV-2 structural proteins and a subset of non-structural proteins, but not proteins from influenza, seasonal coronaviruses or other pathogenic viruses. We conclude that SARS-CoV-2 causes development of new-onset IgG autoantibodies in a significant proportion of hospitalized COVID-19 patients and are positively correlated with immune responses to SARS-CoV-2 proteins.

SUMMARY:Progressive cerebrovascular atherosclerosis and consecutive stroke are among the most common causes of dementia. However, specific risk factors for vascular dementia are still not known. Human telomeres shorten with each cell division in vitro and with donor age in vivo. In human fibroblasts in vitro, the telomere shortening rate decreased with increasing antioxidative capacity. There was a good intra-individual correlation between the age-corrected telomere lengths in fibroblasts and peripheral blood mononuclear cells. In 186 individuals including 149 geriatric patients (age range, 55-98 yr), leukocyte telomeres in patients with probable or possible vascular dementia were significantly shorter than in three age-matched control groups, namely in cognitively competent patients suffering from cerebrovascular or cardiovascular disease alone, in patients with probable Alzheimer's dementia, and in apparently healthy control subjects. No correlation was found to polymorphisms in the apolipoprotein E and glutathione-S-transferase genes. Telomere length may be an independent predictor for the risk of vascular dementia. (Lab Invest 2000, 80:1739 -1747.P rogressive cerebrovascular atherosclerosis and consecutively stroke are the second most common causes of dementia in Europe and the United States, and the most common causes in Asia and in many developing countries (Konno et al, 1997). The search for prognostic factors for late-onset dementia, and especially those with a vascular component, is a high research priority because (a) dementia is a major burden to any "greying" society, (b) stroke and vascular risk factors are not only causal for vascular dementia (VaD) but also contribute to the pathogenesis of significant fractions of both Alzheimer's dementia (AD) and dementia with Lewy bodies cases, (c) dementia associated with stroke and vascular risk might be treatable or even preventable if patients at high risk could be identified early enough, (d) apart from age, there are no well-documented risk factors specifically for vascular dementia (Gorelick, 1997), and (e) the penetrance of identified or suspected genetic risk factors for late-onset dementia varies widely, limiting their use as prognostic factors.Telomeres in somatic human cells shorten with each cell division in vitro, and telomere length in peripheral blood mononuclear cells (PBMC) (Frenck et al, 1998;Rufer et al, 1999) or endothelial cells (Chang and Harley, 1995) decreases with age. In immortal cells, including the vast majority of tumors, telomere shortening is counteracted by the activation of telomerase or, in few cases, of an alternative mechanism (Prescott and Blackburn, 1999). Ectopic expression of telomerase is sufficient to immortalize at least some human cells (Bodnar et al, 1998). Together, this data suggests a key role for telomeres as a biological clock, counting the successive rounds of replication and eventually triggering senescence in human cells. Maintenance of telomeres has been causally implicated in both hyperproliferative and h...

Abstract.A novel member of the cadherin family of cell adhesion molecules has been characterized by cloning from rat liver, sequencing of the corresponding cDNA, and functional analysis after heterologous expression in nonadhesive $2 cells, cDNA clones were isolated using a polyclonal antibody inhibiting Ca2+-dependent intercellular adhesion of hepatoma cells. As inferred from the deduced amino acid sequence, the novel molecule has homologies with E-, P-, and N-cadherins, but differs from these classical cadherins in four characteristics. Its extracellular domain is composed of five homologous repeated domains instead of four characteristic for the classical cadherins. Four of the five domains are characterized by the sequence motifs DXNDN and DXD or modifications thereof representing putative Ca2+-binding sites of classical cadherins. In its NH2-terminal region, this cadherin lacks both the precursor segment and the endogenous protease cleavage site RXKR found in classical cadherins. In the extracellular EC1 domain, the novel cadherin contains an AAL sequence in place of the HAV sequence motif representing the common cell adhesion recognition sequence of E-, P-, and N-cadherin. In contrast to the conserved cytoplasmic domain of classical cadherins with a length of 150-160 amino acid residues, that of the novel cadherin has only 18 amino acids. Examination of transfected $2 cells showed that despite these structural differences, this cadherin mediates intercellular adhesion in a Ca2+-dependent manner. The novel cadherin is solely expressed in liver and intestine and was, hence, assigned the name LI-cadherin. In these tissues, LI-cadherin is localized to the basolateral domain of hepatocytes and enterocytes. These results suggest that LI-cadherin represents a new cadherin subtype and may have a role in the morphological organization of liver and intestine.C ELL-cell interactions are of fundamental importance for the development and the maintenance of tissues and organs in multicellular organisms. The basic morphogenetic processes involved in organogenesis, including cellular aggregation, segregation, and migration, are mediated and controlled by an increasingly large and complex number of cell adhesion molecules that exhibit a well-regulated spatiotemporal pattern of expression during development and regeneration (for review see Simons and Fuller, 1985;Ekblom et al

While B-DNA, the most common DNA conformation, displays rather regular twist angles and base stacking between successive base pairs, left-handed Z-DNA is characterized by the alternation of two different dinucleotide conformations with either a large twist and a small slide or a small twist and a large slide between adjacent base pairs. This results in poor stacking within the latter dinucleotide repeat that is in apparent contradiction to the rigidity and conformational stability of Z-DNA at high ionic strength. However, at d(CpG) steps the cytidine deoxyribose is situated such that its 04' sits directly over the six-membered ring of the guanine.We show here that the particular positionings of the two 04' lone-pair electrons provide stability through an intracytidine 04'-@-H6-C6 hydrogen bond and an n --* ir interaction with the guanidinium system of the stacked base. Our model is based on the assumption of a strong polarization of the guanine bases in Z-DNA that is consistent with the Z-DNAspecific guanine 06 and N7 coordination to metal and organic cations and the proximity of its N2 and C8 positions to neighboring phosphate groups, as well as several other Z-DNA-specific conformational features.In contrast to the influence of the ring oxygen on the reactivity and structural properties of the anomeric carbon center in pyranoses and furanoses, which has been investigated extensively (e.g., refs. 1-3), the structural consequences arising from the presence of the oxygen lone-pair electrons in the sugar framework of oligonucleotides have been discussed in much less detail. In double-stranded RNA fragments, ribose 04' (sometimes termed 01') can stabilize the A conformation by accepting a hydrogen bond from the 2'-hydroxyl group from the adjacent 5'-ribose (4, 5). In crystal structures of B-DNA dodecamers with sequences of the type CGCXXXXXXGCG (X is usually A or T), 04' oxygens in the central region of the duplex stabilize the minor groove hydration spine via a series of hydrogen bonds (6). The stacking of several deoxyribose 04' oxygens on the aromatic rings of the synthetic dye Hoechst 33258 seems to contribute significantly to the binding of the dye to the minor groove of B-DNA dodecamers (7-10).Stacking of a deoxyribose onto an adenine base with one of the oxygen lone pairs pointing into the base six-membered ring was also observed in the crystal structure of the cyclic 5',3'-deoxydinucleotide ApAp (11).The large slide for stacked bases at d(CpG) steps in Z-DNA with the resulting deoxyribose-base stacking can be noted in early illustrations of the Z duplex (12, 13) but was not specifically mentioned in descriptions of the structure. Three crystal structures of left-handed hexamers with sequence d(CGCGCG) were determined with particularly high precision. These are the original mixed spermine/magnesium form (12), the magnesium form (14, 15), and the pure-spermineThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement"...

In the equilibrium between B-DNA and Z-DNA in poly(dC-dG), the [Co(NH3)6]3+ ion stabilizes the Z form 4 orders of magnitude more effectively than the Mg2+ ion. The structural basis of this difference is revealed in Z-DNA crystal structures of d(CpGpCpGpCpG) stabilized by either Na+/Mg2+ or Na+/Mg2+ plus [Co(NH3)6]3+. The crystals diffract X-rays to high resolution, and the structures were refined at 1.25 A. The [Co(NH3)6]3+ ion forms five hydrogen bonds onto the surface of Z-DNA, bonding to a guanine O6 and N7 as well as to a phosphate group in the ZII conformation. The Mg2+ ion binds through its hydration shell with up to three hydrogen bonds to guanine N7 and O6. Higher charge, specific fitting of more hydrogen bonds, and a more stable complex all contribute to the great effectiveness of [Co(NH3)6]3+ in stabilizing Z-DNA.

We investigated structural and functional aspects of the first mutation in TNNC1, coding for the calcium‐binding subunit (cTnC) of cardiac troponin, which was detected in a patient with hypertrophic cardiomyopathy [ Hoffmann B, Schmidt‐Traub H, Perrot A, Osterziel KJ & Gessner R (2001) Hum Mut17, 524]. This mutation leads to a leucine–glutamine exchange at position 29 in the nonfunctional calcium‐binding site of cTnC. Interestingly, the mutation is located in a putative interaction site for the nonphosphorylated N‐terminal arm of cardiac troponin I (cTnI) [ Finley NL, Abbott MB, Abusamhadneh E, Gaponenko V, Dong W, Seabrook G, Howarth JW, Rana M, Solaro RJ, Cheung HC et al. (1999) EJB Lett453, 107–112]. According to peptide array experiments, the nonphosphorylated cTnI arm interacts with cTnC around L29. This interaction is almost abolished by L29Q, as observed upon protein kinase A‐dependent phosphorylation of cTnI at serine 22 and serine 23 in wild‐type troponin. With CD spectroscopy, minor changes are observed in the backbone of Ca2+‐free and Ca2+‐saturated cTnC upon the L29Q replacement. A small, but significant, reduction in calcium sensitivity was detected upon measuring the Ca2+‐dependent actomyosin subfragment 1 (actoS1)‐ATPase activity and the sliding velocity of thin filaments. The maximum actoS1‐ATPase activity, but not the maximum sliding velocity, was significantly enhanced. In addition, we performed our investigations at different levels of protein kinase A‐dependent phosphorylation of cTnI. The in vitro assays mainly showed that the Ca2+ sensitivity of the actoS1‐ATPase activity, and the mean sliding velocity of thin filaments, were no longer affected by protein kinase A‐dependent phosphorylation of cTnI owing to the L29Q exchange in cTnC. The findings imply a hindered transduction of the phosphorylation signal from cTnI to cTnC.

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The cadherin superfamily comprises a large number of cell adhesion molecules, several of which are expressed in the gastrointestinal tract. LI‐cadherin represents a novel type of cadherin within the cadherin superfamily distinguished from other cadherins by structural and functional features described in this review. In the mouse and human, LI‐cadherin is selectively expressed on the basolateral surface of enterocytes and goblet cells in the small and large intestine, whereas in the rat this cadherin is additionally detectable in hepatocytes. LI‐cadherin is capable of mediating Ca2+‐dependent homophilic cell‐cell adhesion independent of interactions with the cytoskeleton, indicating that the adhesive function of this novel cadherin is complementary to that of E‐cadherin and desmosomal cadherins co expressed in the intestinal mucosa.