Baricitinib therapy in COVID-19: A pilot study on safety and clinical impactDear Editor , 38.1 (37.7-38.7) 0.356 Breath rate N/min, median (IQR), 23 (19.5-24.2) 22 (19.7-24) 0.665 SpO2 (%),median (IQR) 91 (90-92.5) 92 (91.2-93) 0.157 PaO2/FiO2, median (IQR) 290 (199.2-292.2) 268.6 (264.4-295) 0.603 Pulse rate, median (IQR) 82 (73-88.3) 90 (87.2-94.5) 0.069 SBP mm/Hg, median (IQR) 120 (110-131.2) 105 (100-111.25) 0.003 DBP mm/Hg, median (IQR) 70 (60-80) 62.5 (60-66.25) 0.094 WBC (x10 9 /L), median (IQR) 7.8 (5.8-10.8) 8.2 (7.3-8.8) 0.908 Neutrophils (x10 9 /L), median (IQR) 6,5 (4.5-7.7) 6.9 (6.4-7.6) 0.707 Lymphocytes (x10 9 /L), median (IQR) 0.7 (0.7-1.2) 0.89 (0.7-0.9) 1.0 0 0 Hemoglobin (g/L), median (IQR) 118 (102-134.2) 125 (108-134) 0.568 Platelets (x10 9 /L), median (IQR) 203 (174-227) 366 (340-407) 0.0 0 0 ALT (U/L), median (IQR) 28.5 (23.5-52) 44 (37-50) 0.157 AST (U/L), median (IQR) 34 (26.2-48) 44 (34.7-47) 0.525 Creatinine (mg/dl), median (IQR)1.0 (0.9-1.1) 1.00 (0.9-1) 0.583 CRP (mg/dl), median (IQR) 8.2 (5.8-14.5) 3 (1.5-3.2) 0.002 Procalcitonin ng/ml, median (IQR) 0.7 (0.4-1.1) 1.2 (0.8-2.1) 0.902 MEWS, median (IQR) 3 ( 2-3.25) 3 (3-4) 0.544 Abbreviations and symbols: N = number;% = percentage; °C: grade Celsius; min = minute; SpO2 = peripheral capillary oxygen saturation; PaO2/FiO2 = ratio of arterial oxygen partial pressure to fractional inspired oxygen; SBP = systolic blood pressure; DBP = diastolic blood pressure; WBC = white blood cells; AST = serum glutamic oxaloacetic transaminase; ALT = serum alanine aminotransferase; MEWS = Modified Early Warning Score; IQR: Interquartile range.

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ITP and dITP exist in all cells. dITP is potentially mutagenic, and the levels of these nucleotides are controlled by inosine triphosphate pyrophosphatase (EC 3.6.1.19). Here we report the cloning, expression, and characterization of a 21.5-kDa human inosine triphosphate pyrophosphatase (hITPase), an enzyme whose activity has been reported in many animal tissues and studied in populations but whose protein sequence has not been determined before. At the optimal pH of 10.0, recombinant hITPase hydrolyzed ITP, dITP, and xanthosine 5-triphosphate to their respective monophosphates whereas activity with other nucleoside triphosphates was low. K m values for ITP, dITP, and xanthosine 5-triphosphate were 0.51, 0.31, and 0.57 mM, respectively, and k cat values were 580, 360, and 640 s ؊1 , respectively. A divalent cation was absolutely required for activity. The gene encoding the hITPase cDNA sequence was localized by radiation hybrid mapping to chromosome 20p in the interval D20S113-D20S97, the same interval in which the ITPA inosine triphosphatase gene was previously localized. A BLAST search revealed the existence of many similar sequences in organisms ranging from bacteria to mammals. The function of this ubiquitous protein family is proposed to be the elimination of minor potentially mutagenic or clastogenic purine nucleoside triphosphates from the cell.

The VirB proteins of Agrobacterium tumefaciens form a transport pore to transfer DNA from bacteria to plants. The assembly of the transport pore will require interaction among the constituent proteins. The identification of proteins that interact with one another can provide clues to the assembly of the transport pore. We studied interaction among four putative transport pore proteins, VirB7, VirB8, VirB9 and VirB10. Using the yeast two-hybrid assay, we observed that VirB8, VirB9, and VirB10 interact with one another. In vitro studies using protein fusions demonstrated that VirB10 interacts with VirB9 and itself. These results suggest that the outer membrane VirB7-VirB9 complex interacts with the inner membrane proteins VirB8 and VirB10 for the assembly of the transport pore. Fusions that contain small, defined segments of the proteins were used to define the interaction domains of VirB8 and VirB9. All interaction domains of both proteins mapped to the N-terminal half of the proteins. Two separate domains at the N-and C-terminal ends of VirB9 are involved in its homotypic interaction, suggesting that VirB9 forms a higher oligomer. We observed that the alteration of serine at position 87 of VirB8 to leucine abolished its DNA transfer function. Studies on the interaction of the mutant protein with the other VirB proteins showed that the VirB8S87L mutant is defective in interaction with VirB9. The mutant, however, interacted efficiently with VirB8 and VirB10, suggesting that the VirB8-VirB9 interaction is essential for DNA transfer.

Candida albicans biofilms are structured microbial communities with high levels of drug resistance. Farnesol, a quorum-sensing molecule that inhibits hyphal formation in C. albicans, has been found to prevent biofilm formation by C. albicans. There is limited information, however, about the molecular mechanism of farnesol against biofilm formation. We used cDNA microarray analysis to identify the changes in the gene expression profile of a C. albicans biofilm inhibited by farnesol. Confocal scanning laser microscopy was used to visualize and confirm normal and farnesol-inhibited biofilms. A total of 274 genes were identified as responsive, with 104 genes up-regulated and 170 genes down-regulated. Independent reverse transcription-PCR analysis was used to confirm the important changes detected by microarray analysis. In addition to hyphal formation-associated genes (e.g., TUP1, CRK1, and PDE2), a number of other genes with roles related to drug resistance (e.g., FCR1 and PDR16), cell wall maintenance (e.g., CHT2 and CHT3), and iron transport (e.g., FTR2) were responsive, as were several genes encoding heat shock proteins (e.g., HSP70, HSP90, HSP104, CaMSI3, and SSA2). Further study of these differentially regulated genes is warranted to evaluate how they may be involved in C. albicans biofilm formation. Consistent with the down-regulation of the cell surface hydrophobicity-associated gene (CSH1), the water-hydrocarbon two-phase assay showed a decrease in cell surface hydrophobicity in the farnesol-treated group compared to that in the control group. Our data provide new insight into the molecular mechanism of farnesol against C. albicans biofilm formation.Candida albicans is a pleiomorphic fungus that can exist as either a commensal or an opportunistic pathogen and is capable of causing superficial to life-threatening infections. Predisposing factors for C. albicans infections include immunosuppressive therapy, antibiotic therapy, human immunodeficiency virus infection, diabetes, and old age. In addition, structured microbial communities attached to surfaces, commonly referred to as biofilms (29), have increasingly been found to be the sources of C. albicans infections. Biomaterials such as stents, shunts, prostheses (voice, heart valve, and knee prostheses), implants (lens and breast implants and dentures), endotracheal tubes, pacemakers, and various types of catheters have all been shown to facilitate C. albicans colonization and biofilm formation (1,20,27,28). It is estimated that biofilms might be involved in 65% of infections (30).Biofilms are spatially organized heterogeneous communities of cells embedded within an extrapolymeric matrix. In comparison with planktonic cells, biofilm cells display unique phenotypic traits (10, 11), the most outstanding of which is that they are notoriously resistant to both antimicrobial agents and host immune factors. Biofilm-associated infections are therefore difficult to treat because of their decreased susceptibilities to antimicrobial therapy. It is reported that C. alb...

Chinese herbal medicine has been practiced for the prevention, treatment, and cure of diseases for thousands of years. Herbal medicine involves the use of natural compounds, which have relatively complex active ingredients with varying degrees of side effects. Some of these herbal medicines are known to cause nephrotoxicity, which can be overlooked by physicians and patients due to the belief that herbal medications are innocuous. Some of the nephrotoxic components from herbs are aristolochic acids and other plant alkaloids. In addition, anthraquinones, flavonoids, and glycosides from herbs also are known to cause kidney toxicity. The kidney manifestations of nephrotoxicity associated with herbal medicine include acute kidney injury, CKD, nephrolithiasis, rhabdomyolysis, Fanconi syndrome, and urothelial carcinoma. Several factors contribute to the nephrotoxicity of herbal medicines, including the intrinsic toxicity of herbs, incorrect processing or storage, adulteration, contamination by heavy metals, incorrect dosing, and interactions between herbal medicines and medications. The exact incidence of kidney injury due to nephrotoxic herbal medicine is not known. However, clinicians should consider herbal medicine use in patients with unexplained AKI or progressive CKD. In addition, exposure to herbal medicine containing aristolochic acid may increase risk for future uroepithelial cancers, and patients require appropriate postexposure screening.

SIRT1, a NAD+ dependent class III deacetylase, takes part in many important biological processes. Previous studies show that SIRT1 is overexpressed in some cancers and plays an essential role in tumorigenesis. However, the association between SIRT1 and colorectal cancer (CRC) is still unclear. We found that many CRC specimens had strong SIRT1 expression, which had an obvious correlation with poor prognosis of CRC patients. Meanwhile, SIRT1 expression had a co-localization with CD133, a current universal marker to characterize colorectal cancer stem cells (CSCs). In vitro studies also revealed that SIRT1 was overexpressed in colorectal CSC-like cells. Moreover, SIRT1 deficiency decreased percentage of CD133+ cells, attenuated the abilities of colony and sphere formation, and inhibited tumorigenicity in vivo in CRC cells. Further study demonstrated that the expressions of several stemness-associated genes, including Oct4, Nanog, Cripto, Tert and Lin28, were reduced by SIRT1 knockdown in CRC cells. Taken together, our findings suggest that SIRT1 plays a crucial role in keeping the characteristics of CSCs cells. SIRT1 is a potential independent prognostic factor of CRC patients after tumor resection with curative intent, and will contribute to providing a promising new approach to target at CSCs in CRC treatment.

Phosphoenolpyruvate carboxylase (PEPC) catalyzes the first step in the fixation of atmospheric CO(2) during C(4) photosynthesis. The crystal structure of C(4) form maize PEPC (ZmPEPC), the first structure of the plant PEPCs, has been determined at 3.0 A resolution. The structure includes a sulfate ion at the plausible binding site of an allosteric activator, glucose 6-phosphate. The crystal structure of E. coli PEPC (EcPEPC) complexed with Mn(2+), phosphoenolpyruvate analog (3,3-dichloro-2-dihydroxyphosphinoylmethyl-2-propenoate), and an allosteric inhibitor, aspartate, has also been determined at 2.35 A resolution. Dynamic movements were found in the ZmPEPC structure, compared with the EcPEPC structure, around two loops near the active site. On the basis of these molecular structures, the mechanisms for the carboxylation reaction and for the allosteric regulation of PEPC are proposed.