\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[greek,english]{babel}



\usepackage{float}








\begin{document}

\title{Wip1 inhibitor CCT007093 alleviates immune exhaustion of lymphocytes via
p65 NF-\selectlanguage{greek}κ\selectlanguage{english}B and YY1 in chronic hepatitis B virus infection in mice\selectlanguage{english}}



\author[1]{Yu-Syuan You}%
\author[1]{Wan-Ting Chang}%
\author[2]{Chia-Lang Hsu}%
\author[1]{Yan-Fong Lu}%
\author[1]{Hui-Ying Wang}%
\author[3]{InKyeom Kim}%
\author[1]{Shiang-Jong Tzeng}%
\affil[1]{National Taiwan University College of Medicine}%
\affil[2]{National Taiwan University Hospital}%
\affil[3]{Kyungpook National University School of Medicine}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Background and Purpose: Prolonged viral infections often lead to
lymphocyte exhaustion, marked by heightened inhibitory receptor
expression like PD-1, compromising host defense mechanisms. Although
monoclonal antibodies like anti-PD-1 can alleviate exhausted
lymphocytes, their cost limits widespread use. The unexplored potential
of chemical checkpoint inhibitors in rejuvenating immune responses
prompted our investigation. Experimental Approach: We focused on
CCT007093, a Wip1 inhibitor, screened out for its unique ability to
concurrently reduce PD-1 and Fc\selectlanguage{greek}γ\selectlanguage{english}RIIB expression, using a murine model of
immune exhaustion induced by chronic hepatitis B virus (HBV) infection.
Key Results: CCT007093 treatment to HBV-infected mice resulted in
decreased levels of PD-1 expression, resulting in reduced percentages of
PD-1+/hi CD4 and CD8 T cells in circulation, spleen, and liver. PD-1 and
Fc\selectlanguage{greek}γ\selectlanguage{english}RIIB expression, alongside the percentages of PD-1+/hi and
Fc\selectlanguage{greek}γ\selectlanguage{english}RIIB+/hi CD19+ B cells in these tissues, were similarly diminished.
Moreover, CCT007093-treated intrahepatic lymphocytes exhibited
heightened responsiveness to ex vivo activation. Together, serum HBsAg
levels were significantly reduced in in treated mice compared to
controls. Detailed analysis uncovered p65 NF-\selectlanguage{greek}κ\selectlanguage{english}B as the primary activator
of T cells and B cells, while YY1 emerged as the key regulator,
orchestrating the down-regulation of PD-1 and Fc\selectlanguage{greek}γ\selectlanguage{english}RIIB gene transcription
in response to CCT007093. Conclusions and Implications: Our study
highlights CCT007093's pharmacological efficacy in mitigating immune
exhaustion in HBV-infected mice, selectively enhancing adaptive
immunity. Beyond antiviral applications, it underscores the prowess of
chemical checkpoint inhibitors, exemplified by CCT007093, in alleviating
immune exhaustion induced by viruses and potentially in various cancers.%
\end{abstract}%



\sloppy




\selectlanguage{english}
\FloatBarrier
\end{document}

