bluuebunny/crossref_metadata_2025 huggingface dataset:
Nature of structural inhomogeneities on folding a helix and their influence on spectral measurements
Authors: Gnanakaran S. , Hochstrasser Robin M. , García Angel E.
Published: June 2004

Extensive conformational sampling and calculations of vibrational coupling provide a quantitative basis for the structurally inhomogeneous spectra of the amide unit in aqueous solutions containing folded and unfolded state distributions of helices. Replica exchange molecular dynamics simulations of the capped helical peptide, AA(AAKAA)
3
AAY, is carried out over a range of temperatures, where the system populates the folded and unfolded states. This sampling defines a set of ensembles that characterizes the conformational variability for configurations identified by their fraction of helical content. The effects of hydrogen bonding, both internal and external (with water), and the coupling between amide-I modes are computed as a function of temperature and helical content. End-to-end distance and coupling distributions are also computed. The solvent H-bonding, which is present at all temperatures, shifts the amide-I band toward lower frequency compared with the unsolvated band. Upon thermal denaturation of the peptide, the amide-I band shifts to higher frequency because the increase in solvent H-bonding fails to compensate for the loss in internal (helical) H-bonds. The loss of uniformity of the mode coupling along the helix at higher temperatures accounts for the well-known thermal broadening of the amide IR spectrum. The calculated inhomogeneities of segments of the peptide predict experimental properties of isotope-edited helices.
A detailed physical map of the horse Y chromosome
Authors: Raudsepp Terje , Santani Avni , Wallner Barbara , Kata Srinivas R. , Ren Chengwei , Zhang Hong-Bin , Womack James E. , Skow Loren C. , Chowdhary Bhanu P.
Published: June 2004

We herein report a detailed physical map of the horse Y chromosome. The euchromatic region of the chromosome comprises ≈15 megabases (Mb) of the total 45- to 50-Mb size and lies in the distal one-third of the long arm, where the pseudoautosomal region (PAR) is located terminally. The rest of the chromosome is predominantly heterochromatic. Because of the unusual organization of the chromosome (common to all mammalian Y chromosomes), a number of approaches were used to crossvalidate the results. Analysis of the 5,000-rad horse × hamster radiation hybrid panel produced a map spanning 88 centirays with 8 genes and 15 sequence-tagged site (STS) markers. The map was verified by several fluorescence
in situ
hybridization approaches. Isolation of bacterial artificial chromosome (BAC) clones for the radiation hybrid-mapped markers, end sequencing of the BACs, STS development, and bidirectional chromosome walking yielded 109 markers (100 STS and 9 genes) contained in 73 BACs. STS content mapping grouped the BACs into seven physically ordered contigs (of which one is predominantly ampliconic) that were verified by metaphase-, interphase-, and fiber-fluorescence
in situ
hybridization and also BAC fingerprinting. The map spans almost the entire euchromatic region of the chromosome, of which 20–25% (≈4 Mb) is covered by isolated BACs. The map is presently the most informative among Y chromosome maps in domesticated species, third only to the human and mouse maps. The foundation laid through the map will be critical in obtaining complete sequence of the euchromatic region of the horse Y chromosome, with an aim to identify Y specific factors governing male infertility and phenotypic sex variation.
Direct imaging shows that insulin granule exocytosis occurs by complete vesicle fusion
Authors: Ma Li , Bindokas Vytautas P. , Kuznetsov Andrey , Rhodes Christopher , Hays Lori , Edwardson J. Michael , Ueda Kazuya , Steiner Donald F. , Philipson Louis H.
Published: June 2004

Confocal imaging of GFP-tagged secretory granules combined with the use of impermeant extracellular dyes permits direct observation of insulin packaged in secretory granules, trafficking of these granules to the plasma membrane, exocytotic fusion of granules with the plasma membrane, and eventually the retrieval of membranes by endocytosis. Most such studies have been done in tumor cell lines, using either confocal methods or total internal reflectance microscopy. Here we compared these methods by using GFP–syncollin or PC3–GFP plus rhodamine dextrans to study insulin granule dynamics in insulinoma cells, normal mouse islets, and primary pancreatic beta cells. We found that most apparently docked granules did not fuse with the plasma membrane after stimulation. Granules that did fuse typically fused completely, but a few dextran-filled granules lingered at the membrane. Direct recycling of granules occurred only rarely. Similar results were obtained with both confocal and total internal reflection microscopy, although each technique had advantages for particular aspects of the granule life cycle. We conclude that insulin exocytosis involves a prolonged interaction of secretory granules with the plasma membrane, and that the majority of exocytotic events occur by full, not partial, fusion.
Immunodominant CD4
+
responses identified in a patient vaccinated with full-length NY-ESO-1 formulated with ISCOMATRIX adjuvant
Authors: Chen Qiyuan , Jackson Heather , Parente Phillip , Luke Tina , Rizkalla Mark , Tai Tsin Yee , Zhu He-Cheng , Mifsud Nicole A. , Dimopoulos Nektaria , Masterman Kelly-Anne , Hopkins Wendie , Goldie Heather , Maraskovsky Eugene , Green Simon , Miloradovic Lena , McCluskey James , Old Lloyd J. , Davis Ian D. , Cebon Jonathan , Chen Weisan
Published: June 2004

There is increasing evidence showing the involvement of CD4
+
T cells in initiating and maintaining antitumor immune responses. NY-ESO-1 is expressed by various tumors but not normal tissues except testis. We conducted a cancer clinical trial by using full-length NY-ESO-1 protein formulated with ISCOMATRIX adjuvant and injected into patients intramuscularly. Autologous dendritic cells pulsed with NY-ESO-1 ISCOMATRIX in combination with overlapping synthetic peptides were used to identify immunodominant T cells from a vaccinated patient. We show here the identification and characterization of two novel CD4
+
T cell epitopes. T cells specific to these epitopes not only recognized autologous dendritic cells loaded with NY-ESO-1 but also NY-ESO-1-expressing tumor cell lines treated with IFN-γ. One of the two responses identified was greater than the previously identified immunodominant HLA-DP4-restricted response and correlated with NY-ESO-1-specific CD8
+
T cell induction after vaccination. This T cell response was vaccinated in most patients who expressed HLA-DR2. This study has systematically surveyed patients vaccinated with full-length tumor antigen for a vaccinated CD4 helper T cell response.
Activation of a paramyxovirus fusion protein is modulated by inside-out signaling from the cytoplasmic tail
Authors: Waning David L. , Russell Charles J. , Jardetzky Theodore S. , Lamb Robert A.
Published: June 2004

Many viruses have evolved fusion-mediating glycoproteins that couple the energy released from irreversible protein refolding to the work of membrane fusion. The viral fusion proteins require a triggering event to undergo a cascade of tightly regulated conformational changes. Different isolates of the paramyxovirus SV5 fusion (F) protein have either a short (20-residue) or long (42-residue) cytoplasmic tail (CT), and a long CT suppresses fusion activity in a sequence-specific manner. Addition of a domain to the F protein CT, which has the propensity to form a three-helix bundle, stabilizes the F protein and increases the energy required for fusion activation. Quantitative cell–cell fusion assays and measurement of ectodomain conformation by monoclonal antibody reactivity indicate that this suppression of fusion by the long CT or addition of a three-helix bundle occurs at a step preceding initial membrane merger. The data suggest that F protein activation involves CT signaling to the ectodomain.
Dissecting the maize genome by using chromosome addition and radiation hybrid lines
Authors: Kynast Ralf G. , Okagaki Ron J. , Galatowitsch Mark W. , Granath Shannon R. , Jacobs Morrison S. , Stec Adrian O. , Rines Howard W. , Phillips Ronald L.
Published: June 2004

We have developed from crosses of oat (
Avena sativa
L.) and maize (
Zea mays
L.) 50 fertile lines that are disomic additions of individual maize chromosomes 1-9 and chromosome 10 as a short-arm telosome. The whole chromosome 10 addition is available only in haploid oat background. Most of the maize chromosome disomic addition lines have regular transmission; however, chromosome 5 showed diminished paternal transmission, and chromosome 10 is transmitted to offspring only as a short-arm telosome. To further dissect the maize genome, we irradiated monosomic additions with γ rays and recovered radiation hybrid (RH) lines providing low- to medium-resolution mapping for most of the maize chromosomes. For maize chromosome 1, mapping 45 simple-sequence repeat markers delineated 10 groups of RH plants reflecting different chromosome breaks. The present chromosome 1 RH panel dissects this chromosome into eight physical segments defined by the 10 groups of RH lines. Genomic
in situ
hybridization revealed the physical size of a distal region, which is represented by six of the eight physical segments, as being ≈20% of the length of the short arm, representing ≈one-third of the genetic chromosome 1 map. The distal ≈20% of the physical length of the long arm of maize chromosome 1 is represented by a single group of RH lines that spans >23% of the total genetic map. These oat-maize RH lines provide valuable tools for physical mapping of the complex highly duplicated maize genome and for unique studies of inter-specific gene interactions.
Annexin 11 is required for midbody formation and completion of the terminal phase of cytokinesis
Authors: Tomas Alejandra , Futter Clare , Moss Stephen E.
Published: June 2004

Annexins are Ca2+-binding, membrane-fusogenic proteins with diverse but poorly understood functions. Here, we show that during cell cycle progression annexin 11 translocates from the nucleus to the spindle poles in metaphase and to the spindle midzone in anaphase. Annexin 11 is recruited to the midbody in late telophase, where it forms part of the detergent-resistant matrix that also contains CHO1. To investigate the significance of these observations, we used RNA interference to deplete cells of annexin 11. A combination of confocal and video time-lapse microscopy revealed that cells lacking annexin 11 fail to establish a functional midbody. Instead, daughter cells remain connected by intercellular bridges that contain bundled microtubules and cytoplasmic organelles but exclude normal midbody components such as MKLP1 and Aurora B. Annexin 11–depleted cells failed to complete cytokinesis and died by apoptosis. These findings demonstrate an essential role for annexin 11 in the terminal phase of cytokinesis.
The fission yeast heterochromatin protein Rik1 is required for telomere clustering during meiosis
Authors: Tuzon Creighton T. , Borgstrom Britta , Weilguny Dietmar , Egel Richard , Cooper Julia Promisel , Nielsen Olaf
Published: June 2004

Telomeres share the ability to silence nearby transcription with heterochromatin, but the requirement of heterochromatin proteins for most telomere functions is unknown. The fission yeast Rik1 protein is required for heterochromatin formation at centromeres and the mating-type locus, as it recruits the Clr4 histone methyltransferase, whose modification of histone H3 triggers binding by Swi6, a conserved protein involved in spreading of heterochromatin. Here, we demonstrate that Rik1 and Clr4, but not Swi6, are required along with the telomere protein Taz1 for crucial chromosome movements during meiosis. However, Rik1 is dispensable for the protective roles of telomeres in preventing chromosome end-fusion. Thus, a Swi6-independent heterochromatin function distinct from that at centromeres and the mating-type locus operates at telomeres during sexual differentiation.
Identification and functional analysis of the essential and regulatory light chains of the only type II myosin Myo1p in Saccharomyces cerevisiae
Authors: Luo Jianying , Vallen Elizabeth A. , Dravis Christopher , Tcheperegine Serguei E. , Drees Becky , Bi Erfei
Published: June 2004

Cytokinesis in Saccharomyces cerevisiae involves coordination between actomyosin ring contraction and septum formation and/or targeted membrane deposition. We show that Mlc1p, a light chain for Myo2p (type V myosin) and Iqg1p (IQGAP), is the essential light chain for Myo1p, the only type II myosin in S. cerevisiae. However, disruption or reduction of Mlc1p–Myo1p interaction by deleting the Mlc1p binding site on Myo1p or by a point mutation in MLC1, mlc1-93, did not cause any obvious defect in cytokinesis. In contrast, a different point mutation, mlc1-11, displayed defects in cytokinesis and in interactions with Myo2p and Iqg1p. These data suggest that the major function of the Mlc1p–Myo1p interaction is not to regulate Myo1p activity but that Mlc1p may interact with Myo1p, Iqg1p, and Myo2p to coordinate actin ring formation and targeted membrane deposition during cytokinesis. We also identify Mlc2p as the regulatory light chain for Myo1p and demonstrate its role in Myo1p ring disassembly, a function likely conserved among eukaryotes.
Absence of BLM leads to accumulation of chromosomal DNA breaks during both unperturbed and disrupted S phases
Authors: Li Wenhui , Kim Soo-Mi , Lee Joon , Dunphy William G.
Published: June 2004

Bloom's syndrome (BS), a disorder associated with genomic instability and cancer predisposition, results from defects in the Bloom's helicase (BLM) protein. In BS cells, chromosomal abnormalities such as sister chromatid exchanges occur at highly elevated rates. Using Xenopus egg extracts, we have studied Xenopus BLM (Xblm) during both unperturbed and disrupted DNA replication cycles. Xblm binds to replicating chromatin and becomes highly phosphorylated in the presence of DNA replication blocks. This phosphorylation depends on Xenopus ATR (Xatr) and Xenopus Rad17 (Xrad17), but not Claspin. Xblm and Xenopus topoisomerase IIIα (Xtop3α) interact in a regulated manner and associate with replicating chromatin interdependently. Immunodepletion of Xblm from egg extracts results in accumulation of chromosomal DNA breaks during both normal and perturbed DNA replication cycles. Disruption of the interaction between Xblm and Xtop3α has similar effects. The occurrence of DNA damage in the absence of Xblm, even without any exogenous insult to the DNA, may help to explain the genesis of chromosomal defects in BS cells.
Me write pretty one day
Authors: Wells William A.
Published: June 2004

The scientific literature is exploding in quantity even as it stands still in literary quality. In this brief guide, I suggest a few small steps that the individual can take to make his or her writing clear, straightforward, and digestible.
SOCS1 Is a Suppressor of Liver Fibrosis and Hepatitis-induced Carcinogenesis
Authors: Yoshida Takafumi , Ogata Hisanobu , Kamio Masaki , Joo Akiko , Shiraishi Hiroshi , Tokunaga Yoko , Sata Michio , Nagai Hisaki , Yoshimura Akihiko
Published: June 2004

Hepatocellular carcinomas (HCCs) mainly develop from liver cirrhosis and severe liver fibrosis that are established with long-lasting inflammation of the liver. Silencing of the suppressor of the cytokine signaling-1 (SOCS1) gene, a negative regulator of cytokine signaling, by DNA methylation has been implicated in development or progress of HCC. However, how SOCS1 contributes to HCC is unknown. We examined SOCS1 gene methylation in >200 patients with chronic liver disease and found that the severity of liver fibrosis is strongly correlated with SOCS1 gene methylation. In murine liver fibrosis models using dimethylnitrosamine, mice with haploinsufficiency of the SOCS1 gene (SOCS1−/+ mice) developed more severe liver fibrosis than did wild-type littermates (SOCS1+/+ mice). Moreover, carcinogen-induced HCC development was also enhanced by heterozygous deletion of the SOCS1 gene. These findings suggest that SOCS1 contributes to protection against hepatic injury and fibrosis, and may also protect against hepatocarcinogenesis.
Allergen-responsive CD4+CD25+ Regulatory T Cells in Children who Have Outgrown Cow's Milk Allergy
Authors: Karlsson Malin R. , Rugtveit Jarle , Brandtzaeg Per
Published: June 2004

Cow's milk allergy in children is often of short duration, which makes this disorder an interesting clinical model for studies of tolerance to dietary antigens. Here, we studied T cell responses in 21 initially allergic children who, after a milk-free period of >2 mo, had cow's milk reintroduced to their diet. Children who outgrew their allergy (tolerant children) had higher frequencies of circulating CD4+CD25+ T cells and decreased in vitro proliferative responses to bovine β-lactoglobulin in peripheral blood mononuclear cells (PBMCs) compared with children who maintained clinically active allergy. No significant difference in proliferative activity stimulated by the polyclonal mitogen phytohemagglutinin was observed between the two groups. Depletion of CD25+ cells from PBMCs of tolerant children led to a fivefold increase in in vitro proliferation against β-lactoglobulin. This suggests that tolerance is associated with the appearance of circulating CD4+CD25+ regulatory T (Treg) cells that are capable of suppressing the effector T cells generated 1 wk after reintroduction of cow's milk. The suppressive function of the CD4+CD25+ Treg cells was shown to be partly cell contact dependent. Collectively, our study provides human data to suggest that mucosal induction of tolerance against dietary antigens is associated with the development of CD4+CD25+ Treg cells.
The Linkage of Innate to Adaptive Immunity via Maturing Dendritic Cells In Vivo Requires CD40 Ligation in Addition to Antigen Presentation and CD80/86 Costimulation
Authors: Fujii Shin-ichiro , Liu Kang , Smith Caroline , Bonito Anthony J. , Steinman Ralph M.
Published: June 2004

Dendritic cell (DC) maturation is an innate response that leads to adaptive immunity to coadministered proteins. To begin to identify underlying mechanisms in intact lymphoid tissues, we studied α-galactosylceramide. This glycolipid activates innate Vα14+ natural killer T cell (NKT) lymphocytes, which drive DC maturation and T cell responses to ovalbumin antigen. Hours after giving glycolipid i.v., tumor necrosis factor (TNF)–α and interferon (IFN)-γ were released primarily by DCs. These cytokines induced rapid surface remodeling of DCs, including increased CD80/86 costimulatory molecules. Surprisingly, DCs from CD40−/− and CD40L−/− mice did not elicit CD4+ and CD8+ T cell immunity, even though the DCs exhibited presented ovalbumin on major histocompatibility complex class I and II products and expressed high levels of CD80/86. Likewise, an injection of TNF-α up-regulated CD80/86 on DCs, but CD40 was required for immunity. CD40 was needed for DC interleukin (IL)-12 production, but IL-12p40−/− mice generated normal ovalbumin-specific responses. Therefore, the link between innate and adaptive immunity via splenic DCs and innate NKT cells has several components under distinct controls: antigen presentation in the steady state, increases in costimulatory molecules dependent on inflammatory cytokines, and a distinct CD40/CD40L signal that functions together with antigen presentation (“signal one”) and costimulation (“signal two”) to generate functioning CD4+ T helper cell 1 and CD8+ cytolytic T lymphocytes.
A CHEMICAL STUDY OF THE SPECIFIC ELEMENTS OF TUBERCULIN. I
Authors: Mueller J. Howard
Published: June 2004

1. The specific precipitin reaction and the skin reaction given by old tuberculin are attributable to two separate substances present in this material. The cause of the reaction first mentioned is a non-protein gum which will be fully described in the following paper. The cause of the skin reaction is probably but not surely a protein.

2. Methods which have been suggested for the standardization of tuberculin by precipitin or complement fixation reactions should be revised.
STUDIES ON X-RAY EFFECTS
Authors: Hance Robert T. , Clark Harry
Published: June 2004

Two races of paramecium were submitted for varying lengths of time to x-radiation and a large number of individuals were observed to determine the effect on the rate of division. The division rate of both races suffered a slight initial depression lasting for 2 to 5 days following the exposure. This depression is followed by complete recovery.

Within rather wide limits the length of the exposure has, in these experiments, made no appreciable difference. Apparently the maximum effect of the x-rays is produced by relatively short exposures. Continued radiation produces little further change until exposures of 3 and 4 hours are used, when precisely the opposite results are obtained from those obtained with shorter exposures.

Doses repeated at various intervals have in general failed to interfere more markedly with the division rate than a single dose. Repeated radiation causes the cells to become slightly swollen without apparent interference with their viability.
MENINGITIS IN MAN CAUSED BY A FILTERABLE VIRUS
Authors: Scott T. F. McNair , Rivers Thomas M.
Published: June 2004

The clinical pictures presented by two men suffering from an acute bacteria-free lymphocytic meningitis, and the method of obtaining a virus from their spinal fluids were described. Evidence was then adduced to show that the virus was really in the spinal fluids, that the strains of virus obtained from the two patients were identical or closely related, and that the active agent in the spinal fluids was etiologically significant.
THE LIMITED NEUROTROPIC CHARACTER OF THE ENCEPHALITIS VIRUS (ST. LOUIS TYPE) IN SUSCEPTIBLE MICE
Authors: Webster Leslie T. , Clow Anna D.
Published: June 2004

1. St. Louis encephalitis virus injected intracerebrally into susceptible mice multiplies there to reach a titre of 109 intracerebral lethal doses. It is found also in the blood in small amounts immediately following injection and preceding death.

2. Injected intraperitoneally or subcutaneously the virus circulates in the blood for several hours and survives in the spleen for days. It does not multiply in the brain and cause encephalitis, however, unless overwhelming doses are injected or the brain is traumatized.

3. Virus dropped into the nares is demonstrable in the olfactory bulbs at 24 hours, in the piriform lobes at 24 to 48 hours, in the remainder of the brain at 3 days, and in the spinal cord at 4 days. In the brain it reaches a titre of 109 in 6 days. Virus is not readily demonstrable in the blood but is present in the spleen after 48 hours.

4. Virus survives and is capable of multiplying in the spleen.

5. Lesions following nasal instillation of virus appear first in the olfactory bulbs on the 3rd day, in the piriform lobes on the 4th, and in Ammon's horn on the 5th day. The character of the lesions in order of their appearance is exudation of mononuclear cells about superficial blood vessels and in the pia, hyperplasia of the endothelium of the pia, and necrosis of nerve cells of the olfactory tract.
STUDIES ON AN UNCOMPLICATED CORYZA OF THE DOMESTIC FOWL
Authors: Nelson John B.
Published: June 2004

A strain of fowl coryza of slow onset was carried through 20 successive passages in susceptible birds over a period of approximately 19 months. During this period it retained its initial characteristics as did also a coryza of rapid onset which was similarly maintained. 88 per cent of 72 birds infected with the coryza of slow onset showed a nasal discharge after an incubation period of 12 days or more; the actual limits being 9 to 31 days. 98 per cent of 54 birds infected with the coryza of rapid onset showed a nasal discharge on the 1st or 2nd day after injection. The duration of both coryzas was prolonged.

Bacteriological examination indicated that Hemophilus gallinarum which is invariably present in the nasal exudate of birds infected with the coryza of rapid onset is not associated with the coryza of slow onset.
STUDIES ON THE COMMON COLD
Authors: Dochez A. R. , Mills K. C. , Kneeland Yale
Published: June 2004

1. Studies of the cultivation of the virus of common cold in tissue medium, and the capacity of the culture virus to induce infection in human volunteers are reported.

2. Detailed descriptions are given of the methods employed to isolate the virus, preserve and cultivate it, and to test its activity in human volunteers.

3. The virus of common cold can easily be isolated from properly selected patients and cultivated in tissue medium.

4. When kept in the original nasopharyngeal washings, the virus will survive at ice box temperature under anaerobic conditions for at least 13 days.

5. If the nasopharyngeal washings are frozen and dried in vacuo, the virus retains its activity for at least 4 months.

6. The virus of common cold has been proven to multiply in medium containing chick embryo tissue. Such cultures retain their capacity to produce typical infections in human beings for many transfers involving a period of several months. Attempts to cultivate the virus have been successful in seven out of eight instances.

7. Prolonged cultivation of the virus in tissue medium eventually leads to a loss of activity.

8. Strains of virus under cultivation maintain their potency best when transfers are made at 2 and 3 day intervals.

9. After removal from the incubator a culture of virus rapidly becomes inactive whether it be kept under seal in the ice box or frozen and dried in vacuo.

10. The destructive action of the medium can be prevented if the culture is mixed with gum acacia before freezing and drying in vacuo.
THE CULTIVATION OF TISSUES FOR PROLONGED PERIODS IN SINGLE FLASKS
Authors: Parker Raymond C.
Published: June 2004

1. Fragments of breast muscle from a 12 day old chick embryo have been kept alive in single flasks for an entire year without being transferred. The nutrient materials were supplied by frequent applications of adult fowl serum diluted with Tyrode solution.

2. When fragments of fixed tissues are cultivated in serum, cell multiplication and cell death are both reduced to an extremely low level.

3. The presence of a plasma coagulum is not essential to the continued survival and further development of tissues cultivated inserum.

4. The fibrinogen, prothrombin, and fibrin of coagulated plasma are not essential to the development of connective tissue fibers in vitro.
PHENOMENON OF LOCAL SKIN REACTIVITY TO BACTERIAL FILTRATES: EFFECT OF BACTERIAL FILTRATES INJECTED INTRAVASCULARLY UPON REACTIONS TO ANTIGEN + ANTIBODY COMPLEXES
Authors: Shwartzman Gregory
Published: June 2004

Rabbits were sensitized by a single intravenous injection of horse serum 6 days prior to the experiments. In these rabbits there appeared hemorrhagic and necrotic reactions in sites of intradermal tests with horse serum when the tests were preceded by 1 hour, or followed 18 to 24 hours later by an intravenous injection of potent bacterial filtrates. The skin-preparatory and reacting potencies of the filtrates were titrated by means of the phenomenon of local skin reactivity to bacterial filtrate. The experiments demonstrated that the ability of bacterial filtrates to elicit reactions in the antigen injected sites in sensitized animals is strictly conditioned by their skin-preparatory potency and seems to be quite independent of their provocative potency. Combinations of animal protein antigens with homologous antisera, which are endowed with provocative potency but are totally devoid of skin-preparatory potency, fail to elicit reactions in antigen-injected sites.

The various methods of elicitation of the phenomenon of local tissue reactivity are summarized and discussed in the text.
THE RELATION BETWEEN ANTIANAPHYLAXIS AND ANTIBODY BALANCE
Authors: Morris Marion C.
Published: June 2004

It has been shown that antianaphylaxis is not caused by a partial saturation of cellular or humoral antibodies by the following facts.

1. Guinea pigs passively sensitized with anti-horse or antipneumococcus serum and specifically desensitized do not manifest as great a reactivity upon resensitization with the same antiserum as upon the original sensitization.

2. Guinea pigs passively sensitized with anti-Friedländer Type B serum or antipneumococcus Type II serum and specifically desensitized do not attain the same degree of reactivity as normal animals when passively sensitized with anti-horse serum.

3. Guinea pigs passively sensitized with anti-Friedländer Type B serum and desensitized with the specific carbohydrate remain as resistant to infection with Friedlander's bacillus Type B as undesensitized guinea pigs. Since in this case, at least, it is agreed that type-specific immunity and type-specific hypersensitiveness are due to the same type-specific antibody, a change in anaphylactic response should be accompanied by a change in immune response, provided this change depends on antibody balance.

4. A determination of the antibody content of the serum of sensitized as well as of desensitized guinea pigs by mouse protection tests indicates that a loss of reactivity in desensitized animals cannot be adequately accounted for on the basis of depletion of circulating antibody.

These experiments suggest that hypersensitiveness and resistance are different manifestations of the same antigen-antibody reaction while antianaphylaxis is a state of refractoriness which is due neither to excess of circulating antibody nor to antibody depletion, but is the result of secondary changes the true nature of which is still not definitely established.
VITAMIN C THERAPY AND PROPHYLAXIS IN EXPERIMENTAL POLIOMYELITIS
Authors: Jungeblut Claus W.
Published: June 2004

1. A group of 34 monkeys were infected intracerebrally with 0.1 cc. of a 10 per cent virus suspension. Following infection, 9 animals were treated with daily injections of 700 to 100 mg., 16 with 50 to 10 mg. and 9 with 5 mg. of vitamin C for a period of 2 weeks. In the whole group there were 6 animals that survived without showing any evidence of paralysis. 2 of these had received 50 to 10 mg. while 4 had received 5 mg. All of 19 untreated control monkeys, infected simultaneously with the same amount of virus, developed paralysis.

2. Another group of 6 monkeys were infected intracerebrally with 0.05 cc. of virus. Following infection, one animal was treated in the same manner with 25 mg. and 5 with 5 mg. of vitamin C. In the whole group there was one animal that survived without showing any evidence of paralysis. This animal had received 5 mg. All of 7 untreated control monkeys, infected simultaneously with the same amount of virus, developed paralysis.

3. A third group of 22 monkeys were infected intracerebrally with 0.01 cc. of virus. Following infection, one animal was treated in the same manner with 100 mg., 2 with 50 to 10 mg., and 19 with 5 mg. of vitamin C. In the whole group there were 12 animals that survived without showing any evidence of paralysis. One of these had received 10 mg., while 11 had received 5 mg. Of 12 untreated control monkeys, infected simultaneously with the same amount of virus, 2 failed to show any paralytic symptoms and 10 developed paralysis.

4. A summary of the results obtained in all three groups shows: (a) that among a total of 62 treated monkeys, 19 survived without paralysis and 43 succumbed to the disease, while of a total of 38 untreated controls, only 2 failed to develop paralysis and 36 succumbed to the disease; (b) that treatment with large doses of vitamin C was without any beneficial effect (all 10 monkeys which had received 700 to 100 mg. developing paralysis, that the administration of intermediate doses was followed by occasional survival without paralysis of the treated animal (3 monkeys surviving of a total of 19 which had received 50 to 10 mg.), and that nearly one-half of the animals which had received small doses escaped the disease (16 monkeys surviving of a total of 33 which had received 5 mg.).

5. Attempts to protect monkeys against subsequent intracerebral infection by the prophylactic administration of vitamin C, either per os or parenterally, have produced negative results.

6. The pathogenesis of infantile paralysis is discussed in the light of the experimental findings and the possibility is suggested that vitamin C represents one of the deficiency factors in the susceptibility problem of the human disease.
PRODUCTION OF HEMORRHAGIC NECROTIC SKIN LESIONS IN THE RABBIT BY MEANS OF HEMOPHILUS INFLUENZAE AND HEMOPHILUS PERTUSSIS
Authors: Witebsky Ernest , Salm Heinz
Published: June 2004

1. The intradermal injection of H. influenzae in the abdominal wall of rabbits induces inflammation, frequently combined with a central pustule. The corresponding injection of H. pertussis causes a bluish violet discoloration of the skin area involved which undergoes slight hemorrhagic necrotic changes within a few days.

2. The intravenous injection of living H. influenzae, 24 hours after the intradermal inoculation with living H. influenzae, is able to transform the respective skin areas into severe hemorrhagic necrotic lesions within 3 to 5 hours.

3. Heat-killed H. influenzae, if injected intravenously, may produce hemorrhagic-necrotic lesions in areas previously prepared with living or heat-killed H. influenzae.

4. H. pertussis, if injected intravenously, may cause, perhaps to a lesser extent, hemorrhagic necrotic lesions in skin areas 24 hours previously injected with H. influenzae.

5. The normal course of the infection of rabbit skin with H. pertussis is not, or not essentially, influenced by intravenous reinjection of living or killed H. influenzae or H. pertussis.

6. The agar washing filtrate of B. typhosus, if injected intravenously, can produce hemorrhagic necrotic lesions in rabbit skin prepared intracutaneously with living as well as with heat-killed H. influenzae. The intravenous injection of B. typhosus agar washing filtrate has no influence on areas prepared with H. pertussis.

7. Conversely, H. influenzae as well as H. pertussis, if injected intravenously, are able to produce hemorrhagic necrotic lesions in rabbit skin prepared 24 hours previously with B. typhosus agar washing filtrate.

8. The effectiveness of suspensions of H. influenzae apparently is confined to the bacteria themselves rather than to the supernatant fluids. This does not exclude the possibility of producing effective exotoxins under special experimental conditions.
THE RAPID INVASION OF THE BODY THROUGH THE OLFACTORY MUCOSA
Authors: Rake Geoffrey
Published: June 2004

1. Prussian blue particles pass rapidly from the surface of the olfactory mucosa and within 2 minutes are found in the tissue spaces, in blood and lymph vessels, in the perineural spaces of the olfactory nerve fibers and in the subarachnoid space and pia-arachnoid membrane.

2. There is great affinity of pigment particles for the olfactory sensory cells.

3. Preliminary treatment of the olfactory mucosa with tannic acid does not alter the speed with which this absorption occurs. It does, however, cause an inflammation of the mucosa and appears to prevent the pigment from entering the olfactory sensory cells.

4. Both pneumococci and S. enteritidis pass through the olfactory mucosa and reach the tissue spaces, the vessels and the subarachnoid space with the same rapidity as the pigment. This can be demonstrated both microscopically and by distribution tests. They invade by passage between the cells of the mucosa and there is no apparent affinity of the organisms for the olfactory sensory cells.

5. Tannic acid treatment of the olfactory mucosa in no way alters this invasion of organisms through the mucosa.

6. The pantropic virus, equine encephalomyelitis, was detected in the forebrain as promptly as were pigment and bacteria; neurotropic viruses, however,—those of St. Louis encephalitis, rabies and louping ill,—were not demonstrated in less than 24 hours.
CHANGES IN THE CUTANEOUS LYMPHATICS OF HUMAN BEINGS AND IN THE LYMPH FLOW UNDER NORMAL AND PATHOLOGICAL CONDITIONS
Authors: McMaster Philip D.
Published: June 2004

Vital dyes injected intradermally enter lymphatic capillaries directly, rendering them visible, and appear later in the draining lymphatic trunks as colored streamers. The method enables one to perceive the state of the lymphatic channels and the rate of lymph flow within them. It yields consistent results when tested under physiological conditions known to increase or decrease lymph flow.

In the horizontally placed normal limb at rest there is slight lymph flow. In a normal leg or arm hanging downward lymph flow ceases although fluid in the limb increases. When a previously dependent arm is raised above the head, or when the foot of a seated subject is propped on a table, lymph flow in the raised limb becomes active. It ceases in the skin of an arm subjected to partial obstruction of the veins by pressure from without, but very active lymph flow appears during the reactive hyperemia which follows upon the release of venous obstruction. It is still greater following release of total circulatory obstruction, and seems to be the same whether or not the limb has previously been engorged with blood. In the ischemic patches which appear in the skin of a limb during total circulatory obstruction (Bier's spots) the lymphatic capillaries are definitely and considerably constricted, whereas they are slightly dilated in the purple, congested regions of the skin round about. On release of obstruction there occurs a strikingly rapid, equal lymphatic drainage from both regions.

The significance of all the findings is discussed.

When dye is injected intradermally and the skin sucked, much of the foreign material is driven into the lymphatics draining the injected area.
BLOOD PLASMA PROTEIN REGENERATION AS INFLUENCED BY INFECTION, DIGESTIVE DISTURBANCES, THYROID, AND FOOD PROTEINS
Authors: Madden S. C. , Winslow P. M. , Rowland J. W. , Whipple G. H.
Published: June 2004

When blood plasma proteins are depleted by bleeding, with return of washed red cells (plasmapheresis), it is possible to bring dogs to a steady state of low plasma protein in the circulation and a uniform plasma protein production on a basal diet. Such dogs become test subjects by which the effect of various factors on plasma protein regeneration can be measured.

Dogs previously the subjects of plasmapheresis, during long rest periods appear to increase their stores of plasma protein building materials and their blood plasma protein concentrations above former normal levels.

A sterile abscess (turpentine) induces a marked reduction in plasma protein regeneration in these test dogs consuming an ample basal diet. The sharp reduction during the initial 24 hours may in part reflect an extravasation of plasma protein into the injured tissue but there also appears to develop a true disturbance of the mechanism which produces plasma proteins.

Digestive disturbances interfere seriously with plasma protein production. Whereas large quantities of live yeast upset digestion and form no plasma protein, autoclaved yeast is well utilized, having a potency ratio of 4.4.

Amino acids have been tested inadequately. A mixture of cystine, glutamic acid, and glycine does seem to have a definite effect upon protein metabolism and plasma protein production.

Iron, under the conditions of these experiments, does not influence the output of plasma proteins. Liver extract (parenteral) is also inert.

The proteins of red blood cells when added to the diet are poorly utilized for plasma protein formation and show a potency ratio of only 10.1.

Kidney protein added to the kidney basal diet shows a potency ratio of about 5 as compared with 4.6 for that basal diet.

A digest of beef stomach and rice polishings shows a potency ratio of about 7.9. Dried powdered serum shows a potency ratio of 3.5, which is much less than fresh serum (2.6).

Powdered thyroid fed in doses sufficient to accelerate body metabolism shows no distinct effect upon plasma protein production not attributable to the protein in the thyroid powder itself.

Long periods (25 to 30 weeks) of plasma depletion and basal diet intake remove much protein from body fluids and tissues. Associated with this protein depletion the dog loses its appetite and may vomit some food. There is loss of hair, a tendency to skin ulceration, and a distinct lowering of resistance to infection. The plasma protein output may fall to fasting levels in spite of food intake sufficient to maintain weight. We believe this condition to be a deficiency state related to severe depletion of the essential protein matrix of the body cells.
THE AUTOLYTIC SYSTEM OF PNEUMOCOCCI
Authors: Dubos René J.
Published: June 2004

1. Living pneumococcus cells contain a group of enzymes, the bacteriolytic system, capable of causing the lysis of heat-killed pneumococci (R and S variants irrespective of type derivation). This lysis expresses itself by a loss of the Gram staining reaction, a disintegration of the cell body, and a clearing of the bacterial suspension.

2. Under certain conditions of treatment with the bacteriolytic complex, it is possible to render the cocci Gram-negative without changing their characteristic morphology, or causing any appreciable clearing of the cell suspension.

3. The enzyme responsible for this change has been partially purified, and some of its properties described.

4. The cellular structure which is responsible for the Gram-positive reaction of pneumococci is resistant to proteolytic enzymes, and is still present when tryptic digestion has reduced the heat-killed cell to a body which has lost 75 per cent of its original weight, and contains only 8 per cent nitrogen.

5. The same enzyme preparation which attacks pneumococci is also capable of liberating reducing sugars from some acetyl amino glucose glucuronides of animal and bacterial origin. The possibility is considered, and discussed, that one and the same enzyme in the autolytic complex is capable of attacking both types of substrates.
MECHANISM OF THE LYSIS OF PNEUMOCOCCI BY FREEZING AND THAWING, BILE, AND OTHER AGENTS
Authors: Dubos René J.
Published: June 2004

Pneumococci, living or dead, are soluble in bile when: (a) the autolytic enzymes are still present in a potentially active form; (b) conditions are favorable for enzymatic action.

Bile solubility of pneumococci involves as a necessary step one, or a few, of the many stages of the autolytic complex.

These observations hold true for the disruption of pneumococci by freezing and thawing, by previous desiccation with cold acetone, and by dilute solutions of antiseptics.

A possible mechanism is discussed to account for these forms of lysis.
PROPAGATION OF RABIES VIRUS IN TISSUE CULTURE
Authors: Webster Leslie T. , Clow Anna D.
Published: June 2004

Rabies virus has been propagated in serum-Tyrode solution containing either embryo mouse brain or embryo chick brain.

The culture virus reached a titre of 3 x 10–5 cc. after 4 days' incubation at 37°C., and survived at least 2 months at 5°C. in the liquid or dry state.
IMMUNIZATION OF GUINEA PIGS WITH A MODIFIED STRAIN OF LYMPHOCYTIC CHORIOMENINGITIS VIRUS
Authors: Traub Erich
Published: June 2004

A strain of choriomeningitis virus which was highly virulent for guinea pigs, as isolated from a naturally infected white mouse, has been markedly attenuated for guinea pigs by serial intracerebral passage through white mice. The change of virulence occurred before the 8th serial passage. The modified virus as a rule produces fever in guinea pigs but no other symptoms, and the infection is followed by a very solid immunity. Parallel passages of the same strain through guinea pigs have maintained its high virulence for this species but slightly reduced its pathogenicity for mice. These observations indicate that the differences in virulence for guinea pigs noted before (1, 2) with different strains of choriomeningitis virus obtained from infected stock mice may be due not only to differences in the susceptibility of guinea pigs but also to variations in the virulence of the virus.

A marked degree of resistance was demonstrable in several guinea pigs on the 4th, 8th, and 10th day after injection with modified virus, when antivirus could not yet be detected in the serum. Circulating antivirus appears therefore to play a secondary part in their immunity, which seems to be closely associated with the tissues as in mice.
PROPERTIES OF THE TYPE SPECIFIC PROTEINS OF ANTIPNEUMOCOCCUS SERA
Authors: Goodner Kenneth , Horsfall Frank L.
Published: June 2004

The generally held view has been that in any immune serum only a single antibody would be induced by and react with a single antigen. Were this true the various manifestations of antibody activity should show a quantitative parallelism. It has already been shown (1), however, that with antipneumococcus horse serum the mouse protective potency does not parallel the maximum amount of specifically precipitable protein except within certain well defined groups of antisera. The simplest explanation of this situation is that different horses form antibodies differing in specific protective capacity, but from our studies it seems probable that in any immune serum there may occur a mixture of antibodies which, while directed against the same antigen, possess different protective capacities, different avidities, etc. It would now appear that this latter hypothesis is the more tenable since the experiments here reported indicate the existence of antibodies of various protective potencies in horse antisera. It would not be unreasonable to hold that the antibodies of a single serum represent a series of substances with varying properties. On the basis of the present immunological fractionation experiments, the following deductions seem permissible.

1. Antipneumococcus horse sera must contain at least three, possibly many, antibody substances which react with the capsular polysaccharide. These are: (a) A substance which precipitates upon the addition of a relatively small amount of polysaccharide. This antibody possesses a low protective potency. (b) A substance which is precipitated with intermediate amounts of polysaccharide and which possesses an extremely high protective value. (c) A third substance which is precipitated only with the addition of relatively large amounts of polysaccharide. The protective value of this antibody is very low It may represent a degraded form.

2. With antipneumococcus rabbit serum the situation is somewhat simpler. This is in accord with the fact that with Type I antipneumococcus sera from this species there is a direct proportionality between the amount of specifically precipitable protein and the protective potency of the serum (1). The results with antipneumococcus rabbit serum indicate the existence of at least two antibody substances: (a) An antibody with high protective value which makes up the greater proportion of the total content. (b) A second substance which is precipitated only upon the addition of relatively large amounts of capsular polysaccharide. The existence of this second antibody is not clearly demonstrated by the present findings but the lower protective ratios obtained as greater amounts of antibody are removed probably indicate its existence. This may also represent degraded material.

The observations on the antibodies of both horse and rabbit antisera will be supported by experiments with immunochemical fractionation which will be reported in a subsequent paper.