The metalloproteinase (MP) family of zinc-dependent proteases, including matrix metalloproteinases (MMPs), a disintegrin and metalloproteases (ADAMs), and a disintegrin and metalloproteinase with ...thrombospondin motifs (ADAMTSs) plays a crucial role in the extracellular matrix (ECM) remodeling and degradation activities. A wide range of substrates of the MP family includes ECM components, chemokines, cell receptors, and growth factors. Metalloproteinases activities are tightly regulated by proteolytic activation and inhibition via their natural inhibitors, tissue inhibitors of metalloproteinases (TIMPs), and the imbalance of the activation and inhibition is responsible in progression or inhibition of several diseases, e.g., cancer, neurological disorders, and cardiovascular diseases. We provide an overview of the structure, function, and the multifaceted role of MMPs, ADAMs, and TIMPs in several diseases via their cellular functions such as proteolysis of other cell signaling factors, degradation and remodeling of the ECM, and other essential protease-independent interactions in the ECM. The significance of MP inhibitors targeting specific MMP or ADAMs with high selectivity is also discussed. Recent advances and techniques used in developing novel MP inhibitors and MP responsive drug delivery tools are also reviewed.
The lung microbiome, which is believed to be stable or at least transient in healthy people, is now considered as a poly-microorganism component contributing to disease pathogenesis. Most research ...studies on the respiratory microbiome have focused on bacteria and their impact on lung health, but there is evidence that other non-bacterial organisms, comprising the viruses (virome) and fungi (mycobiome), are also likely to play an important role in healthy people as well as in patients. In the last few years, the lung mycobiome (previously named the fungal microbiota or microbiome) has drawn closer attention. There is growing evidence that the lung mycobiome has a significant impact on clinical outcome of chronic respiratory diseases (CRD) such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, and bronchiectasis. Thanks to advances in culture independent methods, especially next generation sequencing, a number of fungi not detected by culture methods have been molecularly identified in human lungs. It has been shown that the structure and diversity of the lung mycobiome vary in different populations (healthy and different diseased individuals) which could play a role in CRD. Moreover, the link between lung mycobiome and different biomes of other body sites, especially the gut, has also been unraveled. By interacting with the bacteriome and/or virome, the respiratory mycobiome appears to be a cofactor in inflammation and in the host immune response, and therefore may contribute to the decline of the lung function and the disease progression. In this review, we report the recent limited explorations of the human respiratory mycobiome, and discuss the mycobiome's connections with other local microbial communities, as well as the relationships with the different biomes of other body sites. These studies suggest several outlooks for this understudied emerging field, which will certainly call for a renewal of our understanding of pulmonary diseases.
In Governing the Dead, Linh D. Vu explains how the Chinese Nationalist regime consolidated control by honoring its millions of war dead, allowing China to emerge rapidly from the wreckage of the ...first half of the twentieth century to become a powerful state, supported by strong nationalistic sentiment and institutional infrastructure. The fall of the empire, internecine conflicts, foreign invasion, and war- related disasters claimed twenty to thirty million Chinese lives. Vu draws on government records, newspapers, and petition letters from mourning families to analyze how the Nationalist regime's commemoration of the dead and compensation of the bereaved actually fortified its central authority. By enshrining the victims of violence as national ancestors, the Republic of China connected citizenship to the idea of the nation, promoting loyalty to the "imagined community." The regime constructed China's first public military cemetery and hundreds of martyrs' shrines, collectively mourned millions of fallen soldiers and civilians, and disbursed millions of yuan to tens of thousands of widows and orphans. The regime thus exerted control over the living by creating the state apparatus necessary to manage the dead. Although the Communist forces prevailed in 1949, the Nationalists had already laid the foundation for the modern nation-state through their governance of dead citizens. The Nationalist policies of glorifying and compensating the loyal dead in an age of catastrophic destruction left an important legacy: violence came to be celebrated rather than lamented.
In Governing the Dead
, Linh D. Vu explains how the Chinese Nationalist regime
consolidated control by honoring its millions of war dead, allowing
China to emerge rapidly from the wreckage of the ...first half of the
twentieth century to become a powerful state, supported by strong
nationalistic sentiment and institutional
infrastructure.
The fall of the empire, internecine conflicts, foreign invasion,
and war-related disasters claimed twenty to thirty million Chinese
lives. Vu draws on government records, newspapers, and petition
letters from mourning families to analyze how the Nationalist
regime's commemoration of the dead and compensation of the bereaved
actually fortified its central authority. By enshrining the victims
of violence as national ancestors, the Republic of China connected
citizenship to the idea of the nation, promoting loyalty to the
"imagined community." The regime constructed China's first public
military cemetery and hundreds of martyrs' shrines, collectively
mourned millions of fallen soldiers and civilians, and disbursed
millions of yuan to tens of thousands of widows and orphans. The
regime thus exerted control over the living by creating the state
apparatus necessary to manage the dead.
Although the Communist forces prevailed in 1949, the
Nationalists had already laid the foundation for the modern
nation-state through their governance of dead citizens. The
Nationalist policies of glorifying and compensating the loyal dead
in an age of catastrophic destruction left an important legacy:
violence came to be celebrated rather than lamented.
In 1950, the People’s Republic of China began transforming the Eight Treasures Mountain (Babaoshan) into a national cemetery for its highest-ranking cadres and most devoted supporters. This article ...advances our understanding of how the People’s Republic of China revolutionizes the way it uses the dead to legitimize its rule over the living. While the People’s Republic of China seeks to erase the Imperial and Republican past, it follows its predecessors in shaping national memory by creating a sacred site for the loyal dead. Furthermore, despite atheist self-proclamation, the People’s Republic of China relies on traditional beliefs and practices to memorialize its dead members. The state’s attempts to shape national memory through these means have not been without resistance from the bereaved families, particularly under controversial circumstances. Besides these unsettled conflicts, the People’s Republic of China faces the challenges posed by a growing number of the dead. The People’s Republic of China tries to manage its necro-constituents by turning to information technology and eco-burial.
This article addresses the Taipei National Revolutionary Martyrs’ Shrine (Guomin geming zhonglie ci) as a site of contention over national sovereignty and belonging. The shrine originated in Sun ...Yat-sen's aspiration to commemorate the anti-imperial martyrs of the 1911 Republic and in the Nationalist government's attempt to marshal political allegiance in the 1920s–1940s. Upon fleeing from the mainland to Taiwan after losing to the Communist forces in 1949, the Nationalist leadership renovated the Japanese-built National Protection Shrine in Taipei, transforming it into the National Revolutionary Martyrs’ Shrine to house the displaced spirits of the national dead. Throughout the Cold War era, the spring and autumn sacrifices performed by heads of state and visits to the shrine by foreign dignities served to affirm the sovereignty of the Republic of China vis-à-vis the People's Republic of China. Even though the end of martial law in 1987 opened a new era marked by the Nationalist Party's loss of political hegemony, the shrine continued to adhere to the Nationalist Party's ideology and version of history. Far from embodying a place of remembrance and mourning for war victims, the palace-style compound is a site of contested sovereignty exaggerated by China's extraordinary growth and Taiwan's transforming identity. The enshrined dead have found a new role as both an assertion of the island's autonomy and a reflection of its dynamism. The departed, albeit silent, hold power in the malleability of their memories, and each permutation of how the past is remembered hosts its own tension.
While the cellular cytosol and organelles contain attractive targets for disease treatments, it remains a challenge to deliver therapeutic biomacromolecules to these sites. This is due to the ...selective permeability of the plasma and endosomal membranes, especially for large and hydrophilic therapeutic cargos such as proteins and nucleic acids. In response, many different delivery systems and molecules have been devised to help therapeutics cross these barriers to reach cytosolic targets. Among them are peptide and protein-based systems, which have several advantages over other natural and synthetic materials including their ability to interact with cell membranes. In this review, we will describe recent advances and current challenges of peptide and protein strategies that leverage cell membrane association and modulation to enable cytosolic delivery of biomacromolecule cargo. The approaches covered here include peptides and proteins derived from or inspired by natural sequences as well as those designed de novo for delivery function.
Non‐coding small regulatory RNAs (sRNAs) have an important role in bacterial stress responses. The binding of sRNAs to their target mRNAs is facilitated by RNA‐binding proteins such as Hfq or ProQ. ...The Berry Lab has developed a bacterial three‐hybrid (B3H) assay to detect the binding of RNA with both of these RNA chaperones in vivo, by connecting the strength of an RNA‐protein interaction to the expression of a reporter gene. The interaction between a “prey” protein fused to the α‐subunit of RNA polymerase (RNAP) and a “bait” RNA tethered upstream of a test promoter stabilizes the binding of RNAP and increases transcription of the reporter gene lacZ. Despite the promise of the B3H system and its success in detecting many high‐affinity interactions, low signal‐to‐noise for other RNA‐protein interactions currently limits the broader utility of the assay. Computational structure predictions suggested that certain RNAs of interest could misfold when hybridized with other components of the hybrid RNA construct, e.g. an MS2 hairpin (MS2hp) or an exogenous intrinsic terminator. Such misfolding would likely disrupt a bait RNA’s interaction with the prey protein. To avoid this limitation, this study aims to optimize the hybrid RNA construct to improve the breadth of detectable interactions in the B3H assay. To this end, we designed new hybrid RNA constructs with the addition of a GC‐clamp – a short insert of guanines (G) and cytosines (C) flanking a region of interest – to promote proper folding and optimal display of RNA. Several sRNAs and 5’UTRs were cloned into GC‐clamp designs and their in vivo interactions with Hfq were tested in the B3H assay. Preliminary results demonstrate the promise of a short GC‐clamp in improving the B3H signal for many sRNA‐Hfq interactions, and we are currently working to test these GC constructs with additional RNAs. Increasing the sensitivity and generalizability of the B3H assay to study bacterial RNA‐protein interactions will help shed light on the molecular mechanisms of RNA‐chaperone proteins and the important processes in bacteria they regulate, such as adaptation to stress, biofilm formation and virulence.
This article draws attention to the cultural and social specificities of women’s agency in Republican China and suggests a way to rethink the polarizing impacts of revolution- and war-related deaths ...on women’s lives. Analyzing a number of petitions submitted by widows of martyrs, this article explores the transformation in family-state and gender relations during the Republican era. I argue that the Nationalist martyr compensation law perpetuated the imperial-era standards for the feminine virtues of chastity and sacrifice, circumscribing women’s social and political roles in twentieth-century China. Under the new equality-promoting legal regime and in the absence of familial patriarchs, women had new opportunities to venture outside their domestic quarters and to engage with the state. Yet, the Republican state often made exceptions to the law based on petitioners’ display of feminine virtues. By entering into this negotiation of virtue with the state, Chinese women defined themselves primarily through their performance of moral qualities.
To estimate the proportion of men and women aged 50 years and older who would be classified as "high risk" for fracture and eligible for anti-fracture treatment. The study involved 1421 women and 652 ...men aged 50 years and older, who were recruited from the general population in Ho Chi Minh City, Vietnam. Fracture history was ascertained from each individual. Bone mineral density (BMD) was measured at the lumbar spine and femoral neck by DXA (Hologic Horizon). The diagnosis of osteoporosis was based on the T-scores less than or equal to -2.50 derived from either femoral neck or lumbar spine BMD. The 10-year risks of major fractureand hip fracture were estimated from FRAX version for Thai population. The criteria for recommended treatment were based on the US National Osteoporosis Foundation (NOF). The average age of women and men was ~60 yr (SD 7.8). Approximately 11% (n = 152) of women and 14% (n = 92) of men had a prior fracture. The prevalence of osteoporosis was 27% (n = 381; 95% CI, 25 to 29%) in women and 13% (n = 87; 95% CI, 11 to 16%) in men. Only 1% (n = 11) of women and 0.1% (n = 1) of men had 10-year risk of major fracture greater than or equal to 20%. However, 23% (n = 327) of women and 9.5% (n = 62) of men had 10-year risk of hip fracture greater than or equal to 3%. Using the NOF recommended criteria, 49% (n = 702; 95% CI, 47 to 52%) of women and 35% (n = 228; 95% CI, 31 to 39%) of men would be eligible for therapy. Almost half of women and just over one-third of men aged 50 years and older in Vietnam meet the NOF criteria for osteoporosis treatment. This finding can help develop guidelines for osteoporosis treatment in Vietnam.
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