The cephalosporins are a class of β-lactam antibiotics derived from the fungus Acremonium, known as "Cephalosporium". Together with cephamycins, they constitute. Cephalosporins were discovered in 1945, first sold in 1964; the aerobic mold which yielded cephalosporin C was found in the sea near a sewage outfall in Su Siccu, by Cagliari harbour in Sardinia, by the Italian pharmacologist Giuseppe Brotzu in July 1945. Cephalosporins are indicated for the prophylaxis and treatment of infections caused by bacteria susceptible to this particular form of antibiotic. First-generation cephalosporins are active predominantly against Gram-positive bacteria, such as Staphylococcus and Streptococcus, they are therefore used for skin and soft tissue infections. Successive generations of cephalosporins have increased activity against Gram-negative bacteria, albeit with reduced activity against Gram-positive organisms; the antibiotic may be used for patients who are allergic to penicillin due to the different β-lactam antibiotic structure.

The drug is able to be excreted in the urine. Common adverse drug reactions associated with the cephalosporin therapy include: diarrhea, rash, electrolyte disturbances, pain and inflammation at injection site. Infrequent ADRs include vomiting, dizziness and vaginal candidiasis, pseudomembranous colitis, eosinophilia, neutropenia and fever; the quoted figure of 10% of patients with allergic hypersensitivity to penicillins and/or carbapenems having cross-reactivity with cephalosporins originated from a 1975 study looking at the original cephalosporins, subsequent "safety first" policy meant this was quoted and assumed to apply to all members of the group. Hence, it was stated that they are contraindicated in patients with a history of severe, immediate allergic reactions to penicillins, carbapenems, or cephalosporins. This, should be viewed in the light of recent epidemiological work suggesting, for many second-generation cephalosporins, the cross-reactivity rate with penicillin is much lower, having no increased risk of reactivity over the first generation based on the studies examined.

The British National Formulary issued blanket warnings of 10% cross-reactivity, since the September 2008 edition, suggests, in the absence of suitable alternatives, oral cefixime or cefuroxime and injectable cefotaxime and ceftriaxone can be used with caution, but the use of cefaclor, cefadrocil and cefradine should be avoided. Overall, the research shows that all beta lactams have the intrinsic hazard of serious hazardous reactions in susceptible patients. Only the frequency of these reactions vary, based on the structure. Recent papers have shown that a major feature in determining frequency of immunological reactions is the similarity of the side chains, this is the reason the β-lactams are associated with different frequencies of serious reactions. Several cephalosporins are associated with hypoprothrombinemia and a disulfiram-like reaction with ethanol; these include latamoxef, cefoperazone, cefamandole and cefotetan. This is thought to be due to the N-methylthiotetrazole side-chain of these cephalosporins, which blocks the enzyme vitamin K epoxide reductase and aldehyde dehydrogenase.

Thus, consumption of alcohol after taking Cephalosporin orally or intravenously is contraindicated, in severe cases can lead to death. Cephalosporins are bactericidal and have the same mode of action as other β-lactam antibiotics, but are less susceptible to β-lactamases. Cephalosporins disrupt the synthesis of the peptidoglycan layer forming the bacterial cell wall; the peptidoglycan layer is important for cell wall structural integrity. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by penicillin-binding proteins. PBPs bind to the D-Ala-D-Ala at the end of muropeptides to crosslink the peptidoglycan. Beta-lactam antibiotics mimic the D-Ala-D-Ala site, thereby irreversibly inhibiting PBP crosslinking of peptidoglycan. Resistance to cephalosporin antibiotics can involve either reduced affinity of existing PBP components or the acquisition of a supplementary β-lactam-insensitive PBP; some Citrobacter freundii, Enterobacter cloacae, Neisseria gonorrhoeae, Escherichia coli strains are resistant to cephalosporins.

Some Morganella morganii, Proteus vulgaris, Providencia rettgeri, Pseudomonas aeruginosa, Serratia marcescens strains have developed resistance to cephalosporins to varying degrees. The cephalosporin nucleus can be modified to gain different properties. Cephalosporins are sometimes grouped into "generations" by their antimicrobial properties; the first cephalosporins were designated first-generation cephalosporins, whereas more extended-spectrum cephalosporins were classified as second-generation cephalosporins. Each newer generation has greater Gram-negative antimicrobial properties than the preceding generation, in most cases with decreased activity against Gram-positive organisms. Fourth-generation cephalosporins, have true broad-spectrum activity; the classification of cephalosporins into "generations" is practised, although the exact categorization is imprecise. For example, the fourth generation of cephalosporins is not recognized as such

Let-7 microRNA precursor

The Let-7 microRNA precursor was identified from a study of developmental timing in C. elegans, was shown to be part of a much larger class of non-coding RNAs termed microRNAs. MiR-98 microRNA precursor from human is a let-7 family member. Let-7 miRNAs have now been experimentally confirmed in a wide range of species. MiRNAs are transcribed in long transcripts called primary miRNAs, which are processed in the nucleus by Drosha and Pasha to hairpin structures of about 70 nucleotide; these precursors are exported to the cytoplasm by exportin5, where they are subsequently processed by the enzyme Dicer to a ~22 nucleotide mature miRNA. The involvement of Dicer in miRNA processing demonstrates a relationship with the phenomenon of RNA interference. In human genome, the cluster let-7a-1/let-7f-1/let-7d is inside the region B at 9q22.3, with the defining marker D9S280-D9S1809. One minimal LOH region, between loci D11S1345-D11S1316, contains the cluster miR-125b1/let-7a-2/miR-100; the cluster miR-99a/let-7c/miR-125b-2 is in a 21p11.1 region of HD.

The cluster let-7g/miR-135-1 is in region 3 at 3p21.1-p21.2. The lethal-7 gene was first discovered in the nematode as a key developmental regulator and became one of the first two known microRNAs. Soon, let-7 was found in fruit fly, identified as the first known human miRNA by a BLAST research; the mature form of let-7 family members is conserved across species. In C.elegans, the let-7 family consists of genes encoding nine miRNAs sharing the same seed sequence. Among them, let-7, mir-84, mir-48 and mir-241 are involved in C.elegans heterochronic pathway, sequentially controlling developmental timing of larva transitions. Most animals with loss-of-function let-7 mutation burst through their vulvas and die, therefore the mutant is lethal; the mutants of other let-7 family members have a radio-resistant phenotype in vulval cells, which may be related to their ability to repress RAS. There is only one single let-7 gene in the Drosophila genome, which has the identical mature sequence to the one in C.elegans.

The role of let-7 has been demonstrated in regulating the timing of neuromuscular junction formation in the abdomen and cell-cycle in the wing. Furthermore, the expression of pri-, pre- and mature let-7 have the same rhythmic pattern with the hormone pulse before each cuticular molt in Drosophila; the let-7 family has a lot more members in vertebrates than in Drosophila. The sequences, expression timing, as well as genomic clustering of these miRNAs members are all conserved across species; the direct role of let-7 family in vertebrate development has not been shown as in less complex organisms, yet the expression pattern of let-7 family is indeed temporal during developmental processes. Given that the expression levels of let-7 members are low in human cancers and cancer stem cells, the major function of let-7 genes may be to promote terminal differentiation in development and tumor suppression. Although the levels of mature let-7 members are undetectable in undifferentiated cells, the primary transcripts and the hairpin precursors of let-7 are present in these cells.

It indicates. As one of the genes involved in induced pluripotent stem cell reprogramming, LIN28 expression is reciprocal to that of mature let-7. LIN28 selectively binds the primary and precursor forms of let-7, inhibits the processing of pri-let-7 to form the hairpin precursor; this binding is facilitated by the conserved loop sequence of primary let-7 family members and RNA-binding domains of LIN28 proteins. Lin-28 uses two zinc knuckle domains to recognize the NGNNG motif in the let-7 precursors, while the Cold-shock domain, connected by a flexible linker, binds to a closed loop in the precursors. On the other hand, let-7 miRNAs in mammals have been shown to regulate LIN28, which implies that let-7 might enhance its own level by repressing LIN28, its negative regulator. Expression of let-7 members is controlled by MYC binding to their promoters; the levels of let-7 have been reported to decrease in models of MYC-mediated tumorigenesis, to increase when MYC is inhibited by chemicals. In a twist, there are let-7-binding sites in MYC 3' untranslated region according to bioinformatic analysis, let-7 overexpression in cell culture decreased MYC mRNA levels.

Therefore, there is a double-negative feedback loop between MYC and let-7. Furthermore, let-7 could lead to IMP1 depletion, which destabilizes MYC mRNA, thus forming an indirect regulatory pathway. Let-7 has been demonstrated to be a direct regulator of RAS expression in human cells All the three RAS genes in human, K-, N-, H-, have the predicted let-7 binding sequences in their 3'UTRs. In lung cancer patient samples, expression of RAS and let-7 showed reciprocal pattern, which has low let-7 and high RAS in cancerous cells, high let-7 and low RAS in normal cells. Another oncogene, high mobility group A2, has been identified as a target of let-7. Let-7 directly inhibits HMGA2 by binding to its 3'UTR. Removal of let-7 binding site by 3'UTR deletion cause overexpression of HMGA2 and formation of tumor. Microarray analyses revealed many genes regulating cell cycle and cell proliferation that are responsive to alteration of let-7 levels, including cyclin A2, CDC34, Aurora A and B kinases, E2F5, CDK8, among others.

Subsequent experiments confirmed the direct effects of some of these genes, such as CDC25A and CDK6. Let-7 inhibits several com

Mitchell House (Yarmouth, Maine)

The Mitchell House is a historic house at 333 Main Street in Yarmouth, Maine. Built about 1800, it is a fine local example of Federal period architecture, it is prominent as the home of one of the North Yarmouth Academy's largest early benefactors, Dr. Ammi Mitchell, it was listed on the National Register of Historic Places in 1978. The Mitchell House stands in the village center of Yarmouth, on the north side of Main Street between Center and Mill Streets, it is a two-story wood frame structure, five bays wide, with a hip roof, four brick end chimneys, clapboard siding, a granite foundation. The main facade is divided into three sections, articulated by full-height Doric pilasters; the outer sections each have two sash windows, those on the first floor topped by entablatured lintels. The center section has the main entrance on the first floor, with flanking sidelight windows and a half-round transom above. A 1-1/2 story ell extends north, behind the main block; the house was built about 1800 for a pillar of the local community.

He had lived at today's 33 Center Street. Well known as a practicing physician, he served in the state legislature, was the largest single donor for the founding of North Yarmouth Academy, one of its first trustees. Mitchell died in 1824, aged 62. A owner of the home, Dr. Eleazer Burbank, was a prominent physician and state legislator. National Register of Historic Places listings in Cumberland County, Maine